© The Author 2007. Published by Oxford University Press.
CORRESPONDENCE |
Re: Commonly Studied Single-Nucleotide Polymorphisms and Breast Cancer: Results From the Breast Cancer Association Consortium
Correspondence to: Stuart G. Baker, ScD, Biometry Research Group, National Cancer Institute, EPN 3131, 6130 Executive Blvd, MSC 7354, Bethesda, MD 20892-7354 (e-mail: sb16i{at}nih.gov).
The Breast Cancer Association Consortium did a remarkable job of pooling data from various studies to investigate the association of 16 single-nucleotide polymorphisms (SNPs) and breast cancer (1). The result was no association between the 16 SNPs and cancer after an adjustment for the type I error with 16 tests (2), although one could argue for a much more stringent adjustment based on the type I error needed for a low false-positive report probability (3,4).
Two competing conclusions can be drawn. One is that methods building on this approach should be applied to more genes and that it is only a matter of time before a confirmed discovery of a true association will be made. The opposite conclusion is that the results of no association support other evidence of very weak or no association between common genetic variants and cancer (4), including 1) studies showing that many cancers arise from defects in communication between stromal and parenchymal cells (5), rather than mutations in parenchymal cells; 2) migration studies that find that populations moving from one country to another generally experience the cancer rates of the new country within a generation or two (6), which is too soon to be the result of an inherited genetic mutation; and 3) a twin study showing that genetic contributions to common cancers are small and likely arise from rare mutations, not commonly occurring gene variants such as SNPs (7).
If the first conclusion is drawn and larger gene–cancer association studies are undertaken, an important consideration is how small a relative risk would be worthwhile (in terms of net health benefit) to detect. To put this question in perspective, one needs to consider the sequence of events leading to a worthwhile clinical benefit: 1) the genetic variant must suggest a modifiable risk factor; 2) an intervention must be developed or identified based on this modifiable risk factor; 3) the intervention must be tested in an extremely large randomized cancer prevention trial; and 4) there must be no side effects whose harms would outweigh the small benefits. It is important to realize that larger gene–cancer association studies to detect smaller relative risks yield diminishing net returns due to the larger cost of the gene identification study, larger cost of the resulting cancer prevention trial, and smaller future clinical benefits compared to potential harms.
REFERENCES
(1) The Breast Cancer Association Consortium. (2006) Commonly studied single-nucleotide polymorphisms and breast cancer: results from the breast cancer association consortium. J Natl Cancer Inst 98:1382–96.
(2) Ioannidis JPA. (2006) Common genetic variants for breast cancer: 32 largely refuted candidates and larger prospects. J Natl Cancer Inst 98:1350–53.
(3) Colhoun HM, McKeigue PM, Smith GS. (2003) Problems of reporting genetic associations with complex outcomes. Lancet 361:865–72.[CrossRef][Web of Science][Medline]
(4) Baker SG and Kaprio J. (2006) Common susceptibility genes for cancer: search for the end of the rainbow. Br Med J 332:1150–2.
(5) Soto AM and Sonnenschein C. (2004) The somatic mutation theory of cancer: growing problems with the paradigm? Bioessays 26:1097–107.[CrossRef][Web of Science][Medline]
(6) Ziegler RG, Hoover RN, Pike MC, Hildesheim A, Nomura AMY, West DW, et al. (1993) Migration patterns and breast cancer risk in Asian-American women. J Natl Cancer Inst 85:1819–27.
(7) Baker SG, Lichtenstein P, Kaprio J, Holms N. (2005) Genetic susceptibility to prostate, breast and colorectal cancer among Nordic twins. Biometrics 61:55–63.[CrossRef][Web of Science][Medline]
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