Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in APC mutation carriers.

Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with <100 colorectal adenomas versus patients with ≥100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.

Is colorectal surveillance indicated in patients with PTEN mutations?

AIM: Patients with germline phosphatase and tensin homologue (PTEN) mutations develop hamartomatous lesions in several organs and are at increased risk of various malignancies. We assessed the lifetime risk of benign and malignant gastrointestinal lesions in patients with a proven PTEN mutation. METHOD: Data on gender, mutation, dates of birth, last contact, and diagnosis, location and type of gastrointestinal lesions were collected from nine countries. The lifetime risk of gastrointestinal lesions was calculated by Kaplan-Meier methods. RESULTS: A total of 156 patients (67 men, 43%) from 101 families with a PTEN mutation were included. Patients were born between 1928 and 2008. Benign gastrointestinal polyps were reported in 49 (31%) patients at a mean age of 38 years (range 18-62 years) and were most often hamartomas. Twenty-two (44%) patients had upper as well as lower gastrointestinal lesions, 14 (29%) had only colonic lesions and 13 (27%) had gastrointestinal lesions at unknown sites. The cumulative risk of developing benign gastrointestinal polyps was 70% at age 60. Four patients (two men) developed colorectal carcinoma at 53, 57, 59 and 62 years, respectively. The cumulative risk of developing colorectal carcinoma was 18% at age 60. Except for one carcinoid in the small intestine, no upper gastrointestinal cancers were observed. CONCLUSION: Benign gastrointestinal lesions are common in PTEN mutation carriers, and a three- to four-fold increased lifetime risk of colorectal cancer compared with the general population may exist. Colorectal screening of patients with germline PTEN mutations is recommended, starting at age 40 years.

Evidence for accelerated colorectal adenoma--carcinoma progression in MUTYH-associated polyposis?

BACKGROUND AND AIM: MUTYH-associated polyposis (MAP) is an autosomal recessive inherited disorder characterised by the development of polyposis in the upper and lower gastrointestinal tract and a high risk of colorectal cancer (CRC). We evaluated the natural history of the disease and the outcome of colorectal surveillance and management. METHODS: A large Western European dataset of biallelic MUTYH mutation carriers comprising 254 patients was used. Detailed information was collected on polyp and cancer development in the colorectum, and the outcome of surveillance and surgery. Survival methods were used to calculate the risk of CRC development. RESULTS: The mean follow-up was 9.8 years. Colorectal polyposis was diagnosed at a mean age of 44.8 years (range: 12-77 years). Most patients had <100 colorectal adenomas at diagnosis. CRC was diagnosed in 147 (58%) of the 254 patients (mean age at diagnosis: 48.5, range: 21-77 years). The cumulative lifetime risk of CRC was 63% at age 60 years. There was no correlation between the number of adenomas and the presence of CRC. The cumulative risk of CRC in patients presenting with polyps was 9% after 5 years of follow-up. Patients presenting with CRC had 11% risk of developing a metachronous CRC at 5 years after surgery. Thirty-seven per cent of patients with MAP with CRC who underwent partial colonic resection needed secondary surgery shortly afterwards. CONCLUSIONS: The high risk of developing CRC under surveillance in patients with MAP may suggest an accelerated carcinogenesis. Surveillance of these patients should therefore include colonoscopy at short intervals, for example, at 1-2-year intervals starting from the age of 18 to 20 years. If surgery for CRC is warranted, a (sub)total colectomy is recommended.

Evaluation of management of desmoid tumours associated with familial adenomatous polyposis in Dutch patients.

BACKGROUND: The optimal treatment of desmoid tumours is controversial. We evaluated desmoid management in Dutch familial adenomatous polyposis (FAP) patients. METHODS: Seventy-eight FAP patients with desmoids were identified from the Dutch Polyposis Registry. Data on desmoid morphology, management, and outcome were analysed retrospectively. Progression-free survival (PFS) rates and final outcome were compared for surgical vs non-surgical treatment, for intra-abdominal and extra-abdominal desmoids separately. Also, pharmacological treatment was evaluated for all desmoids. RESULTS: Median follow-up was 8 years. For intra-abdominal desmoids (n=62), PFS rates at 10 years of follow-up were comparable after surgical and non-surgical treatment (33% and 49%, respectively, P=0.163). None of these desmoids could be removed entirely. Eventually, one fifth died from desmoid disease. Most extra-abdominal and abdominal wall desmoids were treated surgically with a PFS rate of 63% and no deaths from desmoid disease. Comparison between NSAID and anti-estrogen treatment showed comparable outcomes. Four of the 10 patients who received chemotherapy had stabilisation of tumour growth, all after doxorubicin combination therapy. CONCLUSION: For intra-abdominal desmoids, a conservative approach and surgery showed comparable outcomes. For extra-abdominal and abdominal wall desmoids, surgery seemed appropriate. Different pharmacological therapies showed comparable outcomes. If chemotherapy was given for progressively growing intra-abdominal desmoids, most favourable outcomes occurred after combinations including doxorubicin.

Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature.

Mutations in the adenomatous polyposis coli (APC) gene cause familial adenomatous polyposis (FAP). Disease severity and the presence of extracolonic manifestations seem to be correlated with the location of the mutation on the APC gene. In this review, large studies describing genotype-phenotype correlations in FAP were evaluated and categorized. Attenuated FAP (AFAP, <100 colorectal adenomas) is correlated with mutations before codon 157, after codon 1595 and in the alternatively spliced region of exon 9. Severe polyposis (>1000 adenomas) is found in patients with mutations between codons 1250 and 1464. Mutations in the remainder of the APC gene cause an intermediate phenotype (hundred to thousands of adenomas). Congenital hypertrophy of the retinal pigment epithelium (CHRPE) and desmoid tumours are associated with mutations between codons 311 and 1444 and after codon 1444, respectively. No consistent correlations were found for upper gastrointestinal tumours. Genotype-phenotype correlations in FAP will be useful in decisions concerning screening and surgical management of FAP.