Low penetrance cancer genes are worth searching for
Baker and Kaprio1 (BMJ of 13 May 2006) have given a serious critical analysis of the value of searching for low penetrance cancer susceptibility genes, and they conclude that the game is not worth the candle. I think this conclusion should not be allowed to go unchallenged.
In essence, all the points made in the paper can be rebutted.
1. Early changes in cancer may be in the stroma rather than in the parenchyma. Whether this is true or not (the authors themselves seem to have doubts), it is irrelevant: an inherited mutation could increase the risk of somatic mutation in either a stromal cell, or a parenchymal cell, or both.
2. Migration studies are obviously informative regarding environmental causes of cancer. They say nothing about whether, within a population, some individuals are at greater risk of cancer than others.
3. With respect to the evidence from identical twins, the argument is of a quantitative nature: a ‘small to moderate contribution’ is a contribution. Of course the inherited contribution observed in identical twins is supported by numerous other studies on the cancer risk in relatives of patients with cancer (see for instance 2 3). In standard oncology textbooks a family history is ranked as a high risk factor for prostate cancer and other cancers.
Baker and Raprio rightly express concern about the fact that finding low penetrance cancer susceptibility genes will be hard and expensive. However, this issue is of a different nature, and this is not the only case where setting priorities in research is complex, whether in the cancer field or in other areas. It is also important to note that genome wide high throughput studies are not the only approach: the discovery that TGFBR and HDM2 as low penetrance cancer susceptibility genes 4 5 are recent examples.
Finally, I must make a conceptual argument. Baker and Raprio do not question that ‘rare genes related to familial cancer’ do exist. These genes have, by definition, high penetrance: but still their penetrance is variable, ranging from about 85% (e.g. BRCA1, BRCA2) to about 30% (e.g. in ataxia-telangectasia). Considering this, it would be quite surprising if other genes with even lower penetrance (e.g., between 1 and 30%), did not exist. Of course it is impossible to predict whether and in what cases identifying such genes might have clinical implications (but see a recent compelling review regarding colon cancer6. It is certainly not impossible that, for instance, genes that cause a slightly increased rate of somatic mutation may be accessible to some form of chemo-prevention.
1. Baker SG, Kaprio J. Common susceptibility genes for cancer: search for the end of the rainbow. Bmj 2006;332(7550):1150-2.
2. Narod SA, Stiller C, Lenoir GM. An estimate of the heritable fraction of childhood cancer. Br J Cancer 1991;63(6):993-9.
3. Cannon-Albright LA, Thomas A, Goldgar DE, Gholami K, Rowe K, Jacobsen M, et al. Familiality of cancer in Utah. Cancer Res 1994;54(9):2378-85.
4. Pasche B, Kolachana P, Nafa K, Satagopan J, Chen YG, Lo RS, et al. TbetaR-I(6A) is a candidate tumor susceptibility allele. Cancer Res 1999;59(22):5678-82.
5. Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 2004;119(5):591-602.
6. de la Chapelle A. Genetic predisposition to colorectal cancer. Nature Reviews Cancer 2004;4(10):769-780.
Competing interests: No competing interests