RT info:eu-repo/semantics/article
T1 Whole-exome sequencing identifies somatic mutations associated with mortality in metastatic clear cell kidney carcinoma
A1 Morales González, Manuel José
A1 Mendoza-Alvarez, Alejandro
A1 Guillen-Guio, Beatriz
A1 Baez-Ortega, Adrian
A1 Hernandez-Perez, Carolina
A1 Lakhwani-Lakhwani, Sita
A1 Maeso, Maria-del-Carmen
A1 Lorenzo-Salazar, Jose M.
A1 Morales, Manuel
A1 Flores, Carlos
A2 Medicina InternaDermatología y Psiquiatría
K1 ccRCC
K1 whole-exome sequencing
K1 kidney cancer
K1 somatic mutation
K1 mortality
AB Clear cell renal cell carcinoma (ccRCC) is among the most aggressive histologicsubtypes of kidney cancer, representing about 3% of all human cancers. Patients atstage IV have nearly 60% of mortality in 2–3 years after diagnosis. To date, most ccRCCstudies have used DNA microarrays and targeted sequencing of a small set of wellestablished, commonly altered genes. An exception is the large multi-omics study of TheCancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC), which identifiednew ccRCC genes based on whole exome-sequencing (WES) data, and molecularprognostic signatures based on transcriptomics, epigenetics and proteomics data.Applying WES to simultaneously interrogate virtually all exons in the human genomefor somatic variation, here we analyzed the burden of coding somatic mutations inmetastatic ccRCC primary tumors, and its association with patient mortality from cancer,in patients who received VEGF receptor-targeting drugs as the first-line therapy. To thisend, we sequenced the exomes of ten tumor–normal pairs of ccRCC patient tissuesfrom primary biopsies at >100× mean depth and called somatic coding variation.Mutation burden analysis prioritized 138 genes linked to patient mortality. A gene setenrichment analysis evidenced strong statistical support for the abundance of genesinvolved in the development of kidney cancer (p = 2.31 × 10−9) and carcinoma(p = 1.22 × 10−5), with 49 genes having direct links with kidney cancer according to thepublished records. Two of these genes, SIPA1L2 and EIF3A, demonstrated independentassociations with mortality in TCGA-KIRC project data. Besides, three mutationalsignatures were found to be operative in the tumor exomes, one of which (COSMICsignature 12) has not been previously reported in ccRCC. Selection analysis yieldedno detectable evidence of overall positive or negative selection, with the exome-wide number of nonsynonymous substitutions per synonymous site reflecting largely neutraltumor evolution. Despite the limited sample size, our results provide evidence forcandidate genes where somatic mutation burden is tentatively associated with patientmortality in metastatic ccRCC, offering new potential pharmacological targets and abasis for further validation studies
YR 2019
FD 2019
LK http://riull.ull.es/xmlui/handle/915/40034
UL http://riull.ull.es/xmlui/handle/915/40034
LA en
DS Repositorio institucional de la Universidad de La Laguna
RD 29-nov-2024