Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz GGISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol 12: R41

Cancer Program, The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA.
Genome biology (Impact Factor: 10.81). 04/2011; 12(4):R41. DOI: 10.1186/gb-2011-12-4-r41
Source: PubMed


We describe methods with enhanced power and specificity to identify genes targeted by somatic copy-number alterations (SCNAs) that drive cancer growth. By separating SCNA profiles into underlying arm-level and focal alterations, we improve the estimation of background rates for each category. We additionally describe a probabilistic method for defining the boundaries of selected-for SCNA regions with user-defined confidence. Here we detail this revised computational approach, GISTIC2.0, and validate its performance in real and simulated datasets.

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    • "Copy number data (gene level) for cancer cell lines was obtained from CCLE (platform: Affymetrix SNP6) [7]. As reported by TCGA and CCLE, the significant focal copy number alterations in individual tumor samples/cancer cell lines were identified from segmented data using GISTIC [15]. Four classes of abnormal segments were considered based on their estimated copy number [16]: "
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    ABSTRACT: Breast cancer is one of the most common cancers with high incident rate and high mortality rate worldwide. Although different breast cancer cell lines were widely used in laboratory investigations, accumulated evidences have indicated that genomic differences exist between cancer cell lines and tissue samples in the past decades. The abundant molecular profiles of cancer cell lines and tumor samples deposited in the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas now allow a systematical comparison of the breast cancer cell lines with breast tumors. We depicted the genomic characteristics of breast primary tumors based on the copy number variation and gene expression profiles and the breast cancer cell lines were compared to different subgroups of breast tumors. We identified that some of the breast cancer cell lines show high correlation with the tumor group that agrees with previous knowledge, while a big part of them do not, including the most used MCF7, MDA-MB-231, and T-47D. We presented a computational framework to identify cell lines that mostly resemble a certain tumor group for the breast tumor study. Our investigation presents a useful guide to bridge the gap between cell lines and tumors and helps to select the most suitable cell line models for personalized cancer studies.
    Full-text · Article · Aug 2015
    • "Notably, aberration profiles in the primary tumors also showed only partial overlap (average of 28%) with their counterparts in the lymph node metastases. Further, Genomic Identification of Significant Targets in Cancer (GISTIC) [Mermel et al., 2011] did not point to CNAs in the uninvolved glandular tissue that would be likely to drive growth of the corresponding tumors (data not shown). Although a portion of CNAs in uninvolved glandular tissue is preserved in the tumors, a considerable fraction shows stochastic distribution, indicating genomic destabilization. "
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    ABSTRACT: Somatic mosaicism for DNA copy number alterations (SMC-CNAs) is defined as gain or loss of chromosomal segments in somatic cells within a single organism. As cells harboring SMC-CNAs can undergo clonal expansion, it has been proposed that SMC-CNAs may contribute to the predisposition of these cells to genetic disease including cancer. Herein, the gross genomic alterations (>500 kbp) were characterized in uninvolved mammary glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array based comparative genomic hybridization showed 10% (6/59) of patients harbored 1 - 359 large SMC-CNAs (mean: 1328 kbp; median: 961 kbp) in a substantial portion of glandular tissue cells, distal from the primary tumor site. SMC-CNAs were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC-CNAs indicating genomic destabilization. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations and rare variants in genes related to maintenance of genomic integrity: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro) and TP53 (p.Arg306*). Co-occurrence of gross SMC-CNAs along with point mutations or rare variants in genes responsible for safeguarding genomic integrity highlights the temporal and spatial neoplastic potential of uninvolved glandular tissue in breast cancer patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2015 · Human Mutation
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    • "Mutated caspase 8 defined a new molecular subtype of OSCC with fewer copy number alterations. Copy number gain of the FGFR1 gene is present in HNSCC (31%), and this gene is amplified in 7% of these tumors (Beroukhim et al., 2010; Mermel et al., 2011; Lin et al., 2014). Clinical trials for several FGF receptor small molecule inhibitors are underway (Lin et al., 2014). "
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    ABSTRACT: Cytogenetic alterations underlie the development of head and neck squamous cell carcinoma (HNSCC), whether tobacco and alcohol use, betel nut chewing, snuff or human papillomavirus (HPV) causes the disease. Many of the molecular genetic aberrations in HNSCC result from these cytogenetic alterations. This review presents a brief introduction to the epidemiology of HNSCC, and discusses the role of HPV in the disease, cytogenetic alterations and their frequencies in HNSCC, their molecular genetic and The Cancer Genome Atlas (TCGA) correlates, prognostic implications, and possible therapeutic considerations. The most frequent cytogenetic alterations in HNSCC are gains of 5p14-15, 8q11-12, and 20q12-13, gains or amplifications of 3q26, 7p11, 8q24, and 11q13, and losses of 3p, 4q35, 5q12, 8p23, 9p21-24, 11q14-23, 13q12-14, 18q23, and 21q22. To understand their effects on tumor cell biology and response to therapy, the cytogenetic findings in HNSCC are increasingly being examined in the context of the biochemical pathways they disrupt. The goal is to minimize morbidity and mortality from HNSCC using cytogenetic abnormalities to identify valuable diagnostic biomarkers for HNSCC, prognostic biomarkers of tumor behavior, recurrence risk, and outcome, and predictive biomarkers of therapeutic response to identify the most efficacious treatment for each individual patient's tumor, all based on a detailed understanding of the next generation biology of HNSCC. © 2014 Wiley Periodicals, Inc.
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