TENTH ANNIVERSARY ARTICLE Leukemia and Preleukemia in Fanconi Anemia Patients A Review of the Literature and Report of the International Fanconi Anemia Registry Arleen D. Auerbach and R. G. Allen
ABSTRACT: Fanconi anemia (FA) is an autosomal recessive disorder characterized clinically by a
progressive pancytopenia, diverse congenital abnormalities, and increased predisposition to malignancy. Although a variable phenotype makes accurate diagnosis on the basis of clinical manifestations difficult in s o m e patients, the u n i q u e sensitivity of FA cells to the clastogenic effect of DNA cross-linking a g e n t s such as diepoxybutane (DEB) c a n be u s e d to facilitate the diagnosis. We review all c a s e s af FA reported to have leukemia, preleukemia, or a bone marrow (BM) clonal chromosomal abnormality a n d include for the first time an analysis of t h e s e conditions observed in patients in the International Fanconi Anemia Registry (IFAR). The incidence of acute myelogenous leukemia (AML) in FA patients is m o r e than 15,000 times that observed in children in the general population. Cytogenetic studies of FA-associated leukemias disclose a high frequency of monasomy 7 and duplications involving lq. There were na occurr e n c e s of t(8;21), t(15;17), or abnormalities of 11q, which are associated with M2, M3, and M5 leukemias, respectively, but n o t with preleukemia. Development of leukemia in FA patients was associated with an exceedingly poor prognosis, with a m e a n age of death of 15 years. We suggest that all FA patients may be considered preleakemic and that this disorder presents a model for s t u d y of the etiology of AML.
INTRODUCTION Fanconi anemia (FA) was originally described as an autosomal recessive disorder characterized by progressive pancytopenia, diverse congenital abnormalities, and predisposition to malignancy [1-3]. More recently, the phenotype has been recognized to be so variable that diagnosis on the basis of clinical manifestations alone is difficult and often unreliable [4]. Although the molecular basis of this syndrome remains unknown, occurrence of FA can now be detected routinely by study of induced chromosomal breakage in cultured lymphocytes, fibroblasts, amniocytes, or chorionic villus cells after exposure of these cells to low concentrations of DNA cross-linking agents [5-8]. Fanconi anemia occurs in all ethnic groups, with a reported gene frequency of 1 : 300 [3]. Because of the difficulty of establishing a clinical diagnosis of FA and the resulting failure to ascertain cases, the true gene frequency may be considerably higher. From the Laboratory far Investigative Dermatology, The Rockefeller University, New York, New York.
Address reprint requests to: Dr. Arleen D. Auerbach, Laboratory for Investigative Dermatology, The Rockefeller University, 1230 York Ave., New York, NY 10021-6399.
Received February 12, 1990; accepted February 15, 1990
1 © 1991 Elsevier Science Publishing Co.. Inc. 655 Avenue of the Americas, New York. NY 10010
Cancer Genet Cytogenet 51:1 12 (1991) 0165-4608/91/$03.50
2
A.D. Auerbach and R. G. Allen Patients with FA usually die of hemorrhage or infection, and relatively few individuals homozygous for the disorder survive their second decade. For many years, FA patients have been recognized to be at increased risk for developing leukemia. Bone marrow (BM) clonal cytogenetic abnormalities have been reported in some of these patients, as well as in some FA patients with no evidence of leukemia at the time of study. These latter cases may be considered to have a preleukemic phase of the disease. We summarize the cases of leukemia and preleukemia described in the literature as well as cases that have been reported to the International Fanconi Anemia Registry (IFAR) at The Rockefeller University. We suggest that all FA patients may be considered preleukemic and that this disorder presents a model for the study of the etiology of acute myelogenous leukemia (AML).
MATERIALS AND METHODS
The present summary is based on a review of the cases in the literature and in the IFAR in which leukemia, preleukemia, or a BM clonal chromosomal abnormality has been reported in FA patients. We present all such cases of which we are aware. The IFAR was established at The Rockefeller University in 1982 to study a large number of FA patients with the full spectrum of diverse features of the syndrome. The registry serves as a centralized repository for clinical, hematologic, and genetic information on patients with FA [8-11]. Patients in the IFAR were ascertained on the basis of the presence of congenital malformations known to be associated with FA, hematologic manifestations such as aplastic anemia or leukemia, both malformations and hematologic manifestations, or family screening. Approximately 50% of the FA patients in the IFAR do not exhibit any major malformations. The primary source of cases in the IFAR is voluntary physician reporting, either directly to Dr. Auerbach at The Rockefeller University, or to Dr. Traute M. SchroederKurth, University of Heidelberg, F.R.G. (primarily cases from West Germany). Chromosome breakage studies, including testing for hypersensitivity to the clastogenic effect of the DNA cross-linking agent diepoxybutane (DEB), were performed in most patients. Those who did not exhibit sensitivity of cultured peripheral blood lymphocytes (PBLs) to cross-link-induced chromosomal breakage were classified as unaffected with FA. To obtain follow-up information on patients, we recently contacted all physicians who reported cases directly to The Rockefeller University. Only these cases are included in this report. RESULTS
Fanconi anemia patients with leukemia or preleukemia reported in the literature are shown in Table 1. We included patients with aplastic anemia and clonal disease in the preleukemic group. Fifty-four cases of leukemia and 14 cases of preleukemia or clonal disease were reported in approximately 700 cases of FA reported in the literature. The mean age at diagnosis of leukemia was 14.8 years and the mean age of death in these patients was 15.5 years. None of the patients were reported to have achieved long-term remission. Although chromosome studies were not included in many of the reports of FA cases with leukemia, chromosome abnormalities were detected in most cases in which chromosome studies were performed. The chromosome abnormalities reported were highly variable; the most frequently occurring changes were monosomy 7 and translocations or duplications involving lq. There were no occurrences of the t(8;21) associated with M2, the t(15;17) associated with M3, or the del 11q or t(9;11) associated with M5 leukemias. Analysis of data from the IFAR (Table 2) showed that 19 of 222 patients (9%) had leukemia or myelodysplastic disease. Results of chromosome studies in these patients
Table 1
Case no.
Leukemic (AML) and preleukemic the literature Age at d e v e l o p m e n t of l e u k e m i a
L e u k e m i c patients (AML) Myeloblastic (M1) 1 11 M y e l o m o n o c y t i c (M4) 2 13 3 7 4 -5 8 6 7 7 5 8 6 9 18 10 26 11 -12 23 13 17 14 12 M o n o c y t i c (M5) 15 10 16 12 17 14 18 16 E r y t h r o l e u k e m i a (M6) 19 15 20 15 21 22 22 -23 15 Megakaryoblastic (M7) 24 9 Not Specified 25 27 26 11 27 12 28 9 29 21 30 19 31 -32 28 33 16 34 15 35 36 37 38 39 40 42 42
-12 -5 --20 --
Age at death
Fanconi anemia patients reported in
Chromosome abnormalities
Reference
12
- 18, + m a r
[12]
13 8 13 8 8 6 6 19 28
NS NS NS None NS NS t{5q;18q) NS None
113l [14, 15] [14, 15] [16] [15] [15] [17]
--
NS
[20]
23 17 --
NS t(5;7)(p15;q22), + 19 6q + , 2 1 q -
[21] [22] [23, 24]
10 13 15 16
None NS 3q+ NS
[25] [26] [27] [28]
15 15 -10 15
-C NS lp+ NS dup{1)(p32;p34),trip(3)(q12;q27),del(7)(p11)
[29-31] [32] [33] [12] [12, 34]
--
NS
[35]
27 12 --21 --28 16 --
NS NS NS NS Hyperdiploidy NS NS None NS t(1;14)(q12 or 21;q32), 4 q - ,Sq + ,7q - ,13q + ,20q t(1;6)(q22 or 2 3 ; p t e r ) ; 5 q t(1;6)(q32;p25) NS - 7,-8,+2mar NS NS d u p ( 3 ) ( q 1 2 - q 2 7 ) , 1 2 q + , l p + ,Tp+ NS
[36] [37] [38] [39] [40, 41] [42] [42] [43] [18] [44]
23 13 -7 21 14 20 23
118] [19]
[44] [45] [46] [47] [121 [12] [12, 48] [12]
[cominm~d)
4 Table 1
Case no.
