Carcinogenesis Advance Access published online on June 14, 2006
Carcinogenesis, doi:10.1093/carcin/bgl093
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1 Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Present address. IFOM, Istituto FIRC di Oncologia Molecolare, Milan, Italy
* To whom correspondence should be addressed. The genetic factors that cause clustering of colorectal cancers (CRCs) other than mutations in the mismatch repair genes are not well understood. Clustering in families who lack mismatch repair gene mutations may be attributable to low-penetrance mutations. Hypothetically, mono-allelic MYH mutations could contribute to the risk of colorectal cancer (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 mismatch repair genes and in 967 healthy controls with comparable ethnic backgrounds. Six of 137 (4.4%) cases carried mono-allelic MYH mutations compared to 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 to 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 mismatch repair gene mutation-negative CRC families.
Received January 31, 2006
Revised April 28, 2006
Accepted May 24, 2006
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Increased frequency of disease-causing MYH mutations in colon cancer families
Paolo Peterlongo 1,
Nandita Mitra 2,
Ana Sanchez de Abajo 3,
Miguel de la Hoya 3,
Chiara Bassi 4,
Lucio Bertario 5,
Paolo Radice 6,
Emily Glogowski 7,
Khedoudja Nafa 8,
Trinidad Caldes 3,
Kenneth Offit 7,
and
Nathan A. Ellis 9 *
2 Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA
3 Molecular Oncology Laboratory, Hospital Clinico San Carlos, Madrid, Spain
4 IFOM, Istituto FIRC di Oncologia Molecolare, Milan, Italy
5 Department of Predictive and Preventive Medicine, Istituto Nazionale Tumori, Milan, Italy
6 IFOM, Istituto FIRC di Oncologia Molecolare, Milan, Italy; Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy
7 Clinical Genetic Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
8 Clinical Genetic Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Present address. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
9 Gastroenterology Section, University of Chicago, Chicago, IL, USA
Nathan A. Ellis, E-mail: nellis{at}medicine.bsd.uchicago.edu
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