ORCID Profile
0000-0003-0658-0467
Current Organisation
University of California, San Diego
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Publisher: Wiley
Date: 06-11-2019
DOI: 10.1002/IJC.32683
Publisher: BMJ
Date: 21-10-2022
Abstract: Patients with serrated polyposis syndrome (SPS) have multiple and/or large serrated colonic polyps and higher risk for colorectal cancer. SPS inherited genetic basis is mostly unknown. We aimed to identify new germline predisposition factors for SPS by functionally evaluating a candidate gene and replicating it in additional SPS cohorts. After a previous whole-exome sequencing in 39 SPS patients from 16 families (discovery cohort), we sequenced specific genes in an independent validation cohort of 211 unrelated SPS cases. Additional external replication was also available in 297 SPS cases. The WNK2 gene was disrupted in HT-29 cells by gene editing, and WNK2 variants were transfected using a lentiviral delivery system. Cells were analysed by immunoblots, real-time PCR and functional assays monitoring the mitogen-activated protein kinase (MAPK) pathway, cell cycle progression, survival and adhesion. We identified 2 rare germline variants in the WNK2 gene in the discovery cohort, 3 additional variants in the validation cohort and 10 other variants in the external cohorts. Variants c.2105C T (p.Pro702Leu), c.4820C T (p.Ala1607Val) and c.6157G A (p.Val2053Ile) were functionally characterised, displaying higher levels of phospho-PAK1/2, phospho-ERK1/2, CCND1, clonogenic capacity and MMP2. After whole-exome sequencing in SPS cases with familial aggregation and replication of results in additional cohorts, we identified rare germline variants in the WNK2 gene. Functional studies suggested germline WNK2 variants affect protein function in the context of the MAPK pathway, a molecular hallmark in this disease.
Publisher: Cold Spring Harbor Laboratory
Date: 29-06-2023
DOI: 10.1101/2023.06.20.23291538
Abstract: International differences in the incidence of many cancer types indicate the existence of carcinogen exposures which make a substantial contribution to cancer burden, vary geographically, and have underlying agents thus far unidentified by conventional epidemiology 1 . This pertains to clear cell renal cell carcinomas (ccRCC), for which obesity, hypertension, and tobacco smoking are risk factors but do not explain its geographical variation in incidence 2 . Some carcinogens generate somatic mutations and past exposures can be inferred from the patterns of mutations found in cancer genomes. Therefore, we sequenced the whole genomes of 962 ccRCC from 11 countries of varying incidence. Somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures likely caused by extracts of Aristolochia plants were present in most cases and rare elsewhere. In Japan, a mutational signature of unknown cause was found in % cases and % elsewhere. Another mutational signature of unknown cause was ubiquitous and associated with kidney cancer incidence rates (p-value × 10 −18 ), with higher numbers of mutations in countries with higher risk. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension suggesting non-mutagenic mechanisms of action underlying these risk factors. The results indicate the existence of multiple, widespread, geographically variable mutagenic exposures to known and unknown agents, which may contribute to the incidence of kidney cancer.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2019
Location: United States of America
Location: Spain
No related grants have been discovered for Marcos Díaz-Gay.