A . D . A u e r b a c h a n d R. G. A l l e n
L e u k e m i c (AML) a n d p r e l e u k e m i c F a n c o n i a n e m i a p a t i e n t s r e p o r t e d in t h e l i t e r a t u r e (Continued) Age at development of leukemia
43 -44 -45 25 46 21 47 16 48 7 49 -50 -51 -52 -53 -54 -Preleukemic patients Refractory anemia 55 25 56 15 Myelodysplastic syndrome 57 11 Aplastic anemia 58 23 59 9 60 17 61 20 62 10 63 17 64 19 65 -66 31 67 16 68 25
Age at death 8 15 26 21 -8 --
---
-
27 -
-
24 -21 31 10 17 --35 17 27
Chromosome abnormalities
Reference
NS NS - 7 - 7 t(1;17)(q21;p13).t(10;?)(q26;?],del(12)(p11) NS 7q - ,9q NS NS NS NS +20, 22,dup(1}(q22;q34), + del(22}(q11)
[12] 112] [49] 1491 I50] [51] 152] 1531 [541 [54] 154] [55]
t(1 ;6)(q12;p25),del(5)(q21q23) +8
[44, 56] [57]
i(7q)
158l
+C Dq + + 1,+mar,-2C +mar +21 2q +, + mar - 21,+mar 2pdup(1](q24-32),t{17;?}(p12-13;?) dup(1)(q12-32) t(1;6)(q22or23;p25),t(2;3?)(q35?;p21?)
[59] [60] [40, 41] 143] [12] [12, 34] [12, 34] 112] 161] 162] [63]
w e r e s i m i l a r to t h e l i t e r a t u r e data. T h e m e a n age of l e u k e m i a d i a g n o s i s a n d m e a n age of d e a t h i n t h e s e p a t i e n t s (14.4 a n d 15.6 years, r e s p e c t i v e l y ) w e r e also r e m a r k a b l y s i m i l a r to t h o s e of p a t i e n t s d e s c r i b e d i n t h e l i t e r a t u r e . T h e m e a n age of d i a g n o s i s of a p l a s t i c a n e m i a i n t h e IFAR c a s e s w i t h l e u k e m i a w a s 7.4 y e a r s as c o m p a r e d w i t h 6.24 -+ 0.69 y e a r s for all IFAR p a t i e n t s . T h e m e d i a n e s t i m a t e d s u r v i v a l ( c a l c u l a t e d u s i n g t h e p r o d u c t - l i m i t m e t h o d of K a p l a n a n d M e i e r ) for all p a t i e n t s i n t h e I F A R w a s 25.2 + 2.5 y e a r s (67.4% of t h e p a t i e n t s are c e n s o r e d ) . T h e m e d i a n e s t i m a t e d s u r v i v a l for p a t i e n t s d e v e l o p i n g l e u k e m i a is 12.0 -+ 2.3 years, a n d t h e m e d i a n e s t i m a t e d s u r v i v a l for p a t i e n t s w i t h o u t l e u k e m i a is 27.0 +- 3.3 years. T h u s , d e v e l o p m e n t of l e u k e m i a i n F A p a t i e n t s is a s s o c i a t e d w i t h a n e x c e e d i n g l y p o o r p r o g n o s i s .
DISCUSSION I n d i v i d u a l s w i t h c h r o m o s o m e b r e a k a g e s y n d r o m e s o f t e n suffer i n c r e a s e d s u s c e p t i b i l ity to m a l i g n a n c i e s [64]. N o t s u r p r i s i n g l y , F A is s t r o n g l y a s s o c i a t e d w i t h a n i n c r e a s e d p r e d i s p o s i t i o n to a v a r i e t y of c a n c e r s . A b o u t h a l f of t h e m a l i g n a n c i e s r e p o r t e d w e r e l e u k e m i a s ; t h e r e m a i n d e r c o n s i s t e d of l i v e r t u m o r s a n d o t h e r c a n c e r s [65]. T h e i n c i d e n c e of A M L i n o u r s u r v e y w a s a p p r o x i m a t e l y 9%. F o r c o m p a r i s o n , d a t a f r o m
Leukemia in Fanconi Anemia
Table 2
IFAR no.
5
L e u k e m i c (AML) a n d p r e l e u k e m i c F a n c o n i a n e m i a p a t i e n t s i n t h e IFAR Age at onset of aplastic anemia
Leukemic patients (AML) Myeloblastic (M1) 90/1 " 5.7 Myeloblastic (M2) 359/1 8 Myelomonocytic (M4) 13/1 6.3 43/1 10.2 Erythroleukemia (M6) 23/1 6.2 Not specified 29/1 1.9 30/1 13 18/1 ~ 5.2 95/1 7.5 129/1 2.1 187 6 247/1 13 288/1 4 326/1 6 338/1 20 357/1 0.5 Preleukemic patients Myelodysplastic syndrome 45/2 5 6/2 6.3 358/1 14 Aplastic anemia 287/1 0.6 107/1': 31
Age at development of leukemia
11
Age at death
Chromosome abnormalities
12
- 18, + mar
8
--
14.6 18.9
14.8 19.2
del(7)(pl 1),6p + ,lq + NS
11.9
12.1
1 8 q + , d u p 1 2 q , 5 q + , - 16
2 23.8 5.2 11.4 2.5 9 17.7 9 32.4 28.2 0.5
2 25.2 7 12.1 3.5
None del(7)(q) - 7, - 8, + 2mar NS NS -7 NS None 2q+,6p+ NS NS
18.3 10.1 28.3
7.5
37.1 23
38.2
9.8 31
21.66 35
NS
2q +, + mar NS t(1;5)(p34;q31) - 13,t(1q;13q),del{7)(q32} dup(1){q24-32),t(17;?)(p12-13;?)
o Same as reference 12, Table 1. J' Same as reference 47, Table 1. ': Same as reference 61. Table 1. AML ~ acute myelogenous leukemia. t h e M a n c h e s t e r C h i l d r e n ' s T u m o r Registry 1 9 5 4 - 1 9 8 0 s h o w s t h a t t h e i n c i d e n c e of c h i l d h o o d m a l i g n a n t d i s e a s e w a s 99.3/106 , t h e rate of l e u k e m i a w a s 32.8/106 , a n d t h e rate of A M L w a s 4.9/106 [66]. T h e i n c i d e n c e of A M L i n c h i l d r e n i n t h e U n i t e d S t a t e s w a s s i m i l a r [67]. T h u s , m o s t of t h e l e u k e m i a s o b s e r v e d i n c h i l d r e n a n d y o u n g a d u l t s i n t h e g e n e r a l p o p u l a t i o n are of l y m p h o i d origin, b u t n e a r l y all F A - a s s o c i a t e d l e u k e m i a s are m y e l o i d . W h e t h e r F A h e t e r o z y g o t e s are at i n c r e a s e d r i s k for l e u k e m i a rem a i n s u n r e s o l v e d [3, 68, 69] b e c a u s e t h e r e is still n o a c c u r a t e m e t h o d of d e t e c t i n g heterozygotes. A l t h o u g h t h e i n c r e a s e d p r e d i s p o s i t i o n to l e u k e m i a m a y b e r e l a t e d to t h e b a s i c d e f e c t i n FA, t h e e t i o l o g y of l e u k e m i a i n F A p a t i e n t s is u n k n o w n . S o m a t i c m u t a t i o n a r i s i n g f r o m c h r o m o s o m a l i n s t a b i l i t y m a y b e of i m p o r t a n c e . T h e o n s e t of l e u k e m i a in FA patients may be triggered by environmental influences. Various alkylating a g e n t s are c a r c i n o g e n i c a n d a u g m e n t t h e i n c i d e n c e of c a n c e r i n t h e g e n e r a l p o p u l a t i o n ; e.g., t h e i n c i d e n c e of A M L is d r a m a t i c a l l y i n c r e a s e d i n c a n c e r p a t i e n t s s e c o n d a r y to c h e m o t h e r a p y w i t h a l k y l a t i n g a g e n t s [70]. T h e s e p a t i e n t s o f t e n e x h i b i t a p r e l e u k e m i c
6
A.D. Auerbach and R. G. Allen phase followed by progression to AML. Nonrandom clonal chromosomal changes, especially - 7 and - 5 / 5 q - , were demonstrated before leukemic evolution. Other chemical agents implicated as leukemogens include benzene, chloramphenicol, and phenylbutazone [71]. The best documented of these, benzene, is associated with chromosome breakage and with development of aplastic anemia. All cases of leukemia evolving in these patients appear to be AML in type. Thus, even at the trace levels of carcinogens present in the environment, the hypersensitivity of FA patients to chemically induced DNA damage might be expected to increase their incidence of cancer. Although relatively few FA patients have had BM cytogenetic studies before onset of leukemia, clonal abnormalities are frequently reported in those cases studied, suggesting clonality during the aplastic anemia phase of the disease. Considerable evidence shows that the presence of chromosomally abnormal clones in the BM heightens the risk for development of leukemia [72]. Appelbaum et el. [73] report that aplastic anemia patients exhibiting clonal cytogenetic abnormalities of marrow cells have an especially high risk for developing leukemia. The specific abnormalities observed are those associated with leukemia and preleukemia, and the investigators suggest that clonal abnormalities in aplastic anemia represent a preleukemic syndrome. Recent studies by de Planque et al. [74, 75] and Tichelli et al. [76] demonstrate that patients with severe aplastic anemia treated without BM transplantation and surviving at least 2 years are at a 10% or greater risk for developing myelodysplasia or AML. The patients in these studies had been treated with supportive care, androgens, and/or immunosuppressive therapy such as antithymocyte globulin. It has been suggested that the high incidence of leukemia in FA patients is related to androgen therapy [64]. However, a number of cases have been described in which onset of clonal disease or AML appeared in the absence of any therapy. The presence of clones with complex karyotypic rearrangements or clones with monosomy 7 or del (7q) in preleukemic patients has been associated with poor prognosis