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The landscape of somatic copy-number alteration across human cancers.

ABSTRACT: A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-kappaBeta pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types.

SUBMITTER: Beroukhim R

PROVIDER: S-EPMC2826709 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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The landscape of somatic copy-number alteration across human cancers.

Beroukhim Rameen R Mermel Craig H CH Porter Dale D Wei Guo G Raychaudhuri Soumya S Donovan Jerry J Barretina Jordi J Boehm Jesse S JS Dobson Jennifer J Urashima Mitsuyoshi M Mc Henry Kevin T KT Pinchback Reid M RM Ligon Azra H AH Cho Yoon-Jae YJ Haery Leila L Greulich Heidi H Reich Michael M Winckler Wendy W Lawrence Michael S MS Weir Barbara A BA Tanaka Kumiko E KE Chiang Derek Y DY Bass Adam J AJ Loo Alice A Hoffman Carter C Prensner John J Liefeld Ted T Gao Qing Q Yecies Derek D Signoretti Sabina S Maher Elizabeth E Kaye Frederic J FJ Sasaki Hidefumi H Tepper Joel E JE Fletcher Jonathan A JA Tabernero Josep J Baselga José J Tsao Ming-Sound MS Demichelis Francesca F Rubin Mark A MA Janne Pasi A PA Daly Mark J MJ Nucera Carmelo C Levine Ross L RL Ebert Benjamin L BL Gabriel Stacey S Rustgi Anil K AK Antonescu Cristina R CR Ladanyi Marc M Letai Anthony A Garraway Levi A LA Loda Massimo M Beer David G DG True Lawrence D LD Okamoto Aikou A Pomeroy Scott L SL Singer Samuel S Golub Todd R TR Lander Eric S ES Getz Gad G Sellers William R WR Meyerson Matthew M

Nature 20100201 7283

A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene loc ...[more]

PMID: 20164920

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Project description:BACKGROUND:Cancer associated copy number variation (CNV) events provide important information for identifying patient subgroups and suggesting treatment strategies. Technical and logistical issues, however, make it challenging to accurately detect abnormal copy number events in a cost-effective manner in clinical studies. RESULTS:Here we present CNV Radar, a software tool that utilizes next-generation sequencing read depth information and variant allele frequency patterns, to infer the true copy number status of genes and genomic regions from whole exome sequencing data. Evaluation of CNV Radar in a public multiple myeloma dataset demonstrated that CNV Radar was able to detect a variety of CNVs associated with risk of progression, and we observed > 70% concordance with fluorescence in situ hybridization (FISH) results. Compared to other CNV callers, CNV Radar showed high sensitivity and specificity. Similar results were observed when comparing CNV Radar calls to single nucleotide polymorphism array results from acute myeloid leukemia and prostate cancer datasets available on TCGA. More importantly, CNV Radar demonstrated its utility in the clinical trial setting: in POLLUX and CASTOR, two phase 3 studies in patients with relapsed or refractory multiple myeloma, we observed a high concordance rate with FISH for del17p, a risk defining CNV event (88% in POLLUX and 90% in CASTOR), therefore allowing for efficacy assessments in clinically relevant disease subgroups. Our case studies also showed that CNV Radar is capable of detecting abnormalities such as copy-neutral loss of heterozygosity that elude other approaches. CONCLUSIONS:We demonstrated that CNV Radar is more sensitive than other CNV detection methods, accurately detects clinically important cytogenetic events, and allows for further interrogation of novel disease biology. Overall, CNV Radar exhibited high concordance with standard methods such as FISH, and its success in the POLLUX and CASTOR clinical trials demonstrated its potential utility for informing clinical and therapeutic decisions.

Project description:Intratumour heterogeneity fuels carcinogenesis and allows circumventing specific targeted therapies. HER2 gene amplification is associated with poor outcome in invasive breast cancer. Heterogeneous HER2 amplification has been described in 5-41% of breast cancers. Here, we investigated the genetic differences between HER2-positive and HER2-negative admixed breast cancer components. We performed an in-depth analysis to explore the potential heterogeneity in the somatic mutational landscape of each individual tumour component. Formalin-fixed, paraffin-embedded breast cancer tissue of ten patients with at least one HER2-negative and at least one HER2-positive component was microdissected. Targeted next-generation sequencing was performed using a customized 53-gene panel. Somatic mutations and copy number variations were analysed. Overall, the tumours showed a heterogeneous distribution of 12 deletions, 9 insertions, 32 missense variants and 7 nonsense variants in 26 different genes, which are (likely) pathogenic. Three splice site alterations were identified. One patient had an EGFR copy number gain restricted to a HER2-negative in situ component, resulting in EGFR protein overexpression. Two patients had FGFR1 copy number gains in at least one tumour component. Two patients had an 8q24 gain in at least one tumour component, resulting in a copy number increase in MYC and PVT1. One patient had a CCND1 copy number gain restricted to a HER2-negative tumour component. No common alternative drivers were identified in the HER2-negative tumour components. This series of 10 breast cancers with heterogeneous HER2 gene amplification illustrates that HER2 positivity is not an unconditional prerequisite for the maintenance of tumour growth. Many other molecular aberrations are likely to act as alternative or collaborative drivers. This study demonstrates that breast carcinogenesis is a dynamically evolving process characterized by a versatile somatic mutational profile, of which some genetic aberrations will be crucial for cancer progression, and others will be mere 'passenger' molecular anomalies.

Dataset Information

The landscape of somatic copy-number alteration across human cancers.

Publications

The landscape of somatic copy-number alteration across human cancers.

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