(D) The top 50 most frequently mutated genes among 276 DDR genes. Specific cancer examples representing gene and pathway associations are listed under each column. Color intensity indicates percentage altered, with the percentage given in each cell. A “co” or “me” symbol in cells indicates a statistically significant (FDR 2% alterations. A “u” symbol in cells indicates a statistically significant enrichment (FDR 2%) in alterations. Gray scale indicates equal contribution from all three alteration types. RGB color indicates mutations (red), deep deletions (blue), or epigenetic silencing through methylation (green). Color intensity indicates the percentage altered, with the percentage given as a number in each cell. Clustered heatmap indicates the percentage (%) of samples in a cancer type (rows, with cancer types listed right, number of samples between parentheses) altered for at least one core gene in a given DDR pathway (columns, with core gene numbers indicated in parentheses for each pathway, bottom). (A) DDR gene alterations are frequent and non-uniformly distributed by type and frequency across cancer types. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.ĭNA 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.Ĭopyright © 2018 The Author(s). A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations.
However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response.
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