Summary We analyzed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, mRNA arrays, microRNA sequencing and reverse phase protein arrays. Our ability to integrate information across platforms provided key insights into previously-defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at > 10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the Luminal A subtype. We identified two novel protein expression-defined subgroups, possibly contributed by stromal/microenvironmental elements, and integrated analyses identified specific signaling pathways dominant in each molecular subtype including a HER2/p-HER2/HER1/p-HER1 signature within the HER2-Enriched expression subtype. Comparison of Basal-like breast tumors with high-grade Serous Ovarian tumors showed many molecular commonalities, suggesting a related etiology and similar therapeutic opportunities. The biologic finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biologic subtypes of breast cancer.
This study explores the roles of genome copy number abnormalities (CNAs) in breast cancer pathophysiology by identifying associations between recurrent CNAs, gene expression, and clinical outcome in a set of aggressively treated early-stage breast tumors. It shows that the recurrent CNAs differ between tumor subtypes defined by expression pattern and that stratification of patients according to outcome can be improved by measuring both expression and copy number, especially high-level amplification. Sixty-six genes deregulated by the high-level amplifications are potential therapeutic targets. Nine of these (FGFR1, IKBKB, ERBB2, PROCC, ADAM9, FNTA, ACACA, PNMT, and NR1D1) are considered druggable. Low-level CNAs appear to contribute to cancer progression by altering RNA and cellular metabolism.
Comparative genomic hybridization was applied to 5 breast cancer cell lHes and 33 primary tumors to discover and map regions of the genome with increased DNAsequence copy-number. Two-thirds of primary tumors and almost all cell lines showed increased DNA-sequence copynumber affecting a total of 26 chromosomal subregions. Most of these loci were distinct from those of currently known amplified genes in breast cancer, with sequences originating from 17q22-q24 and 20q13 showing the highest frequency of amplification. The results indicate that these chromosomal regions may contain previously unknown genes whose increased expression contributes to breast cancer progression.Chromosomal regions with increased copy-number often spanned tens of Mb, suggesting involvement of more than one gene in each region.Increased expression of specific genes plays an important role in the pathogenesis of solid tumors (1-3). Gene amplification, characterized by distinct cytogenetic structures, such as homogeneously stained regions, double-minute chromosomes (1-7), is commonly found in tumor cells and is considered an important mechanism by which tumor cells gain increased levels of expression of critical genes. Increased copy-numbers also occur as a result of extensive chromosomal rearrangements, such as duplications, isochromosomes, extra marker chromosomes, and acentric chromosomal fragments that may affect the gene dosage of numerous genes simultaneously. In breast cancer, cytogenetic evidence of increased DNA-sequence copy-number is common (4-7). For example, homogeneously stained regions have been found in 60% of primary breast carcinomas (7). Although genetic analysis has found amplification of oncogenes, such as ERBB2 (17q12), MYC (8q24), PRADII CYCLIN D (11q13), FLG (8p12), BEK (10q24), and IGFR-1/FES (15q24-q25) (8-12), in most cases these do not explain the presence of large homogeneously stained regions (13). Thus, amplification of currently unknown genes may often occur in breast cancer.We have recently developed a method, comparative genomic hybridization (CGH), for surveying entire genomes for DNA-sequence copy-number variation (14, 15). In CGH, the relative intensities of tumor DNA (detected using green fluorescence) and normal reference DNA (detected with red fluorescence) after hybridization to normal metaphase chromosomes is used to reveal and map regions of increased DNA-sequence copy number (14-16). These loci are visualized as chromosomal region(s) with predominantly green fluorescence ( Fig. 1) and quantified by digital image analysis as an increased green-to-red fluorescence intensity ratio (Fig. 2). As no specific probes or previous knowledge of aberrations is required, CGH is especially suitable for identification and mapping of previously unknown DNA copy-number changes that may highlight locations of important genes. In the present study, we have used CGH to identify and map increases in DNA-sequence copy number in 15 breast cancer cell lines and 33 uncultured primary breast tumors. MATERIALS AND ME...
Purpose: To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau (VHL) gene in the cancer genome, unique to clear cell renal cancer (ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics. Experimental Design: As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter. Results: We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC. Conclusion: Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.Considerable progress has been made in understanding the genetic basis of kidney cancer (1, 2). The susceptibility genes associated with several forms of inherited renal cell cancer (RCC) have been identified by rigorous analysis of families using genetic linkage analysis and positional cloning (3 -7). The most common subtype of RCC is the conventional clear cell type (ccRCC), which accounts for f75% of cases. In both familial and sporadic ccRCC, allelic inactivation of the von
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