Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas

Grazi GL

Research output: Contribution to journalArticle

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 approximately 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.
Original languageEnglish
Pages (from-to)239-254.e6
JournalCell Reports
Volume23
Issue number1
DOIs
Publication statusPublished - Apr 3 2018
Externally publishedYes

Fingerprint

DNA Repair-Deficiency Disorders
Atlases
DNA Damage
Repair
Genes
Genome
DNA Repair
DNA
Neoplasms
Homologous Recombination
Ovarian Neoplasms
Mutation
BRCA1 Gene
Loss of Heterozygosity
p53 Genes
Epigenomics
Gene expression
Learning systems
Classifiers
Gene Expression

Keywords

  • DNA damage footprints
  • DNA damage repair
  • The Cancer Genome Atlas PanCanAtlas project
  • epigenetic silencing
  • integrative statistical analysis
  • mutational signatures
  • protein structure analysis
  • somatic copy-number alterations
  • somatic mutations

Cite this

Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. / Grazi GL.

In: Cell Reports, Vol. 23, No. 1, 03.04.2018, p. 239-254.e6.

Research output: Contribution to journalArticle

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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 approximately 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.",
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T1 - Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas

AU - Grazi GL

AU - Knijnenburg, T. A.

AU - Wang, L.

AU - Zimmermann, M. T.

AU - Chambwe, N.

AU - Gao, G. F.

AU - Cherniack, A. D.

AU - Fan, H.

AU - Shen, H.

AU - Way, G. P.

AU - Greene, C. S.

AU - Liu, Y.

AU - Akbani, R.

AU - Feng, B.

AU - Donehower, L. A.

AU - Miller, C.

AU - Shen, Y.

AU - Karimi, M.

AU - Chen, H.

AU - Kim, P.

AU - Jia, P.

AU - Shinbrot, E.

AU - Zhang, S.

AU - Liu, J.

AU - Hu, H.

AU - Bailey, M. H.

AU - Yau, C.

AU - Wolf, D.

AU - Zhao, Z.

AU - Weinstein, J. N.

AU - Li, L.

AU - Ding, L.

AU - Mills, G. B.

AU - Laird, P. W.

AU - Wheeler, D. A.

AU - Shmulevich, I.

AU - Network, Cancer Genome Atlas Research

AU - Jr, R. J. Monnat

AU - Xiao, Y.

AU - Wang, C.

AU - Marino, M. (come contributors)

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PY - 2018/4/3

Y1 - 2018/4/3

N2 - 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 approximately 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.

AB - 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 approximately 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.

KW - DNA damage footprints

KW - DNA damage repair

KW - The Cancer Genome Atlas PanCanAtlas project

KW - epigenetic silencing

KW - integrative statistical analysis

KW - mutational signatures

KW - protein structure analysis

KW - somatic copy-number alterations

KW - somatic mutations

U2 - 10.1016/j.celrep.2018.03.076

DO - 10.1016/j.celrep.2018.03.076

M3 - Article

VL - 23

SP - 239-254.e6

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 1

ER -