Journal article
Cooperation and antagonism among cancer genes: the renal cancer paradigm
Cancer research (Chicago, Ill.), Vol.73(14), pp.4173-4179
07/15/2013
DOI: 10.1158/0008-5472.CAN-13-0360
PMCID: PMC4051157
PMID: 23832661
Abstract
It is poorly understood how driver mutations in cancer genes work together to promote tumor development. Renal cell carcinoma (RCC) offers a unique opportunity to study complex relationships among cancer genes. The four most commonly mutated genes in RCC of clear-cell type (the most common type) are two-hit tumor suppressor genes, and they cluster in a 43-Mb region on chromosome 3p that is deleted in approximately 90% of tumors: VHL (mutated in ∼80%), PBRM1 (∼50%), BAP1 (∼15%), and SETD2 (∼15%). Meta-analyses that we conducted show that mutations in PBRM1 and SETD2 co-occur in tumors at a frequency higher than expected by chance alone, indicating that these mutations may cooperate in tumorigenesis. In contrast, consistent with our previous results, mutations in PBRM1 and BAP1 tend to be mutually exclusive. Mutation exclusivity analyses (often confounded by lack of statistical power) raise the possibility of functional redundancy. However, mutation exclusivity may indicate negative genetic interactions, as proposed herein for PBRM1 and BAP1, and mutations in these genes define RCC with different pathologic features, gene expression profiles, and outcomes. Negative genetic interactions among cancer genes point toward broader context dependencies of cancer gene action beyond tissue dependencies. An enhanced understanding of cancer gene dependencies may help to unravel vulnerabilities that can be exploited therapeutically.
Details
- Title: Subtitle
- Cooperation and antagonism among cancer genes: the renal cancer paradigm
- Creators
- Samuel Peña-Llopis - Departments of Internal Medicine, Developmental Biology, and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USAAlana ChristieXian-Jin XieJames Brugarolas
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.73(14), pp.4173-4179
- Publisher
- United States
- DOI
- 10.1158/0008-5472.CAN-13-0360
- PMID
- 23832661
- PMCID
- PMC4051157
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Grant note
- R01 CA129387 / NCI NIH HHS R01CA129387 / NCI NIH HHS
- Language
- English
- Date published
- 07/15/2013
- Academic Unit
- Preventive and Community Dentistry; Biostatistics; Dental Research
- Record Identifier
- 9983917684702771
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