Increased frequency of disease-causing MYH mutations in colon cancer families

Abstract

The genetic factors that cause clustering of colorectal cancers (CRCs) other than mutations in the mismatch repair (MMR) genes are not well understood. Clustering in families who lack MMR gene mutations may be attributable to low-penetrance mutations. Hypothetically, mono-allelic MYH mutations could contribute to the risk of CRC in these families. Using Fisher's exact test and logistic regression, we compared the frequency of the known disease-causing MYH mutations Y165C, G382D and 466delE in 137 probands (117 cases with CRC and 20 cases diagnosed on the basis of adenomatous polyps only) from families with three or more CRCs but negative for mutations in the MMR genes and in 967 healthy controls with comparable ethnic backgrounds. Of 137 cases, 6 (4.4%) carried mono-allelic MYH mutations compared with 16 of 967 (1.6%) controls. In addition, three bi-allelic MYH mutation carriers, who eventually developed MYH-associated polyposis, were also identified in families with pedigree structures consistent with dominant inheritance of CRC susceptibility. By Fisher's exact tests, there was a statistically different frequency of cases with any MYH mutation (mono- or bi-allelic carriers; P-value = 0.002) and of cases with mono-allelic MYH mutation (P = 0.04) compared with the controls. Using a logistic regression model, the unadjusted odds ratio associated with any MYH mutation was 4.14 (P-value < 0.001); for mono-allelic carriers, it was 2.79 (P-value = 0.04). Adjusting for ethnic backgrounds, gender and age, the odds ratio associated with any disease-causing MYH mutation was 3.23 (P-value = 0.01); for mono-allelic carriers, it was 1.99 (P-value = 0.20). Overall, the results support previous studies suggesting that mono-allelic mutations of MYH constitute low-penetrance CRC-causing alleles. These data further support a model in which low-penetrance alleles are enriched in MMR gene mutation-negative CRC families.

ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis)

“…The polyp burden of individuals affected with MAP is variable, and although the data are limited, current evidence suggests that biallelic mutations can be found in up to 30% of patients with 15-100 adenomas and in ~7% of patients with >100 adenomas. 3 Biallelic mutations have been identified in patients with no detectable polyposis.…”

“…3 Lynch syndrome and FAP have sometimes also been referred to as Gardner syndrome (FAP with extracolonic features), Muir-Torre syndrome (Lynch syndrome with sebaceous skin lesions), and Turcot syndrome (FAP with medulloblastomas or Lynch syndrome with glioblastomas). Clinical testing for these genes has progressed rapidly in the past few years with advances in technologies and the lower cost of reagents, especially for sequencing.…”

Heterogeneous molecular mechanisms underlie attenuated familial adenomatous polyposis

“…17 Moreover, both biallelic and monoallelic mutation carriers are more likely to have first and/or second-degree relatives with colorectal cancer compared with noncarriers. 29 These observations, as well as those reported on colon cancer families who lack mismatch repair gene defects, 30 suggest that MUTYH heterozygous mutations represent low-penetrance colorectal cancer-causing alleles. On the other hand, recently performed meta-analyses produced conflicting results, indicating both a nonsignificant relative risk of colorectal cancer 31,32 and a small but significantly increased risk of cancer 33 for monoallelic mutation carriers.…”

Targeting base excision repair to improve cancer therapies

“…The clinical finding of biallelic mutation has been confirmed by subsequent preclinical and clinical studies (Nielsen et al, 2005;Sieber et al, 2004;Tenesa et al, 2006) controls from Scotland, supported by a meta-analysis from published data on the association between mutations at MYH and colorectal cancer risk, has suggested that a small but significant mono-allelic effect may also exist (Farrington et al, 2005). Recent data suggest phenotypic similarities between colorectal cancers characterized by mismatch repair defects and those characterized by biallelic mutation of MYH (Aaltonen et al, 2007;Peterlongo et al, 2006). Other studies are emerging which associate mutations in hMYH with other human cancers such as gastric cancer (Zhang et al, 2006).…”