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

Paolo Peterlongo, Nandita Mitra, Ana Sanchez de Abajo, Miguel de la Hoya, Chiara Bassi, Lucio Bertario, Paolo Radice, Emily Glogowski, Khedoudja Nafa, Trinidad Caldes, Kenneth Offit, Nathan Ellis

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2243-2249
Number of pages7
JournalCarcinogenesis
Volume27
Issue number11
DOIs
StatePublished - Nov 15 2006
Externally publishedYes

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Colonic Neoplasms
Mutation
Colorectal Neoplasms
DNA Mismatch Repair
Penetrance
Logistic Models
Genes
Cluster Analysis
Alleles
Odds Ratio
Adenomatous Polyps
Pedigree

ASJC Scopus subject areas

  • Cancer Research

Cite this

Peterlongo, P., Mitra, N., de Abajo, A. S., de la Hoya, M., Bassi, C., Bertario, L., ... Ellis, N. (2006). Increased frequency of disease-causing MYH mutations in colon cancer families. Carcinogenesis, 27(11), 2243-2249. https://doi.org/10.1093/carcin/bgl093

Increased frequency of disease-causing MYH mutations in colon cancer families. / Peterlongo, Paolo; Mitra, Nandita; de Abajo, Ana Sanchez; de la Hoya, Miguel; Bassi, Chiara; Bertario, Lucio; Radice, Paolo; Glogowski, Emily; Nafa, Khedoudja; Caldes, Trinidad; Offit, Kenneth; Ellis, Nathan.

In: Carcinogenesis, Vol. 27, No. 11, 15.11.2006, p. 2243-2249.

Research output: Contribution to journalArticle

Peterlongo, P, Mitra, N, de Abajo, AS, de la Hoya, M, Bassi, C, Bertario, L, Radice, P, Glogowski, E, Nafa, K, Caldes, T, Offit, K & Ellis, N 2006, 'Increased frequency of disease-causing MYH mutations in colon cancer families', Carcinogenesis, vol. 27, no. 11, pp. 2243-2249. https://doi.org/10.1093/carcin/bgl093
Peterlongo P, Mitra N, de Abajo AS, de la Hoya M, Bassi C, Bertario L et al. Increased frequency of disease-causing MYH mutations in colon cancer families. Carcinogenesis. 2006 Nov 15;27(11):2243-2249. https://doi.org/10.1093/carcin/bgl093
Peterlongo, Paolo ; Mitra, Nandita ; de Abajo, Ana Sanchez ; de la Hoya, Miguel ; Bassi, Chiara ; Bertario, Lucio ; Radice, Paolo ; Glogowski, Emily ; Nafa, Khedoudja ; Caldes, Trinidad ; Offit, Kenneth ; Ellis, Nathan. / Increased frequency of disease-causing MYH mutations in colon cancer families. In: Carcinogenesis. 2006 ; Vol. 27, No. 11. pp. 2243-2249.
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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.",
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