and with the progression to leukemia [72]. A review of clinical and cytogenetic correlations in preleukemia from the Sixth International Workshop on Chromosomes in Leukemia [77] reported that demonstration of a clonal cytogenetic abnormality in these patients provided a positive indication of the neoplastic nature of the disease. A shorter survival time was associated with a greater degree of clonal complexity. Consistent with our observations in FA patients, none of the preleukemic patients in this series had t(8;21), t(15;17), or abnormalities involving chromosome 11, suggesting that leukemic patients with these abnormalities do not exhibit a preleukemic phase. Thus, it is not surprising that these specific abnormalities associated with AML are not found in FA patients with leukemia if we consider all patients affected with FA to be preleukemic. It is unfortunate that our understanding of the cellular defect in FA remains obscure, limiting our ability to understand the predisposition to leukemia in these patients. The mechanism underlying the hypersensitivity of FA cells to DNA crosslinking agents remains unknown. Cultured FA cells exhibit a prolonged G2 phase transit and a frequent occurrence of permanent G 2 phase arrest [78, 59]. This defect in FA cell cycle is highly sensitive to the ambient oxygen environment; the number of cells arrested in G 2 is significantly greater in cell cultures maintained under 20% ambient oxygen than in those kept under 5% ambient oxygen [78]. Furthermore, the frequency of chromosome breakage observed in FA cells can be diminished by decreasing the oxygen concentration of the culture atmosphere; e.g., FA cells cultured under an atmosphere containing 5% oxygen exhibit significantly lower levels of chromosome breakage than cells of the same line maintained under an ambient oxygen concentration of 20%. Similarly, antioxidants have been used to inhibit clastogenic effects. Nordenson [80] reported that superoxide dismutase (SOD) and catalase had a
Leukemia in Fanconi Anemia
7
protective effect to FA lymphocytes in culture and that SOD ameliorated the toxicity of mitomycin C in FA fibroblasts [81]. A similar protective effect for SOD, catalase, and L-cysteine was reported by Raj and Heddle [82]. Low molecular weight antioxidants such as tocopherol, glutathione, butylated hydroxytoluene (BHT), and ascorbate also have some protective effects on FA cell cultures [83]. Use of antioxidants to limit the number of clastogen-induced mutations demonstrates only that free radicals are ultimately responsible for breakage caused by these chemicals, however. Any speculation that steady-state oxidant levels are aberrant in FA cells is unwarranted if supported on this basis alone. In at least some cases, the whole blood activity of SOD of FA patients is lower than normal blood levels [83]. The sensitivity of FA cells to an oxidizing environment has been postulated to result from either an increased rate of oxygen free radical generation or a decreased rate of free radical removal by cellular scavengers [84]. Glutathione reductase activity also appears to be diminished in several FA patients [27]. Decreases in SOD and glutathione reductase activities do not appear to occur consistently in all FA patients, however; indeed existing evidence indicates that none of the known free radical scavenging pathways are grossly defective in FA cells [83]. No compelling evidence has been presented to support the postulate that the rate of free radical generation is actually altered in FA, and the existence of a prooxidizing state in FA cells remains predominantly a matter of conjecture. Aside from the possibility that the intracellular environment of FA cells is in some way more conducive to induction of damage, hypersensitivity of FA cells to clastogens has also been suggested to be actually a result of decreased DNA repair capacity. Fujiwara et al. [85] and Averbeck et al. [86] reported diminished DNA interstrand cross-link repair in FA cells. Conversely, other investigators have failed to confirm their observations and report normal repair in FA cells after exposure to a wide variety of cross-linking agents [87]. Deficient excision repair [88], defective DNA ligase activity [89], abnormal intracellular distribution of topoisomerases [90], alterations in the nucleotide pool [91], and decreased adenosine diphosphateribosyl transferase activity [92] are among other repair defects that have been reported. The occurrence of abnormalities in such a large number of diverse repair mechanisms suggests that the defect giving rise to FA may occur in a gene that influences the activity of many biochemical pathways. Nevertheless, none of these aberrations are ubiquitous in FA.
CONCLUSION Fanconi anemia results from a single autosomal recessive gene, yet its phenotype is highly pleiotropic. Even affected siblings often differ in their phenotype. Multiple biochemical mechanisms and pathways have been postulated to be responsible for the increase in sensitivity of FA DNA to clastogenic chemicals; however, evidence is presently insufficient to implicate any of these putative defects as the underlying cause of the disease. The diversity of phenotypes and biochemical aberrations associated with FA may result from interaction of different sets of genes with the defective gene or could arise from interactions of the defect with environmental agents. Although FA is associated with increased incidence of myeloid leukemias, no welldocumented lymphoid leukemias have been reported in FA patients. The increased incidence of AML and the absence of lymphoid leukemias in FA patients suggests that FA may be a preleukemic condition for AML. Leukemia would result from a new clone of abnormal cells arising either directly as a result of the intrinsic cellular defect or from damage to a stem cell resulting from exposure to an environmental toxin. In view of the lack of agreement as to the biochemical basis for FA, the underlying
8
A . D . Auerbach and R. G. Allen
m e c h a n i s m of the disease will probably remain u n k n o w n until the defective gene has been identified. The "reverse genetics" approach using restriction fragment length p o l y m o r p h i s m analysis is currently being used in our laboratory to map the FA gene. Once the c h r o m o s o m a l location of the gene has been m a p p e d and the defective gene identified, it should become possible not only to understand the cause of FA but also to explain the pleiotropic nature of the disease. This work was supported in part by Public Health Service Grants No. HL 32987 from the National Institutes of Health (to A.D.A.), by Clinical Research Grant No. 6-521 from the March of Dimes Birth Defects Foundation (to A.D.A.), by a General Clinical Research Center Grant No. RRO0102 from the National Institutes of Health to The Rockefeller University Hospital, and by support from the Fanconi Anemia Research Fund (to A.D.A.) and the Pew Memorial Trust to the Laboratory for Investigative Determatology. We thank the numerous physicians who referred patients to the IFAR, Christine L. Frissora for help in obtaining follow-up information on the IFAR patients, and Andr~ Rogatko for statistical analysis of the IFAR data.
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9
(1978): Fanconi's anaemia, with special reference to erythrokinetic features. S Afr Med J 53:43-50. Schroeder TM, Pohler E, Hufnagl HD, Stahl-Maug6 C (1979): Fanconi's anemia: Terminal leukemia and "forme fruste" in one family. Clin Genet 16:260-268. G6zda~o~lu S, (~avdar AO, Arcasoy A, Babacan E, Sanal 0 (1980): Fanconi's aplastic anemia, analysis of 18 cases. Acta Haematol 64:131-135. Stein AC, Blank DM, Bennett AJ, Gold BD, Berger J (1981): Acute myelomonocytic leukemia in a patient with Fanconi's anemia. J Oral Surg 39:624-627. Alimena G, Avvisati G, De Cuia MR, Gallo E, Novelli G, Dallapiccola B (1983): Retrospective diagnosis of a Fanconi's anemia patient by diepoxybutane (DEB) test results in parents. Haematologica 68:97-103. Roozendall KJ, Nelis KOAH (1981): Leukemia in a case of Fanconi's anemia. Clin Genet 25:208.
