Cancer genetics, precision prevention and a call to action

Abstract

More than 15 years have passed since the identification, through linkage, of 'first-wave' susceptibility genes for common cancers (BRCA1, BRCA2, MLH1 and MSH2). These genes have strong frequency-penetrance profiles, such that the associated clinical utility probably remains relevant regardless of the context of ascertainment. 'Second-wave' genes, not tractable by linkage, were subsequently identified by mutation screening of candidate genes (PALB2, ATM, CHEK2, BRIP1, RAD51C and RAD51D). Their innately weaker frequency-penetrance profiles have rendered delineation of cancer associations, risks and variant pathogenicity challenging, thereby compromising their clinical application. Early germline exome-sequencing endeavors for common cancers did not yield the long-anticipated slew of 'next-wave' genes but instead implied a highly polygenic genomic architecture requiring much larger experiments to make any substantive inroads into gene discovery. As such, the 'genetic economics' of frequency penetrance clearly indicates that focused identification of carriers of first-wave-gene mutations is most impactful for cancer control. With screening, prevention and early detection at the forefront of the cancer management agenda, we propose that the time is nigh for the initiation of national population-testing programs to identify carriers of first-wave gene mutation carriers. To fully deliver a precision prevention program, long-term, large-scale mutation studies that capture longitudinal clinical data and serial biosamples are required.

Figure 1. Risk penetrance profile for genetic susceptibility factors for:

(a) Breast cancer; (b) Colorectal cancer

Figure 2. Attributes for a precision prevention programme, by cancer

(1) Contribution by frequency-penetrance of high penetrance susceptibility genes (2) Heritability and % excess familial risk explained by common (GWAS) alleles (3) Receiver operator performance of totality of known lifestyle/non-genetic factors (4) Incidence (Annual cases in UK: + <5,000; ++ 5,000-9,999; +++ 10,000-19,999; ++++ 20,000-39,999; +++++, ≥40,000) (5) Mortality (10 year survival + >80%; ++ 60-80%; +++ 40-60%; ++++: 20-40%; +++++ <20%) (6) Natural history of disease is well understood (eg robust biomarkers to predict poor prognosis disease) (7) Effective and acceptable screening tool and confirmatory test consistent with delivery of national screening programme. (8) Effective and acceptable chemoprophylaxis eg breast cancer (tamoxifen, AIs, SERMS) and colorectal cancer (aspirin) (9) Elective and acceptable option for presymptomatic surgical removal of organ at risk.