IOTH ANNIVERSARY ARTICLE Cancer in Ataxia-Telangiectasia Patients Frederick Hecht and Barbara K. Hecht

ABSTRACT: A gene locus for ataxia-telangiectasia (A-T) is in chromosome region 1 lq22 to 11q23 and predisposes to cancer. Ataxia-telangiectasia patients appear to have two separate clinical patterns of malignancy. One pattern involves solid tumors, which have not been stressed and which include malignancies in the oral cavity, breast, stomach, pancreas, ovary, and bladder. Detection of a solid tumor in an A-T patient should serve as a warning. It heralds a markedly elevated risk of another malignancy in that patient. The second pattern of neoplasia in A-T is well recognized and consists of lymphocytic leukemia and non-Hadgkin's lymphama. These malignancies may relate to immunodeficiency in A-T and to chromosome breakage and rearrangement, which are a feature of A-T. These two patterns of malignancy may be truly separate and reflect different mechanisms of malignancy in A-T, or they may not really be separate but instead reflect a single mechanism of malignancy. The situation in A-T is reminiscent of that in the acquired immunodeficiency syndrome (AIDS), in which Kaposi's sarcoma occurs with mild immunodeficiency and pneumocystis carinii pneumonia accurs with more profound immunodeficiency owing to the human immunodeficiency virus. Next to pulmonary disease, cancer is the leading cause of death in A-T.

INTRODUCTION We have had an interest in ataxia-telangiectasia (A-T) since 1966 w h e n we discovered that it led to chromosome instability and lymphocytic leukemia [1]. Ataxia-telangiectasia is an important model of a genetic disease predisposing to cancer. The discovery in 1988 that an A-T gene is in chromosome region 11q22-23 will accelerate research and advance learning about this cancer gene locus [2]. In this article, we focus on neoplasms in A-T patients. First, however, we trace briefly the development of knowledge of A-T, stressing that infections of the lungs, not cancers, are the leading cause of death in A-T.

MILESTONES A-T is a highly intricate disease with m a n y clinical facets. It has myriad laboratory manifestations and is n o w a prime target for the molecular pursuit of cancer genes [2]. We can approach A-T from several angles, i n c l u d i n g chromosome instability [1, 3] or encompass it by a m u l t i d i s c i p l i n a r y approach as has been accomplished brilliantly in two books [4, 5]. Fromthe Genetics Center and Cancer Center of Genetrix,Inc.and SouthwestBiomedicalResearchInstitute, Scottsdale, Arizona,and Jacksonville,Florida. Address requests for reprints to: Dr. Frederick Hecht, 4134 McGirts Boulevard, Jacksonville, FL 32210. 9

© 1990 Elsevier Science PublishingCo., Inc. 655 Avenueof the Americas, New York, NY 10010

Cancer Genet Cytogenet46:9-19 (1990) 0165-4608/90/$03.50

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F. Hecht and B. K. Hecht

Table 1

Highlights in the history of A-T from 1926 to 1988

Year

Highlight

References

1926 1941 1957-1958 1961-1962 1963-1964 1965 1966 1966 1972 1973 1974 1975 1975 1976 1976 1977 1978 1980 1980 1982 1984 1985 1987 1988

First clinical description of A-T Second clinical description Delineation and naming of A-T Identification of immunodeficiency Association with lymphoma Autosomal recessive inheritance Association with leukemia Chromosome instability Elevation of a-fetoprotein Lymphocyte clones Clinical radiation hypersensitivity Chromosome 14 rearrangements Cellular radiation hypersensitivity Chromosomal radiation hypersensitivity Malignancies increased in A-T heterozygotes Genetic heterogeneity by complementation Elevation of carcinoembryonic antigen Chromosomes 7 and 14 changes First conference on A-T First book on ArT Second conference on A-T Second book on A-T Breast cancer increased in A-T heterozygotes Mapping of A-T gene to 11q22-23

[6] [7] [8, 9] [15, 16] [12, 17] [18] [1, 10] [1] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [4] [4] [5] [5] [29] [2]

Abbreviation: A-T, ataxia-telangiectasia.