24. Kwee ML, Kuyt LP (1989): Fanconi Anemia in the Netherlands. In: Fanconi anemia. Clinical, Cytogenetic and Experimental Aspects, TM Schroeder-Kurth, AD Auerbach, G Obe, eds. Springer-Verlag, New York, pp. 18-33. 25. L6vy JM, Stoll C, Korn R (1974): Sur un cas de leuc6mie aigu6 chez une filiette atteinte d'an6mie de Fanconi. Revue de la litt6rature. Nouv Rev Fr H6matol 14:713-720. 26. Perrimond H, Juhan-Vague I, Th6venieau D, Bayle J, Muratore R, Orsini A (1977): Evolution m~dullaire et h6patique apr~s androg6noth6rapie prolong6e d'une an6mie de Fanconi. Nouv Rev Fr H6matol 18:228. 27. de Vroede M, Feremans W, de Maertelaere-Laurent E, Mandelbaum I, Toppet M, Vamos E, Fondu P (1982): Fanconi's anaemia. Simultaneous onset in 2 siblings and unusual cytological findings. Scand J Haematol 28:431-440. 28. Ahuja HG, Advani SH, Gopal R, Nair CN,Saikia T (1986): Acute nonlymphoblastic leukemia in the first of three siblings affected with Fanconi's syndrome. Am J Pediatr Hematol Oncol 8:347-349. 29. Bargman GJ, Shahidi NT, Gilbert EF, Opitz JM (1977): Studies of malformation syndromes of man. XLVII: Disappearance of spermatogonia in the Fanconi anemia syndrome. Eur J Pediatr 125:162-168. 30. Meisner LF, Taher A, Shahidi NT (1978}: Chromosome changes and leukemic transformation in Fanconi's anemia. In: Aplastic Anemia, S Hibino, F Takaku, NT Shahidi, eds. University of Tokyo Press, Tokyo, pp. 253-271. 31. Taher A, Gilbert E, Shahidi NT (1981): Erythroblastic islands in erythroleukemia. Am J Pediatr Hematol Oncol 3:121-125. 32. Prindull G, Jentsch E, Hansmann I (1979): Fanconi's anaemia developing erythroleukaemia. Scand J Haematol 23:59-63. 33. Rotzak R, Kaplinsky N, Chaki R, Blei F, Berkawitz M, Goldman B, Frankl O (1982): Giant marker chromosome in Fanconi's anemia transforming into erythroleukemia in an adult. Acta Haematol 67:214-216. 34. Berger R, Bernheim A, Le Coniat M, Vecchione D, Schaison G (1980): Chromosomal studies of leukemic and preleukemic Fanconi's anemia patients. Hum Genet 56:59-62. 35. Dharmasena F, Catchpole M, Erber W, Mason D, Gordon-Smith EC (1986): Megakaryoblastic leukaemia and myelofibrosis complicating Fanconi anaemia. Scand J Haemato136:309-313. 36. Cowdell RH, Phizackerley PJR, Pyke DA (1955): Constitutional anemia (Fanconi's syndrome) and leukemia in two brothers. Blood 10:788-801. 37. Gmyrek D, Witkowski R, Syllm-Rapoport I, Jacobasch G (1968): Chromosomal aberrations and abnormalities of red-cell metabolism in a case of Fanconi's anaemia before and after development of leukaemia. German Med Monthly 13:105-111. 38. Ozsoylu S, Hicsomnez G (1972): Leukemia presenting as aplastic anemia. I Pediatr 81:187. 39. G6tz M, Handel H, Pichler E, Weippl G (1974): Fanconi-An~mie. 13bergang in Leuk/~mie nnd Erythrozytenstoffwechselbefunde. Kinderartzl Prax 42:69-74. 40. Hirschman RJ, Shulman NR, Abuelo JG, Whang-Peng J (1969): Chromosomal aberrations in two cases of inherited aplastic anemia with unusual clinical features. Ann Intern Med 71:107-117.
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41. Sarna G, Tomasulo P, Lotz J, Bubinak JF, Shulman NR (1975): Multiple neoplasms in two siblings with a variant form of Fanconi's anemia. Cancer 36:1029-1033. 42. Zawartka M, Restorff-Libiszowska H, Kowalski R, Litwiniszyn-Krzewicka K, Schejbal J (1976): Bialaczka szpikowa w przebiegu Anemii Fanconiego (AF). Wiad Lek 29:145-151. 43. Perona G, Cetto GL, Bernardi F, Todeschini G, D'Andrea F (1977): Fanconi's anemia in adults: Study of three families. Haematologica 62:615-628. 44. Tanzer J, Frocrain C, Desmarest MC (1980): Anomalies du chromosome 1 dans 3 cas de leucemia compliquant une aplasie de Fanconi (FA). Nouv Rev Fr Hematol 22:XCIII. 45. Obeid DA, Hill FGH. Harnden D, Mann JR, Wood BSB (1980): Fanconi anemia. Oxymetholone hepatic tumors, and chromosome aberrations associated with leukemic transition. Cancer 46:1401-1404. 46. Kunze J (1980): Estren-Dameshek-An~mie mit myelomonocyt~irer Leuk~mie (Subtyp der Fanconi-An~mie?). In: Klinische Genetik in der Padiatrie, J Spranger, M Tolksdorf, eds. Stuttgart, Thieme, pp. 213-214. 47. Auerbach AD, Weiner MA, Warburton D, Yeboa K, Lu L, Broxmeyer HE (1982): Acute myeloid leukemia as the first hematologic manifestation of Fanconi anemia. Am J Hematol 12:289-300. 48. Berger R, Bussel A, Schenmetzler C (1977): Somatic segregation and Fanconi anemia. Clin Genet 11:409-415. 49. Stivrins TJ, Davis RB, Sanger W, Fritz J, Purtilo DT (1984): Transformation of Fanconi's anemia to acute nonlymphocytic leukemia associated with emergence of monosomy 7. Blood 64:173-176. 50. Nowell P, Bergman G, Besa E, Wilmoth D, Emanuel B (1984): Progressive preleukemia with a chromosomally abnormal clone in a kindred with the Estren-Dameshek variant of Fanconi's anemia. Blood 64:1135-1138. 51. Gastearena J, Giralt M, Orue MT, Oyarzabal FJ, Perez-Equiza E, Uriz MJ (1986): Fanconi's anemia. Clinical study of six cases. Am J Pediatr Hematol Oncol 8:173-177. 52. Woods WC, Nesbit ME, Buckley J, Lampkin BC, McCreadie S, Kim TH, Piomelli S, Kersey JH, Feig S, Berstein I, Hammond D, for the Children's Cancer Study Group (1985): Correlation of chromosome abnormalities with patient characteristics, histological subtype, and induction success in children with acute nonlymphocytic leukemia. J Clin Oncol 3:3-11. 53. Hows JM, Yin JL, Swirsky MD, Apperley JF, James DCO, Smithers S, Batchelor JR, Goldman JM, Gordon-Smith EC (1986): Histocompatible unrelated volunteer donors compared with HLA nonidentical family donors in marrow transplantation for aplastic anemia and leukemia. Blood 68:1322-1328. 54. Smith S, Marx MP, Jordaan CJ, van Niekerk CH (1989): Clinical aspects of a cluster of 42 patients in South Africa with Fanconi anemia. In: Fanconi Anemia. Clinical, Cytogenetic and Experimental Aspects, TM Schroeder-Kurth, AD Auerbach, G Obe, eds. Springer-Verlag, New York, pp. 34-46. 55. Berger R, Le Coniat M (1989): Cytogenetic studies in Fanconi anemia: induced chromosomal breakage and cytogenetics of leukemia. In: Fanconi Anemia: Clinical, Cytogenetic and Experimental Aspects, TM Schroeder-Kurth, AD Auerbach, G Obe, eds. Springer-Verlag, New York, pp. 93-99. 56. Huret JL, Tanzer F, Guihot F, Frocrain-Herchkovitch C, Savage JRK (1988): Karyotype evolution in the bone marrow of a patient with Fanconi anemia: Breakpoints in clonal abnormalities of this disease. Cytogenet Cell Genet 48:224-227. 57. Standen GR, Hughes IA, Geddes AD, Jones BM, Wardrop CA) (1989): Myelodysplastic syndrome with trisomy 8 in an adolescent with Fanconi anemia and selective IgA deficiency. Am J Hemotol 31:280-283. 58. Huret JL, Benz E, Guilhot F, Brizard A, Tanzer J (1986): Fluctuation of a clone 46,XX,i(7q) in bone marrow in a Fanconi anaemia. Hum Genet 74:98-100. 59. Crossen PE, Mellor )EL, Adams AC, Gunz FW (1972): Chromosome studies in Fanconi's anaemia before and after treatment with oxymetholone. Pathology 4:27-33. 60. Lisker R, Cobo de Guti~rrez A (1974): Cytogenetic studies in Fanconi's anemia. Description of a case with bone marrow clonal evolution. Clin Genet 5:72-76. 61. Carbone P, Barbata G, Mirto S, Granata G (1984): Inherited aplastic anemia with abnormal clones in bone marrow and increased endoreduplication in peripheral lymphocytes. Cancer Genet Cytogenet 13:259-266.
