DNA copy number profiling reveals extensive genomic loss in hereditary BRCA1 and BRCA2 ovarian carcinomas

Kamieniak, Marta M.; Muñoz-Repeto, Iván; Rico, Daniel; Osorio, Ana; Urioste, Miguel; García-Donás, Jesús; Hernando, Susana; Robles-Díaz, Luis; Cajal, Teresa Ramón y; Cazorla, Alicia; Sáez, Raquel; Garcia-Bueno, Jose Maria; Domingo, Samuel; Borrego, Salud; Palacios, José; Wiel, Mark A. van de; Ylstra, Bauke; Benı́tez, Javier; García, María J.

doi:10.1038/bjc.2013.141

Cited by 19 publications

(23 citation statements)

References 44 publications

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“…DLC1 and DLC2 copy number loss percentages in the TCGA breast carcinoma dataset were 33% and 18% respectively (data not shown). No DLC3 copy number losses were found in any of the tumors examined in this study, although losses at the DLC3/STARD8 locus at Xq13 have been reported in ovarian carcinomas [38]. As expected, copy number loss of DLC1 was found to be associated with its reduced expression.…”

Section: Discussionsupporting

confidence: 67%

DLC1 is the principal biologically-relevant down-regulated DLC family member in several cancers

et al. 2016

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The RHO family of RAS-related GTPases in tumors may be activated by reduced levels of RHO GTPase accelerating proteins (GAPs). One common mechanism is decreased expression of one or more members of the Deleted in Liver Cancer (DLC) family of Rho-GAPs, which comprises three closely related genes (DLC1, DLC2, and DLC3) that are down-regulated in a wide range of malignancies. Here we have studied their comparative biological activity in cultured cells and used publicly available datasets to examine their mRNA expression patterns in normal and cancer tissues, and to explore their relationship to cancer phenotypes and survival outcomes. In The Cancer Genome Atlas (TCGA) database, DLC1 expression predominated in normal lung, breast, and liver, but not in colorectum. Conversely, reduced DLC1 expression predominated in lung squamous cell carcinoma (LSC), lung adenocarcinoma (LAD), breast cancer, and hepatocellular carcinoma (HCC), but not in colorectal cancer. Reduced DLC1 expression was frequently associated with promoter methylation in LSC and LAD, while DLC1 copy number loss was frequent in HCC. DLC1 expression was higher in TCGA LAD patients who remained cancer-free, while low DLC1 had a poorer prognosis than low DLC2 or low DLC3 in a more completely annotated database. The poorest prognosis was associated with low expression of both DLC1 and DLC2 (P < 0.0001). In cultured cells, the three genes induced a similar reduction of Rho-GTP and cell migration. We conclude that DLC1 is the predominant family member expressed in several normal tissues, and its expression is preferentially reduced in common cancers at these sites.

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Section: Discussionsupporting

confidence: 67%

DLC1 is the principal biologically-relevant down-regulated DLC family member in several cancers

et al. 2016

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“…The profile of copy number variation (CNV) resembled those previously described for high-grade serous ovarian cancers [20, 21]. Given our targeted design, we focused on gene-specific CNVs of tumor suppressor genes TP53 , PTEN , RB1 , and NF1 , as well as genes involved in HR.…”

Section: Resultsmentioning

confidence: 99%

Paclitaxel is necessary for improved survival in epithelial ovarian cancers with homologous recombination gene mutations

Jean

Katsaros

et al. 2016

Oncotarget

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PURPOSETo investigate the impact of somatic mutations in homologous recombination (HR) genes on the chemotherapeutic response and survival of patients with epithelial ovarian cancer (EOC).EXPERIMENTAL DESIGNWe performed targeted massively parallel sequencing of tumor DNA from 158 patients with EOC. We associated adjuvant chemotherapy and clinical outcome with mutations in selected genes, focusing on those encoding HR proteins.RESULTSHR mutations were found in 47 (30%) tumors. We did not detect an overall survival (OS) difference in advanced stage patients whose tumors had HR mutations compared to those without (median OS of 49.6 months (95% CI 29.9-57.7) vs. 43.3 months (95% CI 31.9-75.47), p = 0.87). However, when stratified by chemotherapy regimen, patients whose tumors had TP53 and HR mutations demonstrated a marked survival advantage when treated with platinum and paclitaxel vs. platinum +/− cyclophosphamide (median OS of 90 months (95% CI 50-NA) vs. 29.5 months (95% CI 17.7-50.5), p = 0.0005).CONCLUSIONSPrevious studies demonstrating a survival advantage for EOC patients with somatic HR mutations have been conducted with almost universal use of both platinum and paclitaxel. Our study is the first to our knowledge to compare cohorts with somatic HR gene mutations treated with and without paclitaxel containing platinum regimens. The survival benefit attributed to the platinum sensitivity of HR deficient ovarian cancers may depend upon the combined use of paclitaxel.

