Abstract
PURPOSEDespite advances in DNA sequencing technology and expanded medical guidelines, the vast majority of individuals carrying pathogenic variants of common cancer susceptibility genes have yet to be identified. An alternative to population-wide genetic screening of healthy individuals would exploit the trend for genetic testing at the time of cancer diagnosis to guide therapy and prevention, combined with augmented familial diffusion or “cascade” of genomic risk information.METHODSUsing a multiple linear regression model, we derived the time interval to detect an estimated 3.9 million individuals in the United States with a pathogenic variant in 1 of 18 cancer susceptibility genes. We analyzed the impact of the proportion of incident patients sequenced, varying observed frequencies of pathogenic germline variants in patients with cancer, differential rates of diffusion of genetic information in families, and family size.RESULTSThe time to detect inherited cancer predisposing variants in the population is affected by the extent of cascade to first-, second-, and third-degree relatives (FDR, SDR, TDR, respectively), family size, prevalence of mutations in patients with cancer, and the proportion of patients with cancer sequenced. In a representative scenario, assuming a 7% prevalence of pathogenic variants across cancer types, an average family size of 3 per generation, and 15% of incident patients with cancer in the United States undergoing germline testing, the time to detect all 3.9 million individuals with pathogenic variants in 18 cancer susceptibility genes would be 46.2, 22.3, 13.6, and 9.9 years if 10%, 25%, 50%, and 70%, respectively, of all FDR, SDR, and TDR were tested for familial mutations.CONCLUSIONPeridiagnostic and cascade cancer genetic testing offers an alternative strategy to achieve population-wide identification of cancer susceptibility mutations.
Highlights
More than 2 decades after the discovery of genetic variants conferring substantial risks for breast, ovarian, prostate, colon, and other malignancies, and despite advances in DNA sequencing technologies, it has become increasingly clear that the promise of genomics as a tool for cancer prevention has yet to be realized.[1]
Sensitivity analysis using a multiple regression model demonstrates that the time to detect pathogenic variants in the population is significantly affected by rates of first-degree relatives (FDR), second-degree relatives (SDR), and third-degree relatives (TDR) tested by cascade, family size, and prevalence of mutations in patients with cancer, followed by the proportion of patients with cancer tested; Table 2 and Figure 1 demonstrate model fit metrics for the simulated data
As a base case, assuming a 7% frequency of clinically actionable germline pathogenic variants in 18 cancer susceptibility genes across all cancer types, based on a SEER weighted adjustment of data derived from patients tested at our Center (Data Supplement), and assuming 15% of incident cancers receiving tumor-normal or germline panel testing, for an average family size of 3 offspring per generation, the time to detect 3.9 million individuals with germline cancer susceptibility mutations would be 46.2, 22.3, 13.6, and 9.9 years, if 10%, 25%, 50%, and 70%, respectively, of FDR, SDR and TDR were tested for the familial mutation
Summary
More than 2 decades after the discovery of genetic variants conferring substantial risks for breast, ovarian, prostate, colon, and other malignancies, and despite advances in DNA sequencing technologies, it has become increasingly clear that the promise of genomics as a tool for cancer prevention has yet to be realized.[1].
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