We first consider milestones in information about A-T. Syllaba and Henner [6] described the disease in 1926. Louis-Bar rediscovered it in 1941 [7], and Boder and Sedgwick gave it p r o m i n e n c e [8, 9]. Miller first recognized the association with l e u k e m i a [10]. Hecht et al. [1] established this association and observed chromosome breakage. In 1988, a gene for A-T was m a p p e d to chromosome 11. It is in the long arm [1] in the region continuing band 11q22 and 11q23. These and other milestones for A-T are s h o w n in Table 1.

PULMONARY DISEASE LEADING CAUSE OF DEATH IN A-T

Cancer is not the leading cause of death in A-T. Although 3 patients in the original Boder-Sedgwick series had cancer, 7 had chronic progressive p u l m o n a r y disease. The p r o m i n e n c e of p u l m o n a r y problems was also noted in the title of Boder and Sedgw i c k ' s original articles on A-T [8, 9]. The predominance of p u l m o n a r y disease is shown in Table 2. Boder and Sedgwick followed 44 A-T patients over the years [11]. To our knowledge, this is the largest cohort of A-T patients to come under longitudinal study. That Boder and Sedgwick are neurologists probably ensured against a bias toward selection for malignancy. Twenty of their patients had died by 1985 [11]. Data were available for 18 of these patients from autopsies and biopsies. The causes of death are shown in Table 3. P u l m o n a r y disease was the commonest cause of death, responsible for nine deaths and contributing to another six. Thus, p u l m o n a r y disease p l a y e d a role in 15 of 18 (83%) of the deaths. Cancer was the second most c o m m o n cause of death, responsible

11

Cancer in Ataxia-Telangiectasia Patients

Table 2

P u l m o n a r y disease versus cancer in the original ataxia-telangiectasia patients of Boder and Sedgwick a Cause of death

Case no.

Pulmonary

1

+

2

+

3

+

4

+

5

+

6 7

+

8

+

Total

7

Cancer

Neoplasm

+ +

T-cell leukemia Malignant lymphoma

+

Round-cell lymphoma

3

Lymphoma and leukemia

a Based on references 8, 9, and 11.

for three deaths and contributing to six, playing a role in nine of the 18 (50%) of the deaths. Fifty-seven complete autopsies of persons with A-T were reported through 1985 [11]. Data on the causes of death are also shown in Table 3. Pulmonary disease again was the leading cause of death. Cancer was clearly second as a cause of death and was involved in nearly half of all deaths. Last, other causes occupy a relatively m i n o r place in A-T deaths. Two deaths were accidental: one occurred during pneumoretograp h y for e x a m i n a t i o n of the thymus (not a r e c o m m e n d e d procedure today), and another occurred in exploratory laparotomy for rectal hemorrhage. Surgery probably has a d d e d risks for A-T patients, as does radiation. Ataxia-telangiectasia is rare as compared with m a n y other diseases. Therefore, certain A-T patients have been recurrently studied by groups of investigators. One

Table 3

P r e d o m i n a n c e of p u l m o n a r y disease as a cause of death in ataxia-telangiectasiaa Boder and Sedgwick cohort

Published autopsies

n(%)

n(%)

9(50) 6(33}

27(47) 15{26}

15(83)

42(74}

3(17) 6(33)

12(21) 15(26)

9(50)

27(47}

Other

0(0)

3(5}

Total

18(100)

57(100}

Causes of death Pulmonary disease Alone With cancer Subtotal Cancer Alone With pulmonary disease Subtotal

8Based on reference 11.

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F. Hecht and B. K. Hecht

Table 4 Reports of one ataxia-telangiectasia patient Country Year

USA

1966 1974 1974 1975 1979

+

USSR

UK

+ + + +

+

Reference [30] [31] [32] [22] [33]

patient with A-T has been investigated at least five times by investigators from three countries (Table 4). Therefore, it is difficult to determine which data are duplicative and sometimes virtually impossible to weed out recurrent reports on some patients.