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11
62. Schindler D, Kubbies M, Hoehn H, Schinzel A, Rabinovitch PS (1987): Confirmation of Fanconi's anemia and detection of a chromosomal aberration (lq12-32 triplication) via BrdU/Hoechst flow cytometry. Am J Pediatr Hematol Oncol 9:172-177. 63. Baron F, Sybert VP, Andrews RG (1989): Cutaneousand extracutaneous neutrophilic infiltrates (Sweet syndrome) in three patients with Fanconi anemia. J Pediatr 115:726-729. 64. German J (1983 ): Patterns ~f ne~p~asia`ass~ciated with the chr~m~some~breakage syndr~mes. In: Chromosome Mutation and Neoplasia, J German, ed. Alan R. Liss, New York, pp. 1983-1997. 65. Alter BP (1987): The bone marrow failure syndromes. In: Hematology of Infancy and Childhood, DG Nathan, FA Oski, eds. W.B. Saunders, Philadelphia, pp. 159-241. 66. Birch JM (1983): Epidemiology of Paediatric Cancer. In: Recent Results in Cancer Research, vol. 88. Paediatric Oncology, W Duncan, ed. Springer-Verlag, Berlin, pp. 1-10. 67. Young JLJr, Miller RW (1975): Incidence of malignant tumors in US children. J Pediatr 86:254-258. 68. Swift M, Caldwell RJ, Chase C (1980): Reassessment of cancer predisposition of Fanconi anemia heterozygotes. J Natl Cancer Inst 65:863-867. 69. Potter NU, Sarmousakis C, Li FP (1983): Cancer in relatives of patients with aplastic anemia. Cancer Genet Cytogenet 9:61-66. 70. Pedersen-Bjergaard J, Philip P, Mortensen BT, Ersboll J, Jensen G, Panduro J, Thomsen M (1981): Acute nonlymphocytic leukemia, preleukemia, and acute myeloproliferative syndrome secondary to treatment of other malignant diseases. Clinical and cytogenetic characteristics and results of in vitro culture of bone marrow and HLA typing. Blood 57:712-723. 71. Bloomfield CD, Brunning RD (1976): Acute leukemia as a terminal event in nonleukemic hematopoietic disorders. Semin Oncol 3:297-316. 72. Nowell PC, Besa EC (1989): Prognostic significance of single chromosome abnormalities in preleukemic states. Cancer Genet Cytogenet 42:1-7. 73. Appelbaum FR, Barrall J, Storb R, Ramberg R, Doney K, Sale GE, Thomas ED (1987): Clonal cytogenetic abnormalities in patients with otherwise typical aplastic anemia. Exp Hematol 15:1134-1139. 74. de Planque MM, Kluin-Nelemans HC, van Krieken HJM, Kluin PM, Brand A, Beverstock GC, Willemze R, van Rood JJ (1988): Evolution of acquired severe aplastic anaemia to myelodysplasia and subsequent leukaemia in adults. Br J Haematol 70:55-62. 75. de Planque MM, Bacigalupo A, Wiirsch A, Hows JM, Devergie A, Frickhofen N, Brand A, Nissen C, for the Severe Aplastic Anaemia Working Party of the European Cooperative Group for Bone Marrow Transplantation (EBMT) (1989): Long-term follow-up of severe aplastic anaemia patients treated with antithymocyte globulin. Br J Haematol 73:121-126. 76. Tichelli A, Gratwohl A, W~rsch C, Nissen C, Speck B (1988): Late haematological complications in severe aplastic anaemia. Br J Haematol 69:413-418. 77. Pierre RV, Catovsky D, Mufti GJ, Swansbury GJ, Mecucci C, Dewald GW, Ruutu T, Van Den Berghe H, Rowley JD, Mitelman F, Reeves BR, Alimena G, Garson OM, Lawler SD, de la Chapelle A, Sixth International Workshop on Chromosomes in Leukemia 1987 (1989): Clinical-cytogenetic correlations in myelodysplasia (preleukemia). Cancer Genet Cytogenet 40:140-161. 78. Hoehn H, Kubbies M, Schindler D, Poot M, Rabinovitch PS (1989): BrdU-Hoechst flowcytometry links the cell kinetic defect of Fanconi anemia to oxygen hypersensitivity. In: Fanconi Anemia. Clinical, Cytogenetic and Experimental Aspects, TM Schroeder-Kurth, AD Auerbach, G Obe, eds. Springer-Verlag, Heidelberg, pp. 161-173. 79. Kubbies M, Schindler D, Hoehn H, Schinzel A, Rabinovitch PS (1985): Endogenous blockage and delay of the chromosome cycle despite normal recruitment and growth phase explain poor proliferation and frequent endomitosis in Fanconi anemia cells. Am J Hum Genet 37:1022-1030. 80. Nordenson I (1977): Effect of superoxide dismutase and catalase on spontaneously occurring chromosome breaks in patients with Fanconi's anemia. Hereditas 86:147-150. 81. Nordenson I, Bjorksten B, Lundh B (1980): Prevention of chromosomal breakage in Fanconi's anemia by cocultivation with normal cells. Hum Genet 56:169-171. 82. Raj AS, Heddle JA (1980): The effect of superoxide dismutase, catalase and L-cysteine on
12
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83.
84. 85. 86.
87.
88. 89.
90.
91. 92.
spontaneous and on mitomycin C induced chromosomal breakage in Fanconi's anemia and normal fibroblasts as measured by the micronucleus method. Mutat Res 78:59-66. Joenje H, Gille JJP (1989): Oxygen metabolism and chromosomal breakage in Fanconi anemia. In: Clinical and Experimental Aspects of Fanconi Anemia, TM Schroeder-Kurth, AD Auerbach, G Obe, eds. Springer-Verlag, Heidelberg, pp. 174-182. Gille JJP, Wortelboer HM, Joenje H (1987): Antioxidant status of Fanconi anemia fibroblasts. Hum Genet 77:28-31. Fujiwara Y, Tatsumi M, Sasaki MS (1977): Cross-link repair in human cells and its possible defect in Fanconi's anemia cells. J Mol Biol 113:635-649. Averbeck D, Papadopoulo D, Moustacchi E (1988): Repair of 4,5',8-trimethylpsoralen plus light-induced DNA damage in normal and Fanconi's anemia cell lines. Photochem Photobiol 48:2015-2020. Poll EHA, Arwert F, Kortbeek HT, Eriksson AW (1984): Fanconi anaemia cells are not uniformly deficient in unhooking of DNA interstrand crosslinks, induced by mitomycin C or 8-methoxypsoralen plus UVA. Hum Genet 68:228-234. Poon PK, O'Brien RL, Parker JW (1974): Defective DNA repair in Fanconi's anemia. Nature 250:223-225. Digweed M, Zakrzewski-Ludcke S, Sperling K (1989): Complementation studies in Fanconi anemia using cell fusion and microinjection of mRNA. In: Fanconi Anemia. Clinical Cytogenetic and Experimental Aspects, TM Schroeder-Kurth, AD Auerbach, G Obe, eds. Springer° Verlag, New York, pp. 236-254. Wunder E, Burghardt U, Lang B, Hamilton L (1981): Fanconi's anemia: Anomaly of enzyme passage through the nuclear membrane? Anomalous intracellular distribution of topoisomerase activity in placental extracts in a case of Fanconi's anemia. Hum Genet 58:149-155. Berger NA, Berger SJ, Catino DM (1982): Abnormal NAD ÷ levels in cells from patients with Fanconi's anemia. Nature 299:271-273. Klocker H, Auer B, Hirsch-Kauffmann M, Altmann H, Burtscher HJ, Schweiger M (1983): DNA repair dependent NAD ÷ metabolism is impaired in cells from patients with Fanconi's anemia. EMBO J 2:303-307.
