Genomic Meta-analysis: Better Colorectal Cancer Screening; New Drug Targets

David J. Kerr, CBE, MD, DSc, FRCP, FMedSci


February 01, 2019

Hello. I'm David Kerr, professor of cancer medicine at the University of Oxford. As many of you know, I'm hugely interested in the biogenetics of colorectal cancer.

There's a lovely paper that has just been published in Nature Genetics looking at colorectal cancer susceptibility.[1] This is the largest study to date that has used whole-genome sequencing. They've done a meta-analysis of genome-wide association studies and brought together a database of approximately 125,000 individuals—cancer patients and controls. This is a lovely piece of work with great statistical fidelity and fantastic bioinformatics.

[The authors] identified an additional 40-50 single nucleotide polymorphisms (SNPs), which explain another proportion of the genetic heritability of colorectal cancer. This suggests—of course, we know this—that colorectal cancer is highly polygenic.

[They also] discovered a few more interesting pathways that may be relevant in the genesis of colorectal cancer. The Hippo-YAP and Krüppel pathways provide the potential for those who are interested in new targets for drug development to consider how these pathways may play a biological role in, potentially, the treatment and prevention of colorectal cancer.

We can use this large study in two ways. The first is to define a genetic algorithm. We take blood and saliva samples, and we can identify normal citizens who may have a four- to fivefold higher lifetime risk of developing colorectal cancer.

Of course, if we can identify these individuals, we can give them lifestyle advice around diet, exercise, avoiding smoking, reducing alcohol, and so on. We can put them into more intensive screening programs. I think that our lateral supportive data suggest that it would probably be cost-effective [to enter] these individuals into colonoscopy screening programs.

Second, we are coming up with new biological pathways, which provide the possibility to evaluate novel, tractable, druggable new targets.

Let me commend the authors again for a lovely piece of work. It's an area in which we, and our collaborators in Oxford, London, and Edinburgh, are very keen to pursue. I think large-scale, collaborative efforts using large, meta-analytical databases of this sort are definitely the way ahead.

[They engender] strength through collaboration, improved science through cooperation, and that sense of the global community working together to provide better understanding of the genetics and biology of colorectal cancer, and potentially to come up with new screening tools.

I'd be very keen to hear what you think about it. Do you think, for example, that these genes could be ready for primetime? Is this a genetic algorithm or a model that we could take to individuals, or should we incorporate them into population-based screening programs? I suspect that I prefer the latter, but I think a strong case could be made for the former.

Thanks for listening, as always. For the time being, Medscapers, ahoy! Over and out. Thank you.


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