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Data from Cancer-Causative Mutations Occurring in Early Embryogenesis

Authors :
Diana Mandelker
Jorge S. Reis-Filho
Mark E. Robson
Zsofia K. Stadler
Kenneth Offit
Marc Ladanyi
Anna-Katerina Hadjantonakis
Michael F. Walsh
Britta Weigelt
David H. Abramson
Nadeem Riaz
Xin Pei
Laetitia Borsu
Elizabeth Comen
Mahsa Vahdatinia
Christopher J. Schwartz
Jacklyn Casanova-Murphy
Yelena Kemel
Utsav Patel
Margaret Sheehan
Sowmya Jairam
Ozge Ceyhan-Birsoy
Michael F. Berger
Ryma Benayed
Ahmet Zehir
Antonio Marra
Ronglai Shen
Kelsey Breen
Arnaud Da Cruz Paula
Andrea M. Gazzo
Edaise M. da Silva
Pier Selenica
Fatemeh Derakhshan
David N. Brown
Ryan N. Ptashkin
Fresia Pareja
Publication Year :
2023
Publisher :
American Association for Cancer Research (AACR), 2023.

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.Significance: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

Details

Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....0de6853c5a564152a6ee2a79f5b4671d
Full Text :
https://doi.org/10.1158/2159-8290.c.6549625