Familial Adenomatous Polyposis 3

A number sign (#) is used with this entry because of evidence that familial adenomatous polyposis-3 (FAP3) is caused by homozygous or compound heterozygous mutation in the NTHL1 gene (602656) on chromosome 16p13.

Description

Familial adenomatous polyposis-3 is an autosomal recessive cancer predisposition syndrome characterized by the development of multiple colonic adenomas, often with progression to colorectal cancer. Carcinomas affecting other tissues may also occur, and the carcinomas tend to develop in middle age or late adulthood (summary by Weren et al., 2015).

For a discussion of genetic heterogeneity of familial adenomatous polyposis, see FAP1 (175100).

Clinical Features

Weren et al. (2015) reported 3 unrelated families in which a total of 7 individuals had multiple colonic adenomas (range, 8-50 adenomas). Four patients developed colorectal cancer. All 3 women had either endometrial hyperplasia or endometrial cancer. Additional more variable findings in these patients included duodenal adenomas, duodenal cancer, prostate cancer, psammomatous meningioma, basal cell carcinoma, breast cancer, pancreatic cancer, and non-Hodgkin lymphoma, most of which were found in 1 patient each.

Rivera et al. (2015) reported a woman of German ancestry who developed colonic adenocarcinoma arising in a villotubular adenoma at age 41, and was later found to have multiple additional extracolonic neoplasms, including bladder carcinoma, intradermal nevi, meningioma, multiple seborrheic keratoses, basal cell carcinoma, multiple colorectal adenomas, squamous cell carcinoma, and invasive ductal breast carcinoma. She died of an unrelated cause at age 59 years. She also had a family history of cancer. Rivera et al. (2015) noted that 6 of the 7 patients reported by Weren et al. (2015) had a diagnosis of multiple primary tumors, suggesting that NTHL1 mutations can cause a wide variety of cancers in addition to colorectal cancer. Rivera et al. (2015) suggested the designation 'NTHL1 syndrome' for this cancer predisposition syndrome.

Inheritance

The transmission pattern of FAP3 in the families reported by Weren et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 7 affected individuals from 3 unrelated families with familial adenomatous polyposis, Weren et al. (2015) identified a homozygous truncating mutation in the NTHL1 gene (Q90X; 602656.0001), which is a base excision repair gene. The mutation was found by whole-exome sequencing of 51 patients from 48 families with a predisposition to colonic adenomatous polyposis, and was confirmed by Sanger sequencing to segregate with the disorder in the 3 families. A heterozygous Q90X mutation was found at a frequency of 0.0036 among 2,329 controls and of 0.0015 in the ExAC database; the highest prevalence of the mutation was found in individuals of European descent. Analysis of patient cells showed that the mutation resulted in nonsense-mediated mRNA decay, consistent with a loss of function. Genetic analysis of 3 carcinomas and 5 adenomas from different patients homozygous for Q90X showed a nonhypermutated profile enriched for C-to-T transitions, and the carcinomas carried somatic mutations in several genes, including APC (611731), TP53 (191170), KRAS (190070), and PIK3CA (171834).

In a German woman with FAP3 and multiple additional extracolonic neoplasms, Rivera et al. (2015) identified compound heterozygous mutations in the NTHL1 gene (602656.0001 and 602656.0002). Six different tumors from the proband were found to carry somatic mutations in driver genes, such as FGFR3 (134934).