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

By T. Knijnenburg, Linghua Wang, Michael T. Zimmermann, N. Chambwe, G. Gao, A. Cherniack, Huihui Fan, Hui Shen, G. Way, Casey S. Greene and 27 more. Cell Reports, 2018

959 citations recorded by the source corpus.

SUMMARY 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.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/d8d9217cda0cc47a372c39f445a8826b99c8c130

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Casey S. Greene
2. G. Way
3. Matthew Meyerson
4. Gad Getz
5. M. Lawrence
6. A. Gimenez-Roqueplo
7. W. Marston Linehan
8. F. McCormick

In Molecular Biology

1. Wanding Zhou
2. Hui Shen
3. Peter W. Laird
4. Elaine R. Mardis
5. Ilya Shmulevich
6. G. Way
7. Casey S. Greene
8. Nikolaus Schultz

In Oncology

1. Christopher Sander
2. Nikolaus Schultz
3. Giovanni Ciriello
4. F. McCormick
5. John N. Weinstein
6. Peter W. Laird
7. Lewis R. Roberts
8. Charles M. Perou

Citations in the corpus

• Scalable Open Science Approach for Mutation Calling of Tumor Exomes Using Multiple Genomic Pipelines (2018, positive): “‘‘The Immune Landscape of Cancer’’ (Thorsson et al., 2018), and the ‘‘Genomicand Molecular Landscape of DNA Damage Repair Deficiency across the CancerGenome Atlas’’ (Knijnenburg et al., 2018).”
• Oncogenic Signaling Pathways in The Cancer Genome Atlas (2018, background): “The focus of this effort is on mitogenic signaling pathways with vidence for functional alterations; other oncogenic processes, such as alterations in DNA repair (Knijnenburg et al., 2018), the spliceosome (Seiler et al.”