ABSTRACT: Fanconi anemia (FA) is an autosomal recessive disorder characterized clinically by a
progressive pancytopenia, diverse congenital abnormalities, and increased predisposition to malignancy. Although a variable phenotype makes accurate diagnosis on the basis of clinical manifestations difficult in s o m e patients, the u n i q u e sensitivity of FA cells to the clastogenic effect of DNA cross-linking a g e n t s such as diepoxybutane (DEB) c a n be u s e d to facilitate the diagnosis. We review all c a s e s af FA reported to have leukemia, preleukemia, or a bone marrow (BM) clonal chromosomal abnormality a n d include for the first time an analysis of t h e s e conditions observed in patients in the International Fanconi Anemia Registry (IFAR). The incidence of acute myelogenous leukemia (AML) in FA patients is m o r e than 15,000 times that observed in children in the general population. Cytogenetic studies of FA-associated leukemias disclose a high frequency of monasomy 7 and duplications involving lq. There were na occurr e n c e s of t(8;21), t(15;17), or abnormalities of 11q, which are associated with M2, M3, and M5 leukemias, respectively, but n o t with preleukemia. Development of leukemia in FA patients was associated with an exceedingly poor prognosis, with a m e a n age of death of 15 years. We suggest that all FA patients may be considered preleakemic and that this disorder presents a model for s t u d y of the etiology of AML.
INTRODUCTION Fanconi anemia (FA) was originally described as an autosomal recessive disorder characterized by progressive pancytopenia, diverse congenital abnormalities, and predisposition to malignancy [1-3]. More recently, the phenotype has been recognized to be so variable that diagnosis on the basis of clinical manifestations alone is difficult and often unreliable [4]. Although the molecular basis of this syndrome remains unknown, occurrence of FA can now be detected routinely by study of induced chromosomal breakage in cultured lymphocytes, fibroblasts, amniocytes, or chorionic villus cells after exposure of these cells to low concentrations of DNA cross-linking agents [5-8]. Fanconi anemia occurs in all ethnic groups, with a reported gene frequency of 1 : 300 [3]. Because of the difficulty of establishing a clinical diagnosis of FA and the resulting failure to ascertain cases, the true gene frequency may be considerably higher. From the Laboratory far Investigative Dermatology, The Rockefeller University, New York, New York.
Address reprint requests to: Dr. Arleen D. Auerbach, Laboratory for Investigative Dermatology, The Rockefeller University, 1230 York Ave., New York, NY 10021-6399.
Received February 12, 1990; accepted February 15, 1990
1 © 1991 Elsevier Science Publishing Co.. Inc. 655 Avenue of the Americas, New York. NY 10010
Cancer Genet Cytogenet 51:1 12 (1991) 0165-4608/91/$03.50
2
A.D. Auerbach and R. G. Allen Patients with FA usually die of hemorrhage or infection, and relatively few individuals homozygous for the disorder survive their second decade. For many years, FA patients have been recognized to be at increased risk for developing leukemia. Bone marrow (BM) clonal cytogenetic abnormalities have been reported in some of these patients, as well as in some FA patients with no evidence of leukemia at the time of study. These latter cases may be considered to have a preleukemic phase of the disease. We summarize the cases of leukemia and preleukemia described in the literature as well as cases that have been reported to the International Fanconi Anemia Registry (IFAR) at The Rockefeller University. We suggest that all FA patients may be considered preleukemic and that this disorder presents a model for the study of the etiology of acute myelogenous leukemia (AML).
MATERIALS AND METHODS
The present summary is based on a review of the cases in the literature and in the IFAR in which leukemia, preleukemia, or a BM clonal chromosomal abnormality has been reported in FA patients. We present all such cases of which we are aware. The IFAR was established at The Rockefeller University in 1982 to study a large number of FA patients with the full spectrum of diverse features of the syndrome. The registry serves as a centralized repository for clinical, hematologic, and genetic information on patients with FA [8-11]. Patients in the IFAR were ascertained on the basis of the presence of congenital malformations known to be associated with FA, hematologic manifestations such as aplastic anemia or leukemia, both malformations and hematologic manifestations, or family screening. Approximately 50% of the FA patients in the IFAR do not exhibit any major malformations. The primary source of cases in the IFAR is voluntary physician reporting, either directly to Dr. Auerbach at The Rockefeller University, or to Dr. Traute M. SchroederKurth, University of Heidelberg, F.R.G. (primarily cases from West Germany). Chromosome breakage studies, including testing for hypersensitivity to the clastogenic effect of the DNA cross-linking agent diepoxybutane (DEB), were performed in most patients. Those who did not exhibit sensitivity of cultured peripheral blood lymphocytes (PBLs) to cross-link-induced chromosomal breakage were classified as unaffected with FA. To obtain follow-up information on patients, we recently contacted all physicians who reported cases directly to The Rockefeller University. Only these cases are included in this report. RESULTS
Fanconi anemia patients with leukemia or preleukemia reported in the literature are shown in Table 1. We included patients with aplastic anemia and clonal disease in the preleukemic group. Fifty-four cases of leukemia and 14 cases of preleukemia or clonal disease were reported in approximately 700 cases of FA reported in the literature. The mean age at diagnosis of leukemia was 14.8 years and the mean age of death in these patients was 15.5 years. None of the patients were reported to have achieved long-term remission. Although chromosome studies were not included in many of the reports of FA cases with leukemia, chromosome abnormalities were detected in most cases in which chromosome studies were performed. The chromosome abnormalities reported were highly variable; the most frequently occurring changes were monosomy 7 and translocations or duplications involving lq. There were no occurrences of the t(8;21) associated with M2, the t(15;17) associated with M3, or the del 11q or t(9;11) associated with M5 leukemias. Analysis of data from the IFAR (Table 2) showed that 19 of 222 patients (9%) had leukemia or myelodysplastic disease. Results of chromosome studies in these patients
Table 1
Case no.
Leukemic (AML) and preleukemic the literature Age at d e v e l o p m e n t of l e u k e m i a
L e u k e m i c patients (AML) Myeloblastic (M1) 1 11 M y e l o m o n o c y t i c (M4) 2 13 3 7 4 -5 8 6 7 7 5 8 6 9 18 10 26 11 -12 23 13 17 14 12 M o n o c y t i c (M5) 15 10 16 12 17 14 18 16 E r y t h r o l e u k e m i a (M6) 19 15 20 15 21 22 22 -23 15 Megakaryoblastic (M7) 24 9 Not Specified 25 27 26 11 27 12 28 9 29 21 30 19 31 -32 28 33 16 34 15 35 36 37 38 39 40 42 42
-12 -5 --20 --
Age at death
Fanconi anemia patients reported in
Chromosome abnormalities
Reference
12
- 18, + m a r
[12]
13 8 13 8 8 6 6 19 28
NS NS NS None NS NS t{5q;18q) NS None
113l [14, 15] [14, 15] [16] [15] [15] [17]
--
NS
[20]
23 17 --
NS t(5;7)(p15;q22), + 19 6q + , 2 1 q -
[21] [22] [23, 24]
10 13 15 16
None NS 3q+ NS
[25] [26] [27] [28]
15 15 -10 15
-C NS lp+ NS dup{1)(p32;p34),trip(3)(q12;q27),del(7)(p11)
[29-31] [32] [33] [12] [12, 34]
--
NS
[35]
27 12 --21 --28 16 --
NS NS NS NS Hyperdiploidy NS NS None NS t(1;14)(q12 or 21;q32), 4 q - ,Sq + ,7q - ,13q + ,20q t(1;6)(q22 or 2 3 ; p t e r ) ; 5 q t(1;6)(q32;p25) NS - 7,-8,+2mar NS NS d u p ( 3 ) ( q 1 2 - q 2 7 ) , 1 2 q + , l p + ,Tp+ NS
[36] [37] [38] [39] [40, 41] [42] [42] [43] [18] [44]
23 13 -7 21 14 20 23
118] [19]
[44] [45] [46] [47] [121 [12] [12, 48] [12]
[cominm~d)
4 Table 1
Case no.
