posted on 2023-04-04, 00:03authored byFresia Pareja, Ryan N. Ptashkin, David N. Brown, Fatemeh Derakhshan, Pier Selenica, Edaise M. da Silva, Andrea M. Gazzo, Arnaud Da Cruz Paula, Kelsey Breen, Ronglai Shen, Antonio Marra, Ahmet Zehir, Ryma Benayed, Michael F. Berger, Ozge Ceyhan-Birsoy, Sowmya Jairam, Margaret Sheehan, Utsav Patel, Yelena Kemel, Jacklyn Casanova-Murphy, Christopher J. Schwartz, Mahsa Vahdatinia, Elizabeth Comen, Laetitia Borsu, Xin Pei, Nadeem Riaz, David H. Abramson, Britta Weigelt, Michael F. Walsh, Anna-Katerina Hadjantonakis, Marc Ladanyi, Kenneth Offit, Zsofia K. Stadler, Mark E. Robson, Jorge S. Reis-Filho, Diana Mandelker
Supplementary Data from Cancer-Causative Mutations Occurring in Early Embryogenesis
Funding
Breast Cancer Research Foundation
Sarah Leigh Fund
NIH
NCI
Sharon Corzine Research Foundation
History
ARTICLE ABSTRACT
Mosaic mutations in normal tissues can occur early in embryogenesis and be associated with hereditary cancer syndromes when affecting cancer susceptibility genes (CSG). Their contribution to apparently sporadic cancers is currently unknown. Analysis of paired tumor/blood sequencing data of 35,310 patients with cancer revealed 36 pathogenic mosaic variants affecting CSGs, most of which were not detected by prior clinical genetic testing. These CSG mosaic variants were consistently detected at varying variant allelic fractions in microdissected normal tissues (n = 48) from distinct embryonic lineages in all individuals tested, indicating their early embryonic origin, likely prior to gastrulation, and likely asymmetrical propagation. Tumor-specific biallelic inactivation of the CSG affected by a mosaic variant was observed in 91.7% (33/36) of cases, and tumors displayed the hallmark pathologic and/or genomic features of inactivation of the respective CSGs, establishing a causal link between CSG mosaic variants arising in early embryogenesis and the development of apparently sporadic cancers.
Here, we demonstrate that mosaic variants in CSGs arising in early embryogenesis contribute to the oncogenesis of seemingly sporadic cancers. These variants can be systematically detected through the analysis of tumor/normal sequencing data, and their detection may affect therapeutic decisions as well as prophylactic measures for patients and their offspring.See related commentary by Liggett and Sankaran, p. 889.This article is highlighted in the In This Issue feature, p. 873