Colorectal Cancer, Hereditary Nonpolyposis, Type 5

A number sign (#) is used with this entry because hereditary nonpolyposis colorectal cancer-5 (HNPCC5) is caused by heterozygous mutation in the MSH6 gene (600678) on chromosome 2p16.

Description

Hereditary nonpolyposis colorectal cancer type 5 is a cancer predisposition syndrome characterized by onset of colorectal cancer and/or extracolonic cancers, particularly endometrial cancer, usually in mid-adulthood. The disorder shows autosomal dominant inheritance with incomplete penetrance (summary by Castellsague et al., 2015).

For a phenotypic description and a discussion of genetic heterogeneity of hereditary nonpolyposis colorectal cancer (HNPCC), see HNPCC1 (120435).

Clinical Features

Miyaki et al. (1997) reported a family with HNPCC5. The proband had adult-onset colorectal carcinoma and endometrial carcinoma, and her sister had endometrial carcinoma. Other sisters who had had endometrial or ovarian carcinoma were assumed to have the same germline MSH6 mutation, as it was detected in their offspring. Although this family did not fulfill the Amsterdam criteria, patients in the family had colonic, endometrial, ovarian, and pancreatic carcinomas. Miyaki et al. (1997) considered it noteworthy that endometrial and ovarian carcinomas were predominant in this family.

Wijnen et al. (1999) found that atypical HNPCC families with MSH6 mutations displayed a very high frequency of atypical hyperplastic lesions and carcinomas of the endometrium: 73% in female MSH6 mutation carriers compared with 29% in MSH2 and 31% in MLH1 carriers. Moreover, delayed age of cancer onset and incomplete penetrance were characteristic clinical features of the MSH6 mutation carriers. The results indicated that tumors of the endometrium (608089) represent the most common clinical manifestation of HNPCC among female MSH6 mutation carriers and that colorectal cancer cannot be considered an obligatory requisite to define HNPCC.

Wagner et al. (2001) found that colorectal cancer was significantly decreased in a large Dutch family with atypical HNPCC and an MSH6 mutation compared to families with mutations in MSH2 (609309) or MLH1 (120436) (p less than 0.001). Endometrial cancer was frequent among female mutation carriers (6 of 13 malignant tumors), and transitional cell carcinoma of the urinary tract was present in 10% of male and female carriers. The mean age of onset of colorectal and endometrial cancer was delayed compared to that in families with MSH2 or MLH1 mutations.

Suchy et al. (2002) described a Polish MSH6 family in which a late-onset endometrial type of ovarian cancer was a feature. In the proband, bilateral ovarian cancer was discovered at the age of 49 years. The father died of colon cancer at the age of 83 years and her paternal grandmother died of endometrial cancer at the age of 69 years. Endometrial cancer was diagnosed at the age of 57 years in a cousin. Ovarian cancer had been reported in an MSH6 family by Wagner et al. (2001).

In a retrospective U.S. population-based study, Kastrinos et al. (2009) found 3 cases of pancreatic cancer among 11 families with MSH6 mutations. Although the numbers were too small to calculate a risk estimate, the authors concluded that pancreatic cancer is a component of HNPCC.

Castellsague et al. (2015) reported 11 families of French Canadian descent from Quebec with HNPCC5. The average age at diagnosis was 44.2 years, and tumors fell within the HNPCC spectrum, but included mainly colorectal and endometrial cancer. Other rare tumors included breast cancer, cervical cancer, ovarian cancer, stomach cancer, and non-Hodgkin lymphoma. Among all families, 8 (73%) of 11 affected carrier females had endometrial cancer, suggesting that this is a typical presenting MSH6-related cancer in women.

Diagnosis

Wijnen et al. (1999) found that 7 of 10 germline mutations in MSH6 had been identified in atypical HNPCC families not fulfilling the Amsterdam criteria.

Among 33 cancer families with proven mutations in the MSH6 gene, Sjursen et al. (2010) found that the sensitivity for diagnostic criteria using the original Amsterdam guidelines, the revised Amsterdam guidelines, and the Bethesda II guidelines were inadequate for detecting potential MSH6 mutation carriers. The sensitivities using these guidelines were less than 50%. Sjursen et al. (2010) suggested that MSH6 mutations may be more common than currently assumed.

Inheritance

Buttin et al. (2004) studied the penetrance and expressivity of MSH6 mutations in kindreds ascertained through endometrial cancer probands unselected for family history. MSH6 mutation status was determined for 59 family members. Of these 59 individuals, 19 (32%) had confirmed cancers or precancers. There was an excess of mutation carriers among the 19 affected family members (11/19, 58%) compared with those among the 40 unaffecteds (8/40, 20%), giving an odds ratio of 5.5. Overall estimated penetrance of the MSH6 mutations was 57.7%.

The transmission pattern of HNPCC5 in the families reported by Castellsague et al. (2015) was consistent with autosomal dominant inheritance and incomplete penetrance.

Molecular Genetics

In the HCT-15 colorectal cancer cell line, Papadopoulos et al. (1995) identified a truncating mutation in the MSH6 gene (600678.0001).

In an HNPCC5 family, Miyaki et al. (1997) identified a heterozygous germline truncating mutation in the MSH6 gene (600678.0004). In addition to the germline mutation, somatic mutations of MSH6 were detected in colorectal and endometrial carcinomas from the proband in this family. These somatic mutations were presumably in the alleles without the germline mutation, suggesting that inactivation of both alleles of MSH6 was the cause of the phenotype and the stimulus for neoplasia.

In 11 probands of French Canadian descent in the Province of Quebec with HNPCC5, Castellsague et al. (2015) identified a heterozygous nonsense mutation in the MSH6 gene (Q4X; 600678.0018). Analysis of 27 additional family members indicated that the mutation cosegregated with cancer in 15 of 23 carriers, consistent with incomplete penetrance. Heterozygous carriers had an average age of cancer diagnosis at 44.2 years; 1 homozygous carrier had onset at age 10 years. All evaluable tumors showed loss of MSH6 protein and microsatellite instability (MSI); no loss of heterozygosity (LOH) was identified in any of the evaluated tumors, but the authors suggested that the gene was likely inactivated by point mutations or deletions. Analysis of this mutation among a larger population-based cohort of French Canadians showed that only 1 of 187 patients with colorectal cancer had the mutation, whereas 7 of 381 patients with endometrial cancer carried the mutation, yielding an odds ratio (OR) of 7.5 (p less than 0.0001).

Population Genetics

In the French Canadian population in Quebec, Castellsague et al. (2015) found evidence of a founder effect of the Q4X MSH6 mutation (600678.0018). Haplotype analysis estimated that the mutation occurred about 513 years ago. The carrier rate in this population was estimated at about 1 in 400.