Developing a second primary tumour is a major clinical problem, with second cancers making up 14% of all incident malignancies in the US. As survival rates for cancer improve, more people will develop a second primary tumour. A small number of people develop three unrelated primary cancers in their lifetime, while some very rare individuals can go on to develop four, five or even more primary cancers.
In a cohort of patients with 3 or more primaries, rare tumour types appear at a reasonably high frequency. Additionally, recent studies have shown significant clustering of different cancer types within families suggesting genetic susceptibility to cancer is not limited to specific tumour types. Thus, this phenomenon provides us with a rational way to examine rare and diverse cancer types in a single cohort and screen for novel and potentially rare susceptibility genes.
In this study we examined the prevalence of mutations in 87 known cancer predisposition genes within an archival cohort of 106 individuals from the Melbourne Collaborative Cohort Study. We have also begun to explore the presence and prevalence of mutations in novel predisposition genes in a second active cohort of 14 individuals from the WEHI-Stafford Fox Rare Cancer Program. Unsurprisingly, mutations in known predisposition genes identified in our cohorts include BRCA2, MLH1, RAD51D, PMS2 and ATM. However, importantly, the frequency of mutations in known predisposition genes within our cohort is very low with only 7/106 (6.6%) of cases attributed to a mutation in one of the known predisposition genes tested. Thus, there are around 100 individuals for whom a mutation was not identified and these require further investigation at the whole genome level to uncover any mutations in unknown predisposition genes.