ORIGINAL CONTRIBUTION

Desmoids and Genotype in Familial Adenomatous Polyposis James Church, M.B.Ch.B. • Xhileta Xhaja, M.D. • Lisa LaGuardia, B.S.N Margaret O’Malley, B.A. • Carol Burke, M.D. • Matthew Kalady, M.D. Sanford R. Weiss Center, M.D., for Hereditary Colorectal Cancer, Department of Colorectal Surgery, Digestive Diseases Institute, Cleveland Clinic Foundation, Cleveland, Ohio

BACKGROUND:  Desmoid disease can be a serious, life-threatening complication of familial adenomatous polyposis. The ability to predict patients at increased desmoid risk is important, but a convincing genotypephenotype correlation for desmoid formation has not yet been described. PURPOSE:  The aim of this study is to assess the relationship between desmoid disease and genotype in patients with familial adenomatous polyposis. DESIGN:  This is a cohort study. PATIENTS:  All patients with familial adenomatous polyposis and a documented pathogenic APC mutation in themselves or a first-degree relative were selected. MAIN OUTCOMES MEASURES:  The comparison of genotype and the presence, stage, and site of desmoid disease are the primary end points of this study. RESULTS:  Three hundred twenty-three patients from 219 families were identified. Mutations spanned the length of the gene, from codon 213 to codon 2051. Desmoid disease was diagnosed in 77 patients from 68 families. Desmoid disease was found in 14.9% of patients with a mutation 5′ of codon 400, 23.2% of patients with a mutation from codon 401 to 1400, and in 37.1% of those with a mutation 3′ of 1400. All patients with 5′ mutations had stage I or II abdominal desmoid disease, and all tumors were stable or shrinking. Twelve percent Financial Disclosures: None reported. Poster presentation at the meeting of the International Society for Gastrointestinal Hereditary Tumors, San Antonio, TX, March 31 to April 2, 2011. Correspondence: James Church, M.B.Ch.B., 9500 Euclid Ave, A30, Cleveland, OH 44195. E-mail: [email protected] Dis Colon Rectum 2015; 58: 444–448 DOI: 10.1097/DCR.0000000000000316 © The ASCRS 2015

444

of patients who had desmoid disease with mutations between codons 400 and 1400 had stage III or IV desmoid disease, and 5 of 42 (12%) tumors were growing at the time of the study. There had been 2 desmoidrelated deaths. Almost half (44%) of patients who had desmoid disease with mutations 3′ of codon 1400 had stage III or IV disease. Three of 14 tumors were growing (21%), and there were 4 desmoid-related deaths. LIMITATIONS:  This study was conducted at a tertiary referral center, and there was no systematic surveillance for desmoids. CONCLUSION:  Desmoid disease occurs in patients who have familial adenomatous polyposis with almost any APC mutation, although there is an increased propensity in those with a 3′ mutation. The incidence and severity of the desmoid disease are related to the site of the mutation. KEY WORDS:  Desmoid; Familial adenomatous polyposis;

Genotype.

D

esmoid disease is an important part of the phenotype of familial adenomatous polyposis (FAP) and occurs in approximately 30% of patients affected with a germline APC mutation.1 A proliferation of fibroblasts forms sheet lesions and tumors within the abdomen, in the abdominal wall, and in extra-abdominal locations. The predominance of intra-abdominal tumors and the stimulating effect of surgery are among the phenotypic features that distinguish FAP-associated desmoid disease from sporadic desmoids. Intra-abdominal desmoids occur rarely in the general population, but they are the most common FAP-related desmoids. An important part of the biology of desmoid disease is the perturbation of the wnt/wingless signal transduction pathway leading to the accumulation of nuclear β-catenin and the inappropriate stimulation of downstream genes. In sporadic desmoids, this is often accomplished by a β-catenin gene Diseases of the Colon & Rectum Volume 58: 4 (2015)

445

Diseases of the Colon & Rectum Volume 58: 4 (2015)

