Germline mutations in APC and MUTYH are responsible for the majority of families with attenuated familial adenomatous polyposis

Abstract

A small fraction of families with familial adenomatous polyposis (FAP) display an attenuated form of FAP (AFAP). We aimed to assess the presence of germline mutations in the MUTYH and adenomatous polyposis coli (APC) genes in AFAP families and to compare the clinical features between the two causative genes. Families with clinical AFAP were selected from the Dutch Polyposis Registry according to the following criteria: (a) at least two patients with 10-99 adenomas diagnosed at age >30 years or (b) one patient with 10-99 adenomas at age >30 years and a first-degree relative with colorectal cancer (CRC) with a few adenomas, and, applying for both criteria, no family members with more than 100 polyps before the age of 30 years. All probands were screened for germline mutations in the APC and MUTYH genes. Twenty-five of 315 Dutch families with FAP (8%) met our criteria for AFAP. These families included 146 patients with adenomas and/or CRC. Germline APC mutations were identified in nine families and biallelic MUTYH mutations in another nine families. CRC was identified at a mean age of 54 years (range 24-83 years) in families with APC and at 50 years (range 39-70 years) in families with MUTYH (p = 0.29). APC and biallelic MUTYH mutations are responsible for the majority of AFAP families. Based on our results and those reported in the literature, we recommend colonoscopy once every 2 years in AFAP families, starting surveillance from the late teens in APC mutation carriers and from age 20-25 years in biallelic MUTYH mutation carriers.

Prospective comparison of family medical history with personal genome screening for risk assessment of common cancers

“…Participants' medical and family histories were then re-examined for evidence of hereditary risk. Hereditary risk was assigned if the subject or family met the Amsterdam II or Revised Bethesda Guidelines for Lynch syndrome; 20,21 or met accepted criteria for familial adenomatous polyposis or attenuated FAP, 22,23 MYH-associated polyposis, 24 juvenile polyposis syndrome, 25 or Peutz-Jeghers syndrome 18 (Supplementary Table 2). Research participants or family members who carry a known germline mutation in a colorectal cancer-predisposition gene were classified as hereditary risk.…”

Germline Genetics in Colorectal Cancer Susceptibility and Prognosis

“…Penetrance for cancer in bi-allelic mutation carriers is estimated to be 20% at 40 years and 43% at 50 years of age (Lubbe et al, 2009). Individuals typically present with 10-100 adenomatous polyps, although some bi-allelic mutation carriers do not have any polyps on screening Nielsen et al, 2007). Polyposis of the duodenum can also be observed.…”

“…Polyposis of the duodenum can also be observed. Between 24 and 56% of FAP and attenuated-FAP families lacking mutations in APC have been found to carry bi-allelic mutations in MUTYH, suggesting that mutations in the two genes account for a significant proportion of familial polyposis (Nielsen et al, 2007;Gomez-Fernandez et al, 2009). Two common MUTYH mutations comprising 80-85% of disease causing mutations in Caucasians of Northern European ancestry are Tyr179Cys and Gly396Asp (previously known as Y165C and G382D; Al-Tassan et al, 2002).…”

Genomic era diagnosis and management of hereditary and sporadic colon cancer

“…Clinical diagnosis of classic FAP is established when 100 or more colonic polyps are observed on colonoscopy, or less than 100 colonic polyps are observed in a patient with a family history of FAP [15] . A related syndrome, attenuated FAP, associates with a lower polyp burden (average of 30) and later age at diagnosis of CRC, though it is also caused by APC gene mutations [19] . Identification of a mutation in APC provides molecular confirmation of FAP.…”