Journal article

Pathogenic Germline Variants in 10,389 Adult Cancers

Kuan-lin Huang, R Jay Mashl, Yige Wu, Deborah I Ritter, Jiayin Wang, Clara Oh, Marta Paczkowska, Sheila Reynolds, Matthew A Wyczalkowski, Ninad Oak, Adam D Scott, Michal Krassowski, Andrew D Cherniack, Kathleen E Houlahan, Reyka Jayasinghe, Liang-Bo Wang, Daniel Cui Zhou, Di Liu, Song Cao, Young Won Kim Show all

CELL | CELL PRESS | Published : 2018

Abstract

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 ad..

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Grants


Awarded by NATIONAL CANCER INSTITUTE


Awarded by NATIONAL HUMAN GENOME RESEARCH INSTITUTE


Awarded by NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES


Awarded by NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES


Funding Acknowledgements

The authors wish to acknowledge The Cancer Genome Atlas. This work was supported by the following grants: U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, U24 CA210969, U24 CA210988, U24 CA211006, R01 CA180006, and R01 HG009711.