© The Author 2006. Published by Oxford University Press.
CORRESPONDENCE |
RESPONSE: Re: IGF-1 Gene Polymorphism and Risk for Hereditary Nonpolyposis Colorectal Cancer
Affiliations of authors: The Lancet, New York, NY (MZ); Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX (CIA, MLF)
Correspondence to: Marsha L. Frazier, PhD, Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, 1155 Pressler Blvd., Unit 1365, Houston, TX 77030 (e-mail: mlfrazier{at}mdanderson.org).
Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder caused by DNA mismatch repair (MMR) gene mutations with hMLH1 and hMSH2 being the most frequently mutated (1). Reeves et al. have genotyped a series of MMR gene mutation carriers for a CA-repeat polymorphism in the 5' untranslated region of the insulin-like growth factor 1 (IGF-1) gene to determine whether findings from our recent study on this polymorphism were applicable to other populations. In our study, a group of 121 MMR gene mutation carriers for either MSH2 or MLH1 were genotyped for the IGF-1 gene polymorphism. We found a statistically significant association between shorter IGF-1 CA-repeat lengths and increased age-associated risk for HNPCC among the mutation carriers. When we stratified by MMR gene mutation, the association between HNPCC risk and IGF-1 CA-repeat length was statistically significant for MSH2 gene mutation carriers but not for MLH1 mutation carriers.
It is exciting that the work by Reeves et al. confirms the association between shorter IGF-1 gene CA-repeat lengths (
17) and earlier disease onset in their study of 220 MMR gene mutation carriers. It will be interesting to find out whether shorter IGF-1 gene CA-repeat lengths influence risk for other cancer types as well.
When Reeves et al. stratified by MMR gene mutation, they observed the opposite from what we reported—a statistically significant association between HNPCC risk and IGF-1 CA-repeat length for MLH1 gene mutation carriers but not for MSH2 mutation carriers. Although it is possible that differences between the findings of the studies may have been due to differences in environmental and genetic backgrounds between the two study populations, it is also likely that they are due to the small sample sizes of the study groups created after stratification for the underlying MMR gene mutations. However, because the Cox regression modeling of Reeves et al. suggested that it is the IGF-1 CA-repeat group that was associated with the risk for HNPCC development and not the MMR mutation type per se, we tend to favor the latter hypothesis. Larger studies are needed to determine whether the type of MMR gene that is mutated influences the effect of the IGF-1 CA-repeat polymorphism.
REFERENCES
(1) De la Chapelle A. Genetic predisposition to colorectal cancer. Nat Rev Cancer 2003;4:769–80.
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