Inherited problems of DNA repair are associated with increased cancer risk, but this relationship is only clear for rare, high-risk syndromes. In colorectal cancer, these syndromes usually involve impaired correction of errors arising from DNA replication (e.g. Lynch syndrome, DNA polymerase proofreading), but also include mutations from germline defects in the correction of oxidative damage and of methyl-cytosine deamination. The inherited genetic DNA repair defects increase somatic mutations and the colorectal tumours tend to develop similarly to sporadic CRCs.

This apparently simple situation masks complexity that is not fully understood, such as the following:
- does any increase at all in somatic mutation rates (including therapeutic) raise cancer risk?
- why is CRC especially prone to the effects of elevated mutations at the base pair level?
- are the offspring of carriers of high-risk variants prone to deleterious de novo germline mutations?
- why are alleles like those for Lynch syndrome not selected out of the population?
- although over 200 common polymorphisms modestly affect CRC risk at the population level, why do none of them affect DNA repair genes?
- why have we found so few uncommon CRC risk genes with moderate effects?
- can we use cancer genomes to help our search for new variants in DNA repair genes that raise CRC risk?
- can we use germline variation in DNA repair to help prevent CRC?

In this presentation, I report some new findings in this area and address each of these questions, albeit with variable success. Overall, more mutations do cause increased cancer risk, but it’s complicated and much remains unknown …