Affiliations of authors: Colon Cancer Genetics Group, University of Edinburgh, and MRC Human Genetics Unit, Western General Hospital, Edinburgh
Correspondence to: Albert Tenesa, BSc, School of Molecular and Clinical Medicine, The University of Edinburgh, Colon Cancer Genetics Group, 14th Floor, MRC Human Genetics Unit, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK (email: albert.tenesa{at}ed.ac.uk).
We read with interest the paper by Croitoru et al. (1), in which they examined the role of germline MYH gene mutations in colorectal cancer and proposed an autosomal dominant weakly penetrant mode of inheritance. Previous evidence has suggested a recessive mode of inheritance for colorectal polyposis (2). Hence, the novel proposal by Croitoru et al. would be of major clinical and scientific importance and must be fully justified by the data. We have major concerns about their findings and respectfully refute their interpretation of their data.
The authors compared case patients and control subjects with no MYH gene mutations (genotype Wt/Wt) with case patients and control subjects with either one (genotype Wt/Mut) or two (genotype Mut/Mut) MYH gene mutations. However, the authors' data do not support a dominant mode of inheritance. Individuals with a Wt/Mut genotype had no statistically significant excess colorectal cancer risk compared with those with a Wt/Wt genotype (odds ratio = 1.4; 95% confidence interval = 0.8 to 2.5) (1). Therefore, the authors' decision to pool Wt/Mut individuals with homozygous Mut/Mut case patients for their analyses is not justified. Table 1 summarizes the authors' data from Table 1 (1). We used these data and Fisher's exact test to examine associations between the frequency of germline MYH gene mutations and colorectal cancer risk among case patients and control subjects with different MYH genotypes. Our resultsP = .25 for Wt/Wt versus Wt/Mut, P = 2.1 x 104 for Wt/Wt versus Mut/Mut, and P = 5.3 x 103 for Wt/Mut versus Mut/Mutsuggest that only a recessive model of inheritance is tenable. Thus, the only valid pooling strategy supported by the authors' data is to pool individuals with Wt/Mut and Wt/Wt genotypes (i.e., assume a recessive mode of inheritance).
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Croitoru et al. (1) also presented loss of heterozygosity (LOH) data for tumors from Wt/Mut and Mut/Mut case patients. However, LOH at chromosome 1p in tumors is highly variable and subject to confounding. Thorstensen et al. (3) detected LOH in chromosome 1p in 50% of primary carcinomas, 33% of local recurrences, and 64% of metastases from colorectal cancer patients, whereas Ogunbiyi et al. (4) and Zhou et al. (5) detected LOH in chromosome 1p in 26% and 22% of colorectal cancers, respectively. Rashid et al. (6) found that LOH in chromosome 1p varied with the anatomic location of hyperplastic polyps. Given such variability and the small numbers presented by Croitoru et al. and the fact that their samples were not matched for confounding variables, the difference in LOH frequency at chromosome 1p is best explained by chance.
REFERENCES
(1) Croitoru ME, Cleary SP, Di Nicola N, Manno M, Selander T, Aronson M, et al. Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk. J Natl Cancer Inst 2004;96:16314.
(2) Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingston AL, Williams GT, et al. Inherited variants of MYH associated with somatic G:CT:A mutations in colorectal tumors. Nat Genet 2002;30:22732.[CrossRef][ISI][Medline]
(3) Thorstensen L, Qvist H, Heim S, Liefers GJ, Nesland JM, Giercksky KE, et al. Evaluation of 1p losses in primary carcinomas, local recurrences and peripheral metastases from colorectal cancer patients. Neoplasia 2000;2:51422.[CrossRef][ISI][Medline]
(4) Ogunbiyi OA, Goodfellow PJ, Gagliardi G, Swanson PE, Birnbaum EH, Fleshman JW, et al. Prognostic value of chromosome 1p allelic loss in colon cancer. Gastroenterology 1997;113:7616.[ISI][Medline]
(5) Zhou CZ, Qiu GQ, Zhang F, He L, Peng ZH. Loss of heterozygosity on chromosome 1 in sporadic colorectal carcinoma. World J Gastroenterol 2004;10:14315.[Medline]
(6) Rashid A, Houlihan PS, Booker S, Petersen GM, Giardiello FM, Hamilton SR. Phenotypic and molecular characteristics of hyperplastic polyposis. Gastroenterology 2000;119:32332.[ISI][Medline]
Response to this Correspondence
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