TY - JOUR
T1 - Pathogenic Germline Variants in 10,389 Adult Cancers
AU - The Cancer Genome Atlas Research Network
AU - Huang, Kuan lin
AU - Mashl, R. Jay
AU - Wu, Yige
AU - Ritter, Deborah I.
AU - Wang, Jiayin
AU - Oh, Clara
AU - Paczkowska, Marta
AU - Reynolds, Sheila
AU - Wyczalkowski, Matthew A.
AU - Oak, Ninad
AU - Scott, Adam D.
AU - Krassowski, Michal
AU - Cherniack, Andrew D.
AU - Houlahan, Kathleen E.
AU - Jayasinghe, Reyka
AU - Wang, Liang Bo
AU - Zhou, Daniel Cui
AU - Liu, Di
AU - Cao, Song
AU - Kim, Young Won
AU - Koire, Amanda
AU - McMichael, Joshua F.
AU - Hucthagowder, Vishwanathan
AU - Kim, Tae Beom
AU - Hahn, Abigail
AU - Wang, Chen
AU - McLellan, Michael D.
AU - Al-Mulla, Fahd
AU - Johnson, Kimberly J.
AU - Caesar-Johnson, Samantha J.
AU - Demchok, John A.
AU - Felau, Ina
AU - Kasapi, Melpomeni
AU - Ferguson, Martin L.
AU - Hutter, Carolyn M.
AU - Sofia, Heidi J.
AU - Tarnuzzer, Roy
AU - Wang, Zhining
AU - Yang, Liming
AU - Zenklusen, Jean C.
AU - Zhang, Jiashan (Julia)
AU - Chudamani, Sudha
AU - Liu, Jia
AU - Lolla, Laxmi
AU - Naresh, Rashi
AU - Pihl, Todd
AU - Sun, Qiang
AU - Wan, Yunhu
AU - Wu, Ye
AU - Raphael, Benjamin
N1 - Publisher Copyright:
© 2018 The Authors
PY - 2018/4/5
Y1 - 2018/4/5
N2 - 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 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer. A pan-cancer analysis identifies hundreds of predisposing germline variants.
AB - 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 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer. A pan-cancer analysis identifies hundreds of predisposing germline variants.
KW - LOH
KW - cancer predisposition
KW - germline and somatic genomes
KW - variant pathogenicity
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U2 - 10.1016/j.cell.2018.03.039
DO - 10.1016/j.cell.2018.03.039
M3 - Article
C2 - 29625052
AN - SCOPUS:85044578706
SN - 0092-8674
VL - 173
SP - 355-370.e14
JO - Cell
JF - Cell
IS - 2
ER -