A . D . A u e r b a c h a n d R. G. A l l e n
L e u k e m i c (AML) a n d p r e l e u k e m i c F a n c o n i a n e m i a p a t i e n t s r e p o r t e d in t h e l i t e r a t u r e (Continued) Age at development of leukemia
43 -44 -45 25 46 21 47 16 48 7 49 -50 -51 -52 -53 -54 -Preleukemic patients Refractory anemia 55 25 56 15 Myelodysplastic syndrome 57 11 Aplastic anemia 58 23 59 9 60 17 61 20 62 10 63 17 64 19 65 -66 31 67 16 68 25
Age at death 8 15 26 21 -8 --
---
-
27 -
-
24 -21 31 10 17 --35 17 27
Chromosome abnormalities
Reference
NS NS - 7 - 7 t(1;17)(q21;p13).t(10;?)(q26;?],del(12)(p11) NS 7q - ,9q NS NS NS NS +20, 22,dup(1}(q22;q34), + del(22}(q11)
[12] 112] [49] 1491 I50] [51] 152] 1531 [541 [54] 154] [55]
t(1 ;6)(q12;p25),del(5)(q21q23) +8
[44, 56] [57]
i(7q)
158l
+C Dq + + 1,+mar,-2C +mar +21 2q +, + mar - 21,+mar 2pdup(1](q24-32),t{17;?}(p12-13;?) dup(1)(q12-32) t(1;6)(q22or23;p25),t(2;3?)(q35?;p21?)
[59] [60] [40, 41] 143] [12] [12, 34] [12, 34] 112] 161] 162] [63]
w e r e s i m i l a r to t h e l i t e r a t u r e data. T h e m e a n age of l e u k e m i a d i a g n o s i s a n d m e a n age of d e a t h i n t h e s e p a t i e n t s (14.4 a n d 15.6 years, r e s p e c t i v e l y ) w e r e also r e m a r k a b l y s i m i l a r to t h o s e of p a t i e n t s d e s c r i b e d i n t h e l i t e r a t u r e . T h e m e a n age of d i a g n o s i s of a p l a s t i c a n e m i a i n t h e IFAR c a s e s w i t h l e u k e m i a w a s 7.4 y e a r s as c o m p a r e d w i t h 6.24 -+ 0.69 y e a r s for all IFAR p a t i e n t s . T h e m e d i a n e s t i m a t e d s u r v i v a l ( c a l c u l a t e d u s i n g t h e p r o d u c t - l i m i t m e t h o d of K a p l a n a n d M e i e r ) for all p a t i e n t s i n t h e I F A R w a s 25.2 + 2.5 y e a r s (67.4% of t h e p a t i e n t s are c e n s o r e d ) . T h e m e d i a n e s t i m a t e d s u r v i v a l for p a t i e n t s d e v e l o p i n g l e u k e m i a is 12.0 -+ 2.3 years, a n d t h e m e d i a n e s t i m a t e d s u r v i v a l for p a t i e n t s w i t h o u t l e u k e m i a is 27.0 +- 3.3 years. T h u s , d e v e l o p m e n t of l e u k e m i a i n F A p a t i e n t s is a s s o c i a t e d w i t h a n e x c e e d i n g l y p o o r p r o g n o s i s .
DISCUSSION I n d i v i d u a l s w i t h c h r o m o s o m e b r e a k a g e s y n d r o m e s o f t e n suffer i n c r e a s e d s u s c e p t i b i l ity to m a l i g n a n c i e s [64]. N o t s u r p r i s i n g l y , F A is s t r o n g l y a s s o c i a t e d w i t h a n i n c r e a s e d p r e d i s p o s i t i o n to a v a r i e t y of c a n c e r s . A b o u t h a l f of t h e m a l i g n a n c i e s r e p o r t e d w e r e l e u k e m i a s ; t h e r e m a i n d e r c o n s i s t e d of l i v e r t u m o r s a n d o t h e r c a n c e r s [65]. T h e i n c i d e n c e of A M L i n o u r s u r v e y w a s a p p r o x i m a t e l y 9%. F o r c o m p a r i s o n , d a t a f r o m
Leukemia in Fanconi Anemia
Table 2
IFAR no.
5
L e u k e m i c (AML) a n d p r e l e u k e m i c F a n c o n i a n e m i a p a t i e n t s i n t h e IFAR Age at onset of aplastic anemia
Leukemic patients (AML) Myeloblastic (M1) 90/1 " 5.7 Myeloblastic (M2) 359/1 8 Myelomonocytic (M4) 13/1 6.3 43/1 10.2 Erythroleukemia (M6) 23/1 6.2 Not specified 29/1 1.9 30/1 13 18/1 ~ 5.2 95/1 7.5 129/1 2.1 187 6 247/1 13 288/1 4 326/1 6 338/1 20 357/1 0.5 Preleukemic patients Myelodysplastic syndrome 45/2 5 6/2 6.3 358/1 14 Aplastic anemia 287/1 0.6 107/1': 31
Age at development of leukemia
11
Age at death
Chromosome abnormalities
12
- 18, + mar
8
--
14.6 18.9
14.8 19.2
del(7)(pl 1),6p + ,lq + NS
11.9
12.1
1 8 q + , d u p 1 2 q , 5 q + , - 16
2 23.8 5.2 11.4 2.5 9 17.7 9 32.4 28.2 0.5
2 25.2 7 12.1 3.5
None del(7)(q) - 7, - 8, + 2mar NS NS -7 NS None 2q+,6p+ NS NS
18.3 10.1 28.3
7.5
37.1 23
38.2
9.8 31
21.66 35
NS
2q +, + mar NS t(1;5)(p34;q31) - 13,t(1q;13q),del{7)(q32} dup(1){q24-32),t(17;?)(p12-13;?)
