Journal article
Pathogenic Germline Variants in 10,389 Adult Cancers
Cell, Vol.173(2), pp.355-370.e14
04/05/2018
DOI: 10.1016/j.cell.2018.03.039
PMCID: PMC5949147
PMID: 29625052
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 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.
Details
- Title: Subtitle
- Pathogenic Germline Variants in 10,389 Adult Cancers
- Creators
- Kuan-Lin Huang - Washington University in St. LouisR Jay Mashl - Washington University in St. LouisYige Wu - Washington University in St. LouisDeborah I Ritter - Baylor College of MedicineJiayin Wang - Xi'an Jiaotong UniversityClara Oh - Washington University in St. LouisMarta Paczkowska - Ontario Institute for Cancer ResearchSheila Reynolds - Institute for Systems BiologyMatthew A Wyczalkowski - Washington University in St. LouisNinad Oak - Baylor College of MedicineAdam D Scott - Washington University in St. LouisMichal Krassowski - Ontario Institute for Cancer ResearchAndrew D Cherniack - Broad InstituteKathleen E Houlahan - Ontario Institute for Cancer ResearchReyka Jayasinghe - Washington University in St. LouisLiang-Bo Wang - Washington University in St. LouisDaniel Cui Zhou - Washington University in St. LouisDi Liu - Washington University in St. LouisSong Cao - Washington University in St. LouisYoung Won Kim - Baylor College of MedicineAmanda Koire - Baylor College of MedicineJoshua F McMichael - Washington University in St. LouisVishwanathan Hucthagowder - Molecular Pathology Laboratory NetworkTae-Beom Kim - The University of Texas MD Anderson Cancer CenterAbigail Hahn - Institute for Systems BiologyChen Wang - Mayo ClinicMichael D McLellan - Washington University in St. LouisFahd Al-Mulla - Kuwait UniversityKimberly J Johnson - Washington University in St. LouisOlivier Lichtarge - Baylor College of MedicinePaul C Boutros - Ontario Institute for Cancer ResearchBenjamin Raphael - Princeton UniversityAlexander J Lazar - The University of Texas MD Anderson Cancer CenterWei Zhang - Wake Forest UniversityMichael C Wendl - Washington University in St. LouisRamaswamy Govindan - Washington University in St. LouisSanjay Jain - Washington University in St. LouisDavid Wheeler - Baylor College of MedicineShashikant Kulkarni - Baylor College of MedicineJohn F Dipersio - Washington University in St. LouisJüri Reimand - Ontario Institute for Cancer ResearchFunda Meric-Bernstam - The University of Texas MD Anderson Cancer CenterKen Chen - The University of Texas MD Anderson Cancer CenterIlya Shmulevich - Institute for Systems BiologySharon E Plon - Baylor College of MedicineFeng Chen - Washington University in St. LouisLi Ding - Washington University in St. Louis
- Contributors
- Cancer Genome Atlas Research Network (Contributor)Deqin Ma (Contributor) - University of Iowa, PathologyMohammed M Milhem (Contributor) - University of Iowa, Internal MedicineAaron D Bossler (Contributor) - University of Iowa, Pathology
- Resource Type
- Journal article
- Publication Details
- Cell, Vol.173(2), pp.355-370.e14
- DOI
- 10.1016/j.cell.2018.03.039
- PMID
- 29625052
- PMCID
- PMC5949147
- NLM abbreviation
- Cell
- ISSN
- 0092-8674
- eISSN
- 1097-4172
- Grant note
- U24 CA143843 / NCI NIH HHS R01 CA180006 / NCI NIH HHS U24 CA211000 / NCI NIH HHS U24 CA210972 / NCI NIH HHS R01 CA178383 / NCI NIH HHS U24 CA210957 / NCI NIH HHS U54 HG003079 / NHGRI NIH HHS U24 CA143883 / NCI NIH HHS U24 CA210990 / NCI NIH HHS U24 CA210969 / NCI NIH HHS U24 CA143799 / NCI NIH HHS U24 CA210988 / NCI NIH HHS R01 HG009711 / NHGRI NIH HHS K12 GM084897 / NIGMS NIH HHS U24 CA143867 / NCI NIH HHS U24 CA143858 / NCI NIH HHS U24 CA143882 / NCI NIH HHS R01 DK102520 / NIDDK NIH HHS U54 HG003067 / NHGRI NIH HHS U24 CA143845 / NCI NIH HHS U24 CA143835 / NCI NIH HHS U54 HG003273 / NHGRI NIH HHS U24 CA143840 / NCI NIH HHS U24 CA211006 / NCI NIH HHS U24 CA144025 / NCI NIH HHS U24 CA143866 / NCI NIH HHS U24 CA210950 / NCI NIH HHS U24 CA210949 / NCI NIH HHS R01 GM079656 / NIGMS NIH HHS U24 CA143848 / NCI NIH HHS R01 CA163722 / NCI NIH HHS
- Language
- English
- Date published
- 04/05/2018
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Internal Medicine
- Record Identifier
- 9984185171302771
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