Journal article
Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas
Cell reports (Cambridge), Vol.23(1), pp.239-254.e6
04/03/2018
DOI: 10.1016/j.celrep.2018.03.076
PMCID: PMC5961503
PMID: 29617664
Abstract
DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.
Details
- Title: Subtitle
- Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas
- Creators
- Theo A Knijnenburg - Institute for Systems BiologyLinghua Wang - The University of Texas MD Anderson Cancer CenterMichael T Zimmermann - Medical College of WisconsinNyasha Chambwe - Institute for Systems BiologyGalen F Gao - Massachusetts Institute of TechnologyAndrew D Cherniack - Massachusetts Institute of TechnologyHuihui Fan - Van Andel InstituteHui Shen - Van Andel InstituteGregory P Way - University of PennsylvaniaCasey S Greene - University of PennsylvaniaYuexin Liu - The University of Texas MD Anderson Cancer CenterRehan Akbani - The University of Texas MD Anderson Cancer CenterBin Feng - TESARO Inc., Waltham, MA 02451, USA.Lawrence A Donehower - Baylor College of MedicineChase Miller - Baylor College of MedicineYang Shen - Texas A&M UniversityMostafa Karimi - Texas A&M UniversityHaoran Chen - Texas A&M UniversityPora Kim - The University of Texas Health Science Center at HoustonPeilin Jia - The University of Texas Health Science Center at HoustonEve Shinbrot - Baylor College of MedicineShaojun Zhang - The University of Texas MD Anderson Cancer CenterJianfang LiuHai HuMatthew H Bailey - Washington University in St. LouisChristina Yau - Buck Institute for Research on AgingDenise Wolf - University of California, San FranciscoZhongming Zhao - The University of Texas Health Science Center at HoustonJohn N Weinstein - The University of Texas MD Anderson Cancer CenterLei Li - The University of Texas at AustinLi Ding - Washington University in St. LouisGordon B Mills - The University of Texas MD Anderson Cancer CenterPeter W Laird - Van Andel InstituteDavid A Wheeler - Baylor College of MedicineIlya Shmulevich - Institute for Systems BiologyRaymond J Monnat Jr - University of WashingtonYonghong Xiao - TESARO Inc., Waltham, MA 02451, USA. Electronic address: yxiao@genospace.com.Chen Wang - Mayo Clinic
- 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 reports (Cambridge), Vol.23(1), pp.239-254.e6
- DOI
- 10.1016/j.celrep.2018.03.076
- PMID
- 29617664
- PMCID
- PMC5961503
- NLM abbreviation
- Cell Rep
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Grant note
- U24 CA143843 / NCI NIH HHS P01 CA193124 / NCI NIH HHS U24 CA210957 / NCI NIH HHS U54 HG003079 / NHGRI NIH HHS P30 CA016672 / NCI NIH HHS P01 CA077852 / NCI NIH HHS U24 CA143883 / NCI NIH HHS U24 CA210990 / NCI NIH HHS U24 CA143799 / NCI NIH HHS R35 GM124952 / NIGMS NIH HHS U01 CA176303 / NCI NIH HHS U01 CA217883 / NCI NIH HHS T32 HG000046 / NHGRI NIH HHS R01 LM012806 / NLM NIH HHS R50 CA221675 / NCI NIH HHS R01 CA190635 / NCI NIH HHS U24 CA143867 / NCI NIH HHS U24 CA143858 / NCI NIH HHS U24 CA143882 / NCI NIH HHS U54 HG003067 / NHGRI NIH HHS U24 CA143845 / NCI NIH HHS P50 CA136393 / NCI NIH HHS U24 CA143835 / NCI NIH HHS U54 HG003273 / NHGRI NIH HHS U24 CA143840 / NCI NIH HHS U24 CA144025 / NCI NIH HHS U24 CA143866 / NCI NIH HHS U24 CA210950 / NCI NIH HHS P30 ES013508 / NIEHS NIH HHS U24 CA210949 / NCI NIH HHS U24 CA143848 / NCI NIH HHS R01 CA163722 / NCI NIH HHS
- Language
- English
- Date published
- 04/03/2018
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Internal Medicine
- Record Identifier
- 9984185274702771
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