Genetic Test May Identify CRC Risk in 'Normals'

Hello. I am David Kerr, professor of cancer medicine from the University of Oxford. I picked up a nice paper recently in Annals of Oncology in which there is a new predictive genetic algorithm in terms of colorectal cancer risk.^[1] The first author was Dr Matthew Frampton, but it is supported by two world-class colorectal cancer geneticists: Ian Tomlinson and Richard Houston are long-time friends and collaborators. I am a coauthor on the paper, so there is a tiny data warning associated with it, given that small conflict of interest.

Beautiful piece of work. Over 10 years, this genome-wide association study has tried to find common genetic variants that describe the risk for or susceptibility to colorectal cancer.

If you have a first-degree relative, you have a twofold increased lifetime risk of developing colorectal cancer.

We know that colorectal cancer is a genetic disease. If you have a first-degree relative, you have a twofold increased lifetime risk of developing colorectal cancer. And we know that there is a cluster of familial, strongly penetrant genes which are associated with the development of colorectal cancer. As such, there is now widespread testing for these genes in colorectal cancer families. The problem is, this accounts for only about 3%-5% of the total colorectal cancer burden. The idea about doing the genome-wide association studies is to look for common variants that are therefore relevant to the much wider population of normal individuals, so we can calculate their relative lifetime risk on the basis of these single nucleotide polymorphisms (SNPs).

In this paper, what we show is that there is a gradation of risk depending on the number of SNPs that one finds. We know that there is a framework such that if we look at individuals in the top 10% of risk—those who have maybe 20-30 of these SNPs—there is a doubling of lifetime risk. The top 1% of the population have maybe 30-50 of these risk SNPs; then the lifetime risk is threefold higher than normal. I think that is important.

If we can identify a group of normal individuals at a risk two to three times higher than the average lifetime risk of developing colorectal cancer, these are the individuals I would want to put into a more intensive screening program.

If we look at population screening, if we can identify a group of normal individuals at a risk two to three times higher than the average lifetime risk of developing colorectal cancer, these are the individuals I would want to put into a more intensive screening program. We know that from the cost effect of the health economic analysis that has been done for familial colorectal cancer screening that there is a case to be made,^[2,3,4] and I think that could apply on a population basis to those individuals who are identified by this genetic algorithm, this SNP algorithm of being a two- to threefold higher risk. It's worth knowing about in terms of screening.

At the lower end of the risk, you could argue that those who have a lower than average risk perhaps don't need to be screened with the same frequency or with the same level of intensity [as patients at normal risk]. I am a bit more nervous about that proposition because that means that we would be missing cancers that we would perhaps detect with conventional screening methods. I think that is a harder thing to sell to the individual. Although on the population level, it may make sense in terms of saving money that could be reinvested elsewhere—for example, for intensive screening of the high-risk people.

Fantastic piece of work. Ten years, 50,000 individuals, a lot of SNP typing, and we are edging closer to a test that I think could be applicable at least on the population level.

I would be very keen to hear anything that you would like to post about this rather lovely paper, which captures a huge amount of work—multiple publications in Nature Genetics^[5,6] and so on—which is crystallized into this quite important paper defining the potential use of genetic predictors of colorectal cancer. I am sure we will see this coming along in breast and prostate cancer too.

Thanks for listening. I am very keen to hear what comments you have. For the time being, Medscapers, over and out.

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