Cancer genetics, precision prevention and a call to action.

Nature Genetics
Clare TurnbullRichard S Houlston

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 ...Continue Reading

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Nov 18, 2018·Endocrine-related Cancer·Priscilla A Furth
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Methods Mentioned

BETA
exome-sequencing
lavage

Software Mentioned

InSIGHT
ENIGMA
ClinGen
ClinVar

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