Synapse - Cascading after peridiagnostic cancer genetic testing: An alternative to population-based screening

Cascading after peridiagnostic cancer genetic testing: An alternative to population-based screening Journal Article

Authors:	Offit, K.; Tkachuk, K. A.; Stadler, Z. K.; Walsh, M. F.; Diaz-Zabala, H.; Levin, J. D.; Steinsnyder, Z.; Ravichandran, V.; Sharaf, R. N.; Frey, M. K.; Lipkin, S. M.; Robson, M. E.; Hamilton, J. G.; Vijai, J.; Mukherjee, S.
Article Title:	Cascading after peridiagnostic cancer genetic testing: An alternative to population-based screening
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.
Keywords:	breast; risk; ovarian-cancer; lynch-syndrome; brca2 mutation carriers; family communication; founder mutations; relatives; germline brca1; ashkenazi jewish women
Journal Title:	Journal of Clinical Oncology
Volume:	38
Issue:	13
ISSN:	0732-183X
Publisher:	American Society of Clinical Oncology
Date Published:	2020-05-01
Start Page:	1398
End Page:	1408
Language:	English
ACCESSION:	WOS:000537765800005
DOI:	10.1200/jco.19.02010
PROVIDER:	wos
PMCID:	PMC7193752
PUBMED:	31922925
Notes:	Vijai Joseph's first and last names are reversed on the original publication -- Article -- Source: Wos