(CTNNB1) mutation,2 whereas in FAP-associated desmoids it is the loss of function of APC.3 Patients with FAP are affected by a germline mutation in 1 allele of APC. Loss of the other allele by a sporadic genetic event (mutation or loss of heterozygosity) precipitates an FAP phenotype— polyps in the intestinal mucosa and desmoids in fibroaponeurotic tissue. Surgical trauma often precipitates the inactivation of the second allele within fibroaponeurotic tissue, explaining the frequent association of desmoid disease with surgery in FAP.1 Since exploration of genotype-phenotype associations in FAP was made possible by identification of APC as the gene responsible for the syndrome, there have been many studies describing a relationship between the site of the APC germline mutation and the risk of developing desmoid disease.4–13 Mutations 3′ of codon 1399, or 1444, have been strongly associated with desmoid disease. However, other, more comprehensive analyses have failed to show any association of genotype with incidence of desmoid disease,14–17 creating significant questions about the relationship. A genotype/phenotype association for desmoids would be clinically useful, because it would allow strategic changes in the timing and type of surgery that might minimize desmoid risk. We hypothesize that, instead of incidence, there is a relationship between the severity of the desmoid disease in FAP and genotype.

METHODS Our cohort included all patients with FAP with a known APC gene mutation. Patients were accessed from an institutional review board-approved database (Cologene) and were enrolled from the inception of the database in 1979 to this analysis, performed in 2010. APC sequencing was only possible from the mid-1990s and, at that time, was offered to patients and families with FAP. All patients signed a consent form at enrollment into the registry, and a waiver of consent was obtained for database studies using anonymized data without patient contact. APC genotype was obtained by clinical testing through a Clinical Laboratory Improvement Amendments–approved, commercial laboratory, after pretest counseling of the patient and family. Some patients had already been tested before referral to our registry. The genotypes are described according to the codon affected. Large deletions and mutations that could not be assigned a codon number

were not included in the analysis. For ease of comparison, mutations were divided into 3 groups according to their location: those 5′ of codon 400, those between codon 400 and codon 1399, and those located 3′ of codon 1399. Desmoid disease was diagnosed on the basis of clinical examination, imaging (MRI, and/or CT scans), or at surgery. Biopsies were not necessary for the diagnosis. Abdominal desmoid disease was staged according to a previously published and validated staging system (Table 1),18,19 and the most advanced stage was used in the analysis. The patient genotype was compared against the presence or absence of desmoid disease. The stage of desmoid disease was also analyzed according to the location of the germline mutation. Continuous data were described by using mean and standard deviation, or median and range, according to their distribution. Categorical data were described as numbers and percentages. The significance of differences between groups of categorical data was tested by using the χ2 or Fisher exact test, as appropriate.

RESULTS Three hundred twenty-three patients belonging to 219 families with a documented APC mutation who had the clinical phenotype of FAP were reviewed. Mutations spanned the length of the gene, from codon 213 to codon 2051 (Fig. 1). Desmoid disease was diagnosed in 77 (24%) patients from 68 (31%) families. These patients were compared with 246 patients from 151 families where there was no evidence of desmoids. Results of the comparison can be seen in Table 2. The frequency of 3′ mutations was significantly greater in patients (p = 0.017) and families (p = 0.027) with desmoid disease. Desmoid disease was found in 14.9% of patients with a mutation 5′ of codon 400, compared with 23.2% of patients with a mutation from 400 to 1399, and 37.1% of those with a mutation 3′ of 1400 (or 1399) (p < 0.05). From a family perspective, 17.6% of families with a 5′ mutation had desmoid disease, compared with 35.0% of families with a mutation between codon 400 and 1399, and 38.3% of families with 3′ mutations. The mild inconsistency between family and patient percentages is attributed to the fact that, in families with 5′ mutations, fewer patients were affected per family, ie, the desmoid phenotype was less penetrant.

Table 1.   A staging system for abdominal desmoids in familial adenomatous polyposis18 Parameter

Stage I

Stage II

Stage III

Size Symptoms Growth

Desmoids and genotype in familial adenomatous polyposis.

Desmoid disease can be a serious, life-threatening complication of familial adenomatous polyposis. The ability to predict patients at increased desmoi...
228KB Sizes 0 Downloads 9 Views