It is widely expected that in the near future analysis of germline genomic data will be a standard element in the work-up for many common cancers, providing both an understanding of the genetic aetiology and vulnerabilities of the cancer, as well as identifying the broader implications for cancer risk in both the patient and their close family members. For these ambitions to become real an extensive program of explicitly translational research is needed to address the key questions around the clinical implementation of genomics.

This presentation will describe the Cancer risk module of Cancer 2015; including proposals designed to identify and address these questions at each of the different phases of translational. Central to the program is a trial of extensive germline sequencing (whole exome) in a large sub-group of patients with clinical indicators of genomic risk selected from the population-based cohort of Cancer 2015. This will achieve a unique unbiased assessment of the impact of high-penetrance germline mutations on cancer incidence, independent of the typical issues of ascertainment, as well as providing a pathway for the rapid identification of novel disease genes.

We will describe approaches to the fundamental challenge of interpretation of this data, as well as the complex models available to examine the interaction of rare moderate risk genetic variants and the polygenic contribution of common variation. Beyond generating a more detailed genomic understanding the central aim of the Cancer Risk module is to use this data to guide direct clinical responses. This includes proposals for targeted programs of secondary cancer prevention for patients and selected close family members. We also propose a broadening of the concept of germline-determined targeted therapy that will be examined through the specific example of PARP inhibitors and genetically defined deficits in DNA repair.