The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) started in 2005 with the aim of collecting germline DNA and data on BRCA1/2 mutation carriers in order to identify modifiers of BRCA1/2. With the Breast Cancer Association Consortium and other consortia, and by carrying out genome wide association studies in CIMBA, we have identified over 200 risk loci. Population-based polygenic risk scores (PRS) are strongly associated with breast, ovarian and prostate cancer risks for BRCA1/2 carriers and predict substantial absolute risk differences for men and women at PRS distribution extremes.
It is now recognized that there are many other high and moderate penetrance breast cancer predisposition genes, with mutation carriers being identified through panel screening at familial cancer centres. It has also been shown population-based PRS substantially modify cancer risks for these other mutation carriers, particularly of moderate risk genes such as CHEK2 and ATM. This is of particular relevance for these mutation carriers for which prophylactic surgery is infrequent.
CIMBA+ is therefore planning to collect data, and later germline DNA, on pathogenic and likely pathogenic PALB2, ATM, CHEK2, RAD51D, BRIP1, TP53, CDH1, PTEN, MSH6, FANCM and STK11 female and male mutation carriers. As we have with BRCA1/2 mutation carriers in CIMBA, the aims of CIMBA Plus are to evaluate:
- PRS modification of cancer risk in mutation carriers of additional high and moderate penetrance predisposition genes
- associations with survival, or modification with survival
- genotype-phenotype associations
- tumour pathology
- the cancer spectrum
- penetrance