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Analysis And Comment Cancer genetics

Common susceptibility genes for cancer: search for the end of the rainbow

BMJ 2006; 332 doi: https://doi.org/10.1136/bmj.332.7550.1150 (Published 11 May 2006) Cite this as: BMJ 2006;332:1150

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Response to letter by Professor Luzzatto regarding “Common susceptibility genes for cancer: search for the end of the rainbow”

We thank Professor Luzzatto for the letter

1. Based on the studies we had cited, we start with the premise that
the primary cause of cancer is a defect in communication from the stroma
to the parenchyma. Under this premise we do not think it likely that an
inherited mutation in the parenchyma would have much impact on the risk of
cancer. We do agree that an inherited mutation in the stroma has the
potential to increase the risk of cancer, and for that reason
investigators should take samples from the stroma, which is not usually
the case. However, we cited one study that did not find such inherited
mutations in the stroma. This is an area where more research is needed

2. We agree that, within a population, some individuals are at
greater risk of cancer than others. For example persons exposed an
environmental carcinogen or with a family history of cancer would be at
higher risk of cancer than other persons. Perhaps the question is better
phrased as “Why do some individuals get cancer and some do not although
their environmental exposures appear the same and their family histories
of cancer appear the same?” Of course the nub of the question is whether
or not the environmental exposures and family histories are, in fact,
precisely the same, which is not possible to determine, as environmental
exposures may be overlooked or cancers in other family members may be
imprecisely determined or may be due to environmental exposures.

3. We agree that our twin study estimate of a “small to moderate
contribution” of genes to the incidence of cancer is still a contribution.
However, a key point is that our twin study also estimated a high
penetrance for these genes as would be found in the family studies
mentioned, not the low penetrance common genes that were the focus of our
article.

4. We agree that there are methods for searching for low penetrance
cancer susceptibility genes besides genome wide high throughput studies.
This does not change our opinion that these studies are expensive, because
much of the cost is due to the very large sample sizes that are needed,
regardless of the technology. The low penetrance cancer susceptibility
genes mentioned were identified based on much smaller sample sizes than we
recommended. Until these genes are confirmed in larger studies, we are
skeptical that they are truly associated with cancer.

5. We do not understand why the existence of high penetrance rare
cancer susceptibility genes would imply the existence of low penetrance
common cancer susceptibility genes. Also in the “compelling review
regarding colon cancer”, 95% confidence intervals were reported for the
estimated association between the genes and cancer, but, as mentioned in
our article, to reduce the chance of false positives we recommend a much
higher level for the confidence intervals. Regarding the benefits of
chemoprevention, as discussed in our article, the identification of the
common cancer susceptibility gene would need to lead to the identification
of a modifiable risk factor and its evaluation in a large randomized
trial, which is a long-term and expensive undertaking.

Competing interests:
None declared

Competing interests: No competing interests

20 June 2006
Stuart G. Baker
biostatistician
Jaakko Kaprio
National Cancer Institute 20892