NEOPLASMS Ataxia-Telangiectasia Autopsies Neoplasms have been recorded among the 57 reported complete autopsies: 28 involved a neoplasm, as shown in Table 5. Several patients had multiple neoplasms. Solid tumors are common among neoplasms in A-T patients at autopsy (Table 6). The prevalence of non-Hodgkin's lymphoma and leukemia in A-T is confirmed. IMMUNODEFICIENCY CANCER REGISTRY The Immunodeficiency Cancer Registry (ICR) collects cases of cancer occurring in the 17 diseases classified by the World Health Organization as primary immunodeficiency disease; A-T is one of these disorders. All cases of A-T in the ICR have neoplasms. The base population from which the ICR cases are drawn is that of the world, although only cases of published value or ones voluntarily reported by investigators are included. Thus, the numerator of A-T cases with neoplasia reflects incomplete ascertainment and the denominator of all A-T cases remains undefined. A-T accounts for about one third of all cases in the ICR and represents the largest single cohort in the ICR

[58]. Types of Neoplasms The neoplasms occurring in 108 A-T patients in the IRC [59] are shown in Table 7; the 108 A-T patients have 119 neoplasms, which are grouped by general class in Table 8. The largest class consists of non-Hodgkin's lymphomas, accounting for 49 (41%) of neoplasms. Leukemi~s are next, accounting for 27 (23%) of neoplasms. Together, non-Hodgkin's lymphomas and leukemias account for 76 (64%) of neoplasms in A-T. Of 119 neoplasms, 31 (26%) are solid tumors in A-T in the ICR. These solid tumors vary in type and location. There are seven gastric adenocarcinomas.

Ataxia-Telangiectasia Patients with Multiple Neoplasms The A-T patients in the ICR with two or more neoplasms are shown in Table 9: six of 108 patients with neoplasms (5.5%) had multiple neoplasms; 5 of these 6 patients (83%) had lymphoid neoplasms; five of the six patients (83%) were female, and three of the five females (60%) had tumors of the genitalia.

13

Cancer in Ataxia-Telangiectasia Patients

Table 5 N e o p l a s m s in ataxia-telangiectasia patients at complete autopsies Year

Reference

1964 1964 1964 1966 1967 1967 1967 1968 1968 1968 1969 1969 1969 1970 1970 1970 1971 1972 1972 1975 1976 1977 1978 1979 1979 1980 1981 1982

[34] [17] [17] [35] [36] [36] [37] [38] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57]

Sex/Age (yr) F/17 F/8 M/5 F/13 F/7 M/10 M/10 M/21 F/10 M/9 M/7 F/19 M/9 F/2 F/9 F/14 F/6

M/23 M/9 F/17 F/16 M/12 F/26 F/32 F/24 M/22 M/4 F/3

Neoplasm Ovarian dysgerminoma Small cell lymphosarcoma Generalized reticuloentheliosis, lymphoid tissue Cerebellar medulloblastoma Malignant lymphoma Acute leukemia Lymphosarcoma Malignant lymphoma Reticulum cell lymphoma Hodgkin disease Diffuse histiocytosarcoma Gastric adenocarcinoma Acute lymphoblastic leukemia Reticulum cell sarcoma IgM monoclonal gammopathy Follicular thyroid adenoma Lymphatic leukemia Acute lymphoblastic leukemia Lymphocytic lymphosarcoma Ovarian gonadoblastoma and dysgerminoma Ovarian gonadoblastoma and dysgerminoma T-cell acute lymphoblastic leukemia T-cell subacute leukemia T-cell chronic lymphocytic leukemia, and uterine leiomyosarcoma Hepatocellular carcinoma Renal cell carcinoma, hepatoma, and malignant hepatic mixed tumor Lymphosarcoma Hodgkin's disease

Association of Neoplasms in Ataxia-Telangiectasia The association of m u l t i p l e n e o p l a s m s within A-T patients is shown in Table 10. Because there is an obvious association between non-Hodgkin's l y m p h o m a and l y m p h o i d leukemia, these disorders have been l u m p e d as l e u k e m i a / l y m p h o m a . Of the five patients with l e u k e m i a / l y m p h o m a who also had solid tumors, four had l e u k e m i a and one had l y m p h o m a . Because only one of 49 l y m p h o m a s had an associ-

Table 6 N e o p l a s m s in ataxia-telangiectasia patients at autopsy Patients

Neoplasms

Category of neoplasm

n(%)

n(%)

Solid tumor Non-Hodgkin's lymphoma Leukemia Hodgkin's disease Monoclonal gammopathy

9(34) 10(31} 7(24} 2(7) 1(3)

10(30) 13(39) 7(21) 2(6) 1(3)

