Synapse - Cancer-causative mutations occurring in early embryogenesis

Cancer-causative mutations occurring in early embryogenesis Journal Article

Authors:	Pareja, F.; Ptashkin, R. N.; Brown, D. N.; Derakhshan, F.; Selenica, P.; da Silva, E. M.; Gazzo, A. M.; Paula, A. D. C.; Breen, K.; Shen, R.; Marra, A.; Zehir, A.; Benayed, R.; Berger, M. F.; Ceyhan-Birsoy, O.; Jairam, S.; Sheehan, M.; Patel, U.; Kemel, Y.; Casanova-Murphy, J.; Schwartz, C. J.; Vahdatinia, M.; Comen, E.; Borsu, L.; Pei, X.; Riaz, N.; Abramson, D. H.; Weigelt, B.; Walsh, M. F.; Hadjantonakis, A. K.; Ladanyi, M.; Offit, K.; Stadler, Z. K.; Robson, M. E.; Reis-Filho, J. S.; Mandelker, D.
Article Title:	Cancer-causative mutations occurring in early embryogenesis
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. © 2021 American Association for Cancer Research.
Keywords:	genetics; mutation; neoplasm; neoplasms; allele; alleles; embryo development; genetic screening; genetic testing; embryonic development; humans; human
Journal Title:	Cancer Discovery
Volume:	12
Issue:	4
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2022-04-01
Start Page:	949
End Page:	957
Language:	English
DOI:	10.1158/2159-8290.Cd-21-1110
PUBMED:	34949653
PROVIDER:	scopus
PMCID:	PMC8983494
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85128161168&doi=10.1158%2f2159-8290.CD-21-1110&partnerID=40&md5=e771dc5d4cd72ecc6136b7fb6179f36e
Notes:	Article -- Export Date: 2 May 2022 -- Source: Scopus