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Published on: December 26, 2016
Oncogenic Signaling Pathways in The Cancer Genome Atlas
Francisco Sanchez-Vega1, Marco Mina2, Joshua Armenia1
1Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Abstract:
Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.
Insights
Cancer cells frequently alter key signaling pathways. This study analyzed 9,125 tumors, finding 89% had driver alterations and 57% had targetable changes, revealing combination therapy potential.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Genetic alterations in cell-cycle, apoptosis, and growth pathways are hallmarks of cancer.
- The specific mechanisms and co-occurrence of these alterations vary significantly across tumor types and individual tumors.
Purpose of the Study:
- To comprehensively analyze the landscape of somatic alterations in ten canonical signaling pathways across diverse cancer types.
- To identify patterns of co-occurrence and mutual exclusivity of these pathway alterations.
- To assess the proportion of tumors with targetable alterations for potential therapeutic strategies.
Main Methods:
- Utilized multi-omic data (mutations, copy-number, mRNA expression, gene fusions, DNA methylation) from 9,125 tumors from The Cancer Genome Atlas (TCGA).
- Analyzed alterations in ten key cancer-related pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53, and β-catenin/Wnt.
- Stratified analysis across 33 cancer types and 64 subtypes.
Main Results:
- Eighty-nine percent of analyzed tumors exhibited at least one driver alteration within these ten pathways.
- Fifty-seven percent of tumors displayed at least one alteration potentially targetable by existing drugs.
- Thirty percent of tumors showed multiple targetable alterations, suggesting significant potential for combination therapies.
Conclusions:
- Canonical signaling pathways are pervasively altered in cancer, with specific patterns varying by tumor type.
- A substantial fraction of tumors harbor targetable alterations, highlighting opportunities for precision medicine and combination treatment strategies.
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