Total

29(100)

33(100)

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F. Hecht and B. K. Hecht

Table 7

Neoplasms in ataxia-telangiectasia patients in ICR Type of neoplasm

No. of cases

Non-Hodgkin's lymphoma Leukemia Acute lymphoblastic leukemia Acute leukemia Subacute lymphocytic leukemia Chronic lymphoblastic leukemia Hodgkin's disease Solid tumors Brain tumors Breast carcinoma Gastrointestinal Gastric carcinoma Ileal leiomyoma Pyloric carcinoma Rectal polyps Laryngeal carcinoma Liver carcinoma Ovarian tumor Dysgerminoma Fibroadenoma Gonadoblastoma Parotid carcinoma Skin tumor Basal cell carcinoma Epithelioma Uterine tumor Leiomyoma Leiomyosarcoma Total

49 20 4 1 2 12 3 1 7 1 1 2 1 2 3 1 1 1 3 1 2 1 119

ICR, ImmunodeficiencyCancer Registry.

ated solid tumor, the level of association was 1 of 49 (2%). Because only four of 27 leukemias had solid tumors, the level of association was four of 27 (15%). W h e n l y m p h o m a s and leukemias are considered together, five of 76 patients (19%) had solid tumors. Several salient facts emerge: 1) Hodgkin's disease in A-T is not associated with any other type of neoplasm; 2) leukemia/lymphoma in A-T is associated with

Table 8

Neoplasms in ataxiatelangiectasia patients by category of neoplasm Neoplasms

Category of neoplasm Non-Hodgkin's lymphomas Solid tumors Leukemias Hodgkin's disease Total

n(%) 49(41) 31(26) 27(23) 12(10) 119(100)

Cancer in Ataxia-Telangiectasia Patients

Table 9

15

Ataxia-telangiectasia patients with multiple neoplasms Subsequent neoplasms

First neoplasm ICR case no./sex 53/M 73/F 74/F 95/F 97/F 104/F

Age at diagnosis (yr,mo) 6 6 1,3 33,4 16,7 16,7 16,9 25,9

Age at diagnosis (yr,mo)

Neoplasm(s) Acute lymphoblastic leukemiaa Rectal polyp Epithelioma, foot Leiomyoma, uterus Dysgerminomaa Gonadoblastoma Carcinoma, parotid a Basal cell carcinomaa

27.9 45.5

23.3 30.4 31.4-31.9 31.4-31.9 31.4-31.9 31.4-31.9 31.4-31.9

Neoplasms

Subacute T-cell leukemiaa Chronic T-cell leukemiaa

B-cell lymphoma Chronic T-cell leukemia Rectal polyps Fibroadenoma, ovary Leiomyoma, uterus Leiomyoma, ileum Leiomyoma, uterus

aNeoplasmby which patient is listed in ImmunodeficiencyCancer Registry [59]. solid tumors; and 3) solid tumors are strongly associated in A-T with additional neoplasms. Of 26 patients with solid tumors, five had l e u k e m i a / l y m p h o m a and six had other solid tumors. Thus, of 26 patients with solid tumors, 11 (42%) had an associated neoplasm.

RISKS OF SUBSEQUENT NEOPLASMS IN ATAXIA-TELANGIECTASIA To determine the risks of a patient with one type of neoplasms to develop a subsequent neoplasm, an analysis is presented in Table 11. Hodgkin's disease carries no k n o w n risks in A-T of a subsequent neoplasm. Non-Hodgkin's l y m p h o m a and leukemia also carry very low risks of a subsequent neoplasm. This may reflect the grave problems encountered in treating non-Hodgkin's l y m p h o m a and leukemia in A-T because A-T patients are hypersensitive to radiation and chemotherapy [4, 5, 10, 11, 21, 37, 39, 57] and may not survive long enough to develop a subsequent neoplasm. The occurrence of a solid tumor in an A-T patient is a warning signal of more neoplasms to come. About one fourth of A-T patients with a solid tumor subsequently developed non-Hodgkin's l y m p h o m a or leukemia.

