Cascading After Peridiagnostic Cancer Genetic Testing: An Alternative to Population-Based Screening

Abstract

Purpose: Despite 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.

Methods: Using 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.

Results: The 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.

Conclusion: Peridiagnostic and cascade cancer genetic testing offers an alternative strategy to achieve population-wide identification of cancer susceptibility mutations.

FIG 1.

Tornado plot depicting univariate sensitivity analysis performed using baseline model: 7% prevalence of pathogenic variants across cancer types, an average family size of 3 per generation, 15% of incident patients with cancer undergoing germline testing, and 25% first-degree relatives, 25% second-degree relatives, and 25% third-degree relatives cascading, the time to detect 3.9 million individuals with a germline cancer susceptibility mutation was 22.2 years. The plot shows the effect on the output (number of years) of varying each input variable at a time, keeping all the other input variables at their baseline value. The cascading rate here is defined by the proportion of first-degree, second-degree, and third-degree relatives transmitting information, ranging from 10% to 75%; family size per generation refers to the number of siblings per generation, ranging from 2 to 4; proportion of patients with cancer screened refers to the proportion of incident patients with cancer subjected to germline sequencing of 18 selected genes, ranging from 7.5% to 75%; prevalence of pathogenic mutations refers to the prevalence of pathogenic variants of 18 cancer susceptibility genes in patients with cancer sequenced, ranging from 5% to 15%. The upper and lower bounds for each variable are labeled in the tornado plot.

FIG 2.

Sensitivity analysis; Prevalence (%), patients with mutations of 18 cancer susceptibility genes; Proportion, of 1.7 million incident cancers sequenced; Years to detect 3.9 million mutation carriers. FDR, first-degree relatives; SDR, second-degree relatives; TDR, third-degree relatives.

FIG 3.

Diagram of peridiagnostic genetic testing and familial diffusion of information under the assumptions of a family size of 3 siblings per generation, 15% of patients with cancer receiving germline genetic testing at the time of diagnosis, a 7% frequency of pathogenic mutations found at the time of testing, and 70% diffusion of familial genetic information to first-degree relatives (F), second-degree relatives (S), and third-degree relatives (T). In this example, it is assumed that 220,000 carriers of pathogenic variants have been identified in the United States, with 44,000 additional individuals identified each year by virtue of expanded commercial clinical and direct-to-consumer testing. Y_n represents the cumulative number of individuals with pathogenic variants identified each year. Under these assumptions, the time to detect all 3.9 million individuals with pathogenic variants in the United States is 9.9 years. (*) 419K heterozygous for pathogenic variants identified each year after Y₃ (Data Supplement).

FIG 4.

Sensitivity analysis of the example of a family structure of 3 siblings per generation and a 7% prevalence of pathogenic variants in 1 of 18 clinically actionable cancer susceptibility genes; Proportion, of 1.7 million incident cancers sequenced; Years to detect 3.9 million mutation carriers. FDR, first-degree relatives; SDR, second-degree relatives; TDR, third-degree relatives.