o Same as reference 12, Table 1. J' Same as reference 47, Table 1. ': Same as reference 61. Table 1. AML ~ acute myelogenous leukemia. t h e M a n c h e s t e r C h i l d r e n ' s T u m o r Registry 1 9 5 4 - 1 9 8 0 s h o w s t h a t t h e i n c i d e n c e of c h i l d h o o d m a l i g n a n t d i s e a s e w a s 99.3/106 , t h e rate of l e u k e m i a w a s 32.8/106 , a n d t h e rate of A M L w a s 4.9/106 [66]. T h e i n c i d e n c e of A M L i n c h i l d r e n i n t h e U n i t e d S t a t e s w a s s i m i l a r [67]. T h u s , m o s t of t h e l e u k e m i a s o b s e r v e d i n c h i l d r e n a n d y o u n g a d u l t s i n t h e g e n e r a l p o p u l a t i o n are of l y m p h o i d origin, b u t n e a r l y all F A - a s s o c i a t e d l e u k e m i a s are m y e l o i d . W h e t h e r F A h e t e r o z y g o t e s are at i n c r e a s e d r i s k for l e u k e m i a rem a i n s u n r e s o l v e d [3, 68, 69] b e c a u s e t h e r e is still n o a c c u r a t e m e t h o d of d e t e c t i n g heterozygotes. A l t h o u g h t h e i n c r e a s e d p r e d i s p o s i t i o n to l e u k e m i a m a y b e r e l a t e d to t h e b a s i c d e f e c t i n FA, t h e e t i o l o g y of l e u k e m i a i n F A p a t i e n t s is u n k n o w n . S o m a t i c m u t a t i o n a r i s i n g f r o m c h r o m o s o m a l i n s t a b i l i t y m a y b e of i m p o r t a n c e . T h e o n s e t of l e u k e m i a in FA patients may be triggered by environmental influences. Various alkylating a g e n t s are c a r c i n o g e n i c a n d a u g m e n t t h e i n c i d e n c e of c a n c e r i n t h e g e n e r a l p o p u l a t i o n ; e.g., t h e i n c i d e n c e of A M L is d r a m a t i c a l l y i n c r e a s e d i n c a n c e r p a t i e n t s s e c o n d a r y to c h e m o t h e r a p y w i t h a l k y l a t i n g a g e n t s [70]. T h e s e p a t i e n t s o f t e n e x h i b i t a p r e l e u k e m i c
6
A.D. Auerbach and R. G. Allen phase followed by progression to AML. Nonrandom clonal chromosomal changes, especially - 7 and - 5 / 5 q - , were demonstrated before leukemic evolution. Other chemical agents implicated as leukemogens include benzene, chloramphenicol, and phenylbutazone [71]. The best documented of these, benzene, is associated with chromosome breakage and with development of aplastic anemia. All cases of leukemia evolving in these patients appear to be AML in type. Thus, even at the trace levels of carcinogens present in the environment, the hypersensitivity of FA patients to chemically induced DNA damage might be expected to increase their incidence of cancer. Although relatively few FA patients have had BM cytogenetic studies before onset of leukemia, clonal abnormalities are frequently reported in those cases studied, suggesting clonality during the aplastic anemia phase of the disease. Considerable evidence shows that the presence of chromosomally abnormal clones in the BM heightens the risk for development of leukemia [72]. Appelbaum et el. [73] report that aplastic anemia patients exhibiting clonal cytogenetic abnormalities of marrow cells have an especially high risk for developing leukemia. The specific abnormalities observed are those associated with leukemia and preleukemia, and the investigators suggest that clonal abnormalities in aplastic anemia represent a preleukemic syndrome. Recent studies by de Planque et al. [74, 75] and Tichelli et al. [76] demonstrate that patients with severe aplastic anemia treated without BM transplantation and surviving at least 2 years are at a 10% or greater risk for developing myelodysplasia or AML. The patients in these studies had been treated with supportive care, androgens, and/or immunosuppressive therapy such as antithymocyte globulin. It has been suggested that the high incidence of leukemia in FA patients is related to androgen therapy [64]. However, a number of cases have been described in which onset of clonal disease or AML appeared in the absence of any therapy. The presence of clones with complex karyotypic rearrangements or clones with monosomy 7 or del (7q) in preleukemic patients has been associated with poor prognosis and with the progression to leukemia [72]. A review of clinical and cytogenetic correlations in preleukemia from the Sixth International Workshop on Chromosomes in Leukemia [77] reported that demonstration of a clonal cytogenetic abnormality in these patients provided a positive indication of the neoplastic nature of the disease. A shorter survival time was associated with a greater degree of clonal complexity. Consistent with our observations in FA patients, none of the preleukemic patients in this series had t(8;21), t(15;17), or abnormalities involving chromosome 11, suggesting that leukemic patients with these abnormalities do not exhibit a preleukemic phase. Thus, it is not surprising that these specific abnormalities associated with AML are not found in FA patients with leukemia if we consider all patients affected with FA to be preleukemic. It is unfortunate that our understanding of the cellular defect in FA remains obscure, limiting our ability to understand the predisposition to leukemia in these patients. The mechanism underlying the hypersensitivity of FA cells to DNA crosslinking agents remains unknown. Cultured FA cells exhibit a prolonged G2 phase transit and a frequent occurrence of permanent G 2 phase arrest [78, 59]. This defect in FA cell cycle is highly sensitive to the ambient oxygen environment; the number of cells arrested in G 2 is significantly greater in cell cultures maintained under 20% ambient oxygen than in those kept under 5% ambient oxygen [78]. Furthermore, the frequency of chromosome breakage observed in FA cells can be diminished by decreasing the oxygen concentration of the culture atmosphere; e.g., FA cells cultured under an atmosphere containing 5% oxygen exhibit significantly lower levels of chromosome breakage than cells of the same line maintained under an ambient oxygen concentration of 20%. Similarly, antioxidants have been used to inhibit clastogenic effects. Nordenson [80] reported that superoxide dismutase (SOD) and catalase had a
Leukemia in Fanconi Anemia
7
protective effect to FA lymphocytes in culture and that SOD ameliorated the toxicity of mitomycin C in FA fibroblasts [81]. A similar protective effect for SOD, catalase, and L-cysteine was reported by Raj and Heddle [82]. Low molecular weight antioxidants such as tocopherol, glutathione, butylated hydroxytoluene (BHT), and ascorbate also have some protective effects on FA cell cultures [83]. Use of antioxidants to limit the number of clastogen-induced mutations demonstrates only that free radicals are ultimately responsible for breakage caused by these chemicals, however. Any speculation that steady-state oxidant levels are aberrant in FA cells is unwarranted if supported on this basis alone. In at least some cases, the whole blood activity of SOD of FA patients is lower than normal blood levels [83]. The sensitivity of FA cells to an oxidizing environment has been postulated to result from either an increased rate of oxygen free radical generation or a decreased rate of free radical removal by cellular scavengers [84]. Glutathione reductase activity also appears to be diminished in several FA patients [27]. Decreases in SOD and glutathione reductase activities do not appear to occur consistently in all FA patients, however; indeed existing evidence indicates that none of the known free radical scavenging pathways are grossly defective in FA cells [83]. No compelling evidence has been presented to support the postulate that the rate of free radical generation is actually altered in FA, and the existence of a prooxidizing state in FA cells remains predominantly a matter of conjecture. Aside from the possibility that the intracellular environment of FA cells is in some way more conducive to induction of damage, hypersensitivity of FA cells to clastogens has also been suggested to be actually a result of decreased DNA repair capacity. Fujiwara et al. [85] and Averbeck et al. [86] reported diminished DNA interstrand cross-link repair in FA cells. Conversely, other investigators have failed to confirm their observations and report normal repair in FA cells after exposure to a wide variety of cross-linking agents [87]. Deficient excision repair [88], defective DNA ligase activity [89], abnormal intracellular distribution of topoisomerases [90], alterations in the nucleotide pool [91], and decreased adenosine diphosphateribosyl transferase activity [92] are among other repair defects that have been reported. The occurrence of abnormalities in such a large number of diverse repair mechanisms suggests that the defect giving rise to FA may occur in a gene that influences the activity of many biochemical pathways. Nevertheless, none of these aberrations are ubiquitous in FA.
CONCLUSION Fanconi anemia results from a single autosomal recessive gene, yet its phenotype is highly pleiotropic. Even affected siblings often differ in their phenotype. Multiple biochemical mechanisms and pathways have been postulated to be responsible for the increase in sensitivity of FA DNA to clastogenic chemicals; however, evidence is presently insufficient to implicate any of these putative defects as the underlying cause of the disease. The diversity of phenotypes and biochemical aberrations associated with FA may result from interaction of different sets of genes with the defective gene or could arise from interactions of the defect with environmental agents. Although FA is associated with increased incidence of myeloid leukemias, no welldocumented lymphoid leukemias have been reported in FA patients. The increased incidence of AML and the absence of lymphoid leukemias in FA patients suggests that FA may be a preleukemic condition for AML. Leukemia would result from a new clone of abnormal cells arising either directly as a result of the intrinsic cellular defect or from damage to a stem cell resulting from exposure to an environmental toxin. In view of the lack of agreement as to the biochemical basis for FA, the underlying
8
A . D . Auerbach and R. G. Allen
m e c h a n i s m of the disease will probably remain u n k n o w n until the defective gene has been identified. The "reverse genetics" approach using restriction fragment length p o l y m o r p h i s m analysis is currently being used in our laboratory to map the FA gene. Once the c h r o m o s o m a l location of the gene has been m a p p e d and the defective gene identified, it should become possible not only to understand the cause of FA but also to explain the pleiotropic nature of the disease. This work was supported in part by Public Health Service Grants No. HL 32987 from the National Institutes of Health (to A.D.A.), by Clinical Research Grant No. 6-521 from the March of Dimes Birth Defects Foundation (to A.D.A.), by a General Clinical Research Center Grant No. RRO0102 from the National Institutes of Health to The Rockefeller University Hospital, and by support from the Fanconi Anemia Research Fund (to A.D.A.) and the Pew Memorial Trust to the Laboratory for Investigative Determatology. We thank the numerous physicians who referred patients to the IFAR, Christine L. Frissora for help in obtaining follow-up information on the IFAR patients, and Andr~ Rogatko for statistical analysis of the IFAR data.
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