CONCLUSIONS The association between A-T and l y m p h o m a was first established, and that between A-T and leukemia was next established. Hodgkin's disease occurs in A-T patients, but Hodgkin's disease in A-T is not associated with any other form of neoplasia. It Table 10

Association of neoplasms in ataxia-telangiectasia Associated neoplasm

Type of neoplasm

n

Hodgkin n(%)

Hodgkin's disease Leukemia/lymphoma Solid tumor

12 76 26

(0) 0(0)

Leukemia/lymphoma n(%)

Solid tumor n(%)

0(0}

0(0) 5(19) 6(23)

5(19)

16

F. Hecht and B. K. Hecht Table 11

Risks of subsequent n e o p l a s m in ataxia-telangiectasia patients Risk of subsequent neoplasm

First neoplasm

n

Neoplasm n(%)

Malignancy n(%)

Hodgkin's disease Non-Hodgkin's lymphoma Leukemia Solid tumor

12 48 24 25

0(0) 0(0) 1(4) 6(24)

0(0) 0(0) 0(0) 6(24)

does not carry any k n o w n risk for a subsequent neoplasm and is not increased in frequency in A-T [59]. We conclude therefore that Hodgkin disease is not part of A-T. Solid tumors are comparatively c o m m o n in A-T. They are associated with other n e o p l a s m s in A-T and herald subsequent neoplasms that are malignant. Hence, we c o n c l u d e that solid tumors are a salient part of A-T. One w a y to regard the association between A-T and neoplasia is to imagine a single path [1-5, 13, 16, 17], w h i c h proceeds from the A-T gene to immunodeficiency and thence to neoplasia. Although this p a t h w a y may well exist, there may be another that is more direct. The A-T gene w o u l d act to make a cell neoplastic. In homozygotes, two A-T genes w o u l d m a r k e d l y elevate the risk of malignancy. The A-T gene in single copy w o u l d p r e d i s p o s e heterozygotes to solid forms of cancer [25, 29, and article by Swift et al. in this issue]. This concept might explain the risk of cancer in A~-T heterozygotes. The two patterns of malignancy in A-T might also be considered expressions of a single m e c h a n i s m . We are struck by the possible parallel to AIDS. Persons with h u m a n i m m u n o d e f i c i e n c y virus and m i l d immunodeficiency are p r e d i s p o s e d to Kaposi's sarcoma. In AIDS patients with profound immunodeficiency, pneumocystis carinii p n e u m o n i a tends to develop. Both patterns of malignancy in A-T may thus be discontinuous frames in a moving picture. All malignancies in A-T patients could reflect a unitary m e c h a n i s m of malignancy. The leading possibilities for a unified cause appear to include i m m u n o d e f i c i e n c y and retroviruses. This work was supported by Program Project from the National Cancer Institute (CA-41124) for research on Cancer Cytogenetics and by the Southwest Biomedical Research Institute. REFERENCES 1. Hecht F, Koler RD, Rigas DA, Dahnke GS, Case MP, Tisdale Y, Miller RW (1966}: Leukaemia and lymphocytes in ataxia-tel~ugiectasia. Lancet 2:1193. 2. Gatti RA, Berkel I, Boder E, Braedt G, Charmley P, Concannon P, Ersoy F, Foroud T, Jaspers NGJ, Lange K, Lathrop GM, Lappert M, Naakamura Y, O'Connell P, Paterson M, Salser W, Sanal O, Silver J, Sparkes RS, Susi E, Weeks DE, Wei S, White R, Yoder F (1988): Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature 336:577-580. 3. Hecht F, McCaw BK (1977): Chromosome instability syndromes. In: Genetics of Human Cancer, 1977. JJ Mulvihill, RW Miller, JF Fraumeni Jr, eds. Raven Press, New York, pp. 105-123. 4. Bridges BA, Harnden DG (1982}: Ataxia-Telangiectasia: A Cellular and Molecular Link between Cancer, Neuropatholo~, and Immune Deficiency. John Wiley & Sons, Chichester, UK. 5. Gatti RA, Swift M (1965): Ataxia-Telangiectasia: Genetics, Neuropathology, and Immunol-

C a n c e r in A t a x i a - T e l a n g i e c t a s i a Patients

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Cancer in ataxia-telangiectasia patients.

A gene locus for ataxia-telangiectasia (A-T) is in chromosome region 11q22 to 11q23 and predisposes to cancer. Ataxia-telangiectasia patients appear t...
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