© 2005 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Association Between Biallelic and Monoallelic Germline MYH Gene Mutations and Colorectal Cancer Risk
Affiliations of authors: Samuel Lunenfeld Research Institute (MEC, SPC, MM, JK, RG, SG) and Department of Surgery (RG, SG), Mount Sinai Hospital, Toronto, ON, Canada; Ontario Familial Colorectal Cancer Registry, Cancer Care Ontario, Toronto, ON, Canada (MM, MC, JK, SG)
Correspondence to: Steven Gallinger, MD, MSc, FRCS, Rm. 1225, Mount S inai Hospital, 600 University Ave., Toronto, ON, Canada M5G 1X5 (e-mail: sgallinger{at}mtsinai.on.ca).
Dominant and recessive transmission applies to traits or phenotypes and not to genes themselves. A good example of this terminology is sickle cell disease: homozygous carriers have the disease and heterozygous carriers have the sickle cell trait, a milder phenotype of the disease (1,2). It is, of course, true that published reports to date clearly support a recessive mode of inheritance for MYH-associated polyposis, a phenotype associated with biallelic mutations in MYH (3,4). We decided a priori to examine the incidence of MYH gene mutations as a way to validate the association between biallelic MYH gene mutations and colorectal cancer risk in a large North American population-based case–control series and to analyze the risk of colorectal cancer associated with the heterozygous state.
Although Tenesa et al. used Fisher's exact test to demonstrate, as have we, that biallelic mutations were more common in the colorectal cancer case patients than in the control subjects, their results failed to adequately support their argument that heterozygous carriers had no increased risk of colorectal cancer. We found a non–statistically significant increased risk of colorectal cancer among MYH heterozygotes (odds ratio = 1.4; 95% confidence interval = 0.8 to 2.5) (5). However, our study was inadequately powered to rule out this level of risk. Furthermore, by using the pooled cumulative MYH genotype data available from the literature, we demonstrated a convincing association between mild increased colorectal cancer risk and heterozygous MYH mutations, and although this observation has now been corroborated by another group (6), the need for larger studies to address this issue is obvious.
Our results suggested a statistically significant increased risk of colorectal cancer in first- and second-degree family members of both monoallelic MYH mutation carriers and in all mutation carriers. We disagree with Tenesa et al., who suggest that a purely recessive model is the only possible explanation for this result and continue to assert that the result we obtained by Poisson regression (relative risk = 1.57, 95% confidence interval = 1.05 to 2.36) provides additional evidence for increased colorectal cancer risk in monoallelic carriers. Given the frequency of MYH mutations in the general population and in the absence of consanguinity, we feel we can safely assume that the observed increased risk in family members is due to monoallelic carriers of the mutation present in the proband. Similarly, for biallelic carriers, 25% of siblings of the proband would be expected to carry biallelic mutations, whereas 50% of siblings as well as other first-degree relatives would be expected to carry monoallelic mutations. Thus, the magnitude of this association is too strong to be fully explained by a purely recessive model, and the increased risk must be due to monoallelic carriers.
The purpose of our loss of heterozygosity (LOH) experiments was to examine whether the modest increased risk of colorectal cancer in heterozygous MYH mutation carriers was consistent with Knudson's "two-hit" tumorigenesis model (7). We agree with Tenesa et al. about the variability of published allelotype data, not only for chromosome 1p, but for many chromosomal loci in many tumor types. We confirmed our microsatellite marker LOH results by analyzing the autoradiographic densities corresponding to wild-type and mutant nucleotides (data not shown) and found no internal variability in our results.
The critical difference between different modes of inheritance relies on whether a phenotype is present in heterozygous carriers. In conclusion, our MYH gene mutation case–control frequency data, results of Poisson regression analyses, and LOH data and phenotypic observations, as well as results of pooled analyses by us and by Peterlongo et al. (6), suggest that an increased risk of colorectal cancer conferred by the heterozygous state cannot be ruled out. Homozygous MYH gene mutation carriers are obviously at much greater risk for colorectal cancer than heterozygotes and, as we state in our article, studies with larger sample sizes are clearly necessary to accurately quantify risk of colorectal cancer in heterozygotes.
REFERENCES
(1) Strachan T, Read AP. Human Molecular Genetics 2. New York (NY): John Wiley; 1999.
(2) Wilkie AO. The molecular basis of genetic dominance. J Med Genet 1994;31:89–98.
(3) Sieber OM, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Phillips RK, et al. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 2003;348:791–9.
(4) Sampson JR, Dolwani S, Jones S, Eccles D, Ellis A, Evans DG, et al. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 2003;362:39–41.[CrossRef][Web of Science][Medline]
(5) 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;96:1631–4.
(6) Peterlongo P, Mitra N, Chuai S, Kirchhoff T, Palmer C, Huang H, et al. Colorectal cancer risk in individuals with biallelic or monoallelic mutations of MYH. Int J Cancer. 2004 Dec 1; [Epub ahead of print]; DOI 10.1002/ijc.20767.
(7) Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 1971;68:820–3.
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J Natl Cancer Inst 2005 97: 320-321.
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