Dataset Information

Gender Specific Mutation Incidence and Survival Associations in Clear Cell Renal Cell Carcinoma (CCRCC).

ABSTRACT: Renal cell carcinoma (RCC) is diagnosed in >200,000 individuals worldwide each year, accounting for ~2% of all cancers, but the spread of this disease amongst genders is distinctly uneven. In the U.S. the male:female incidence ratio is approximately 2:1. A potential hypothesis is mutation spectra may differ between tumors dependent upon the gender of the patient, such as mutations of X chromosome encoded genes being more prevalent in male-derived tumors. Combined analysis of three recent large-scale clear cell renal cell carcinoma (CCRCC) mutation sequencing projects identified a significantly increased mutation frequency of PBRM1 and the X chromosome encoded KDM5C in tumors from male patients and BAP1 in tumors from female patients. Mutation of BAP1 had previously been significantly associated with poorer overall survival; however, when stratified by gender, mutation of BAP1 only significantly affected overall survival in female patients. Mutation of chromatin remodeling genes alters gene regulation, but the overall effect of these alterations may also be modified by the presence of other gender specific factors. Thus, the combination of gender and mutation of a specific gene, such as BAP1, may have implications not only for prognosis but also for understanding the role of chromatin remodeling gene mutations in kidney cancer progression.

SUBMITTER: Ricketts CJ

PROVIDER: S-EPMC4618848 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Gender Specific Mutation Incidence and Survival Associations in Clear Cell Renal Cell Carcinoma (CCRCC).

Ricketts Christopher J CJ Linehan W Marston WM

PloS one 20151020 10

Renal cell carcinoma (RCC) is diagnosed in >200,000 individuals worldwide each year, accounting for ~2% of all cancers, but the spread of this disease amongst genders is distinctly uneven. In the U.S. the male:female incidence ratio is approximately 2:1. A potential hypothesis is mutation spectra may differ between tumors dependent upon the gender of the patient, such as mutations of X chromosome encoded genes being more prevalent in male-derived tumors. Combined analysis of three recent large-s ...[more]

PMID: 26484545

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Project description:ObjectiveTo discuss the dual energy spectral computer tomography (CT) imaging features of the pathological grading of clear cell renal cell carcinoma (ccRCC) and the correlation between spectral CT imaging features and pathology.Materials and methodsWe performed analyses of 62 patients with confirmed diagnosis of ccRCC. All patients underwent non-enhanced CT and dual-phase (cortex phase, CP and parenchyma phase, PP) contrast-enhanced CT with dual energy spectral mode. The subjects were pathologically divided into two groups: low-grade group (Fuhrman 1/2) and high-grade group (Fuhrman 3/4). The CT value of each lesion was measured on the monochromatic image at 70 keV. The normalized iodine concentrations (NIC) and the slope of the spectrum curve were calculated. The qualitative morphological parameters, including tumor shape, calcification, pseudocapsule, necrosis, and enhancement mode, were compared between the two groups. The quantitative data were compared using Student's t-test, and the enumeration data were analyzed using the chi-square test between low-grade and high-grade ccRCC.Receiver operating characteristic curve was used to determine the sensitivity and specificity of the quantitative parameters in two groups.ResultsThe CT value, NIC, and mean slope of the low-grade group were increased compared with the high-grade group during CP (P = 0.001, P = 0.043, and P<0.001, respectively). The CT did not differ significantly during PP (P = 0.134); however, the NIC and mean slope varied considerably in the low grade compared with the high-grade group (P = 0.048, P = 0.017, respectively). The CT threshold value, NIC, and slope had high sensitivity and specificity in differentiating low-grade ccRCC from high-grade ccRCC. The tumor shape, pseudocapsule, and necrosis differed significantly between the two groups (P<0.05).ConclusionsDual energy spectral CT with the quantitative analysis of iodine concentration and qualitative analysis of morphological characteristics increases the accuracy of diagnosing the pathological grade of ccRCC.

Project description:Tumorigenic processes are understood to be driven by epi-/genetic and genomic alterations from single point mutations to chromosomal alterations such as insertions and deletions of nucleotides up to gains and losses of large chromosomal fragments including products of chromosomal rearrangements e.g. fusion genes and proteins. Overall comparisons of copy number alterations (CNAs) presented in 48 clear cell renal cell carcinoma (ccRCC) genomes resulted in ratios of gene losses versus gene gains between 26 ccRCC Fuhrman malignancy grades G1 (ratio 1.25) and 20 G3 (ratio 0.58). Gene losses and gains of 15762 CNA genes were mapped to 795 chromosomal cytoband loci including 280 KEGG pathways. CNAs were classified according to their contribution to Fuhrman tumour gradings G1 and G3. Gene gains and losses turned out to be highly structured processes in ccRCC genomes enabling the subclassification and stratification of ccRCC tumours in a genome-wide manner. CNAs of ccRCC seem to start with common tumour related gene losses flanked by CNAs specifying Fuhrman grade G1 losses and CNA gains favouring grade G3 tumours. The appearance of recurrent CNA signatures implies the presence of causal mechanisms most likely implicated in the pathogenesis and disease-outcome of ccRCC tumours distinguishing lower from higher malignant tumours. The diagnostic quality of initial 201 genes (108 genes supporting G1 and 93 genes G3 phenotypes) has been successfully validated on published Swiss data (GSE19949) leading to a restricted CNA gene set of 171 CNA genes of which 85 genes favour Fuhrman grade G1 and 86 genes Fuhrman grade G3. Regarding these gene sets overall survival decreased with the number of G3 related gene losses plus G3 related gene gains. CNA gene sets presented define an entry to a gene-directed and pathway-related functional understanding of ongoing copy number alterations within and between individual ccRCC tumours leading to CNA genes of prognostic and predictive value.

Project description:Previously studies have shown that apoptosis-related genes play an essential role in normal cell turnover, maintaining the immune system function, and inducing cell death. However, their prognostic roles in clear cell renal cell carcinoma (ccRCC) have not been thoroughly investigated. In the present study, apoptosis-related genes expression profiles from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database were used as training dataset and external validation dataset, respectively. According to the systematical analysis of the apoptosis-related gene expression profile, we constructed a gene signature to determine the role of apoptosis-related genes in the survival of ccRCC. We discovered that patients in the low-risk group have a better survival than high-risk group and the signature could serve as an independent prognostic factor. A nomogram, including a signature and clinical factors, were constructed to estimate the individual survival probability. The Gene set enrichment analysis (GSEA) identified some significant pathways which may contribute to understanding the underlying mechanism of ccRCC. In addition, the prognostic efficiency of the risk model was further validated in the disease free survival (DFS) and the ICGC dataset, respectively. We also identified three molecular subtypes (named C1, C2, and C3) based on apoptosis-related gene expression. We found that C1 was corresponding to a worse survival outcome and showed a high drug sensitivity of sorafenib and sunitinib. C2 and C3 were corresponding to a better survival outcome and presented a low drug sensitivity to sorafenib and sunitinib. Moreover, we found that C2 and C3 have more likelihood to be respond to immunotherapy. Together, the apoptosis-related gene signature and three molecular subtypes may promote the understanding of the underlying molecular mechanism of ccRCC, and provided reference for developing individualized treatment of the ccRCC patients.

Dataset Information

Gender Specific Mutation Incidence and Survival Associations in Clear Cell Renal Cell Carcinoma (CCRCC).

Publications

Gender Specific Mutation Incidence and Survival Associations in Clear Cell Renal Cell Carcinoma (CCRCC).

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