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“…A series of 42 formalin‐fixed, paraffin‐embedded (FFPE) HGSOCs previously characterized using high‐resolution array CGH (4 × 180 K, Agilent Technologies, Palo Alto, CA) assuring >80% tumoral cellularity (Kamieniak et al., 2013) was included in the present study. Since the previous study (Kamieniak et al., 2013) aimed to characterize copy number changes in hereditary ovarian tumors and to describe similarities and differences with sporadic tumors the series comprised 30 familial and 12 sporadic HGSOCs. Inclusion of hereditary and sporadic cases in the current study allowed us to evaluate associations between the BRCA status and potential DNA copy number alterations predicting clinical outcome.…”

Section: Methodsmentioning

confidence: 99%

“…The index case of each family was screened for mutations in the BRCA1 and BRCA2 genes by a combination of denaturing high performance liquid chromatography (DHPLC) and sequencing. Details about the screening of germline mutations in the BRCA1 and BRCA2 genes can be found elsewhere (Kamieniak et al., 2013). The 12 sporadic tumors (with no reported first or second degree relative with breast or ovarian cancer) were obtained from one hospital (H. Virgen del Rocio, Seville).…”

Section: Methodsmentioning

confidence: 99%

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Deletion at 6q24.2–26 predicts longer survival of high‐grade serous epithelial ovarian cancer patients

et al. 2014

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Standard treatments for advanced high‐grade serous ovarian carcinomas (HGSOCs) show significant side‐effects and provide only short‐term survival benefits due to disease recurrence. Thus, identification of novel prognostic and predictive biomarkers is urgently needed. We have used 42 paraffin‐embedded HGSOCs, to evaluate the utility of DNA copy number alterations, as potential predictors of clinical outcome. Copy number‐based unsupervised clustering stratified HGSOCs into two clusters of different immunohistopathological features and survival outcome (HR = 0.15, 95%CI = 0.03–0.81; Padj = 0.03). We found that loss at 6q24.2–26 was significantly associated with the cluster of longer survival independently from other confounding factors (HR = 0.06, 95%CI = 0.01–0.43, Padj = 0.005). The prognostic value of this deletion was validated in two independent series, one consisting of 36 HGSOCs analyzed by fluorescent in situ hybridization (P = 0.04) and another comprised of 411 HGSOCs from the Cancer Genome Atlas study (TCGA) (HR = 0.67, 95%CI = 0.48–0.93, Padj = 0.019). In addition, we confirmed the association of low expression of the genes from the region with longer survival in 799 HGSOCs (HR = 0.74, 95%CI = 0.61–0.90, log‐rank P = 0.002) and 675 high‐FIGO stage HGSOCs (HR = 0.76, 95%CI = 0.61–0.96, log‐rank P = 0.02) available from the online tool KM‐plotter. Finally, by integrating copy number, RNAseq and survival data of 296 HGSOCs from TCGA we propose a few candidate genes that can potentially explain the association. Altogether our findings indicate that the 6q24.2–26 deletion is an independent marker of favorable outcome in HGSOCs with potential clinical value as it can be analyzed by FISH on tumor sections and guide the selection of patients towards more conservative therapeutic strategies in order to reduce side‐effects and improve quality of life.

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DNA copy number profiling reveals extensive genomic loss in hereditary BRCA1 and BRCA2 ovarian carcinomas

Cited by 19 publications

References 44 publications

DLC1 is the principal biologically-relevant down-regulated DLC family member in several cancers

DLC1 is the principal biologically-relevant down-regulated DLC family member in several cancers

Paclitaxel is necessary for improved survival in epithelial ovarian cancers with homologous recombination gene mutations

Deletion at 6q24.2–26 predicts longer survival of high‐grade serous epithelial ovarian cancer patients

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