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Possible role of the WDR3 gene on genome stability in thyroid cancer patients.

ABSTRACT: The role of the WDR3 gene on genomic instability has been evaluated in a group of 115 differentiated thyroid cancer (DTC) patients. Genomic instability has been measured according to the response of peripheral blood lymphocytes to ionizing radiation (0.5 Gy). The response has been measured with the micronucleus (MN) test evaluating the frequency of binucleated cells with MN (BNMN), both before and after the irradiation. No differences between genotypes, for the BNMN frequencies previous the irradiation, were observed. Nevertheless significant decreases in DNA damage after irradiation were observed in individuals carrying the variant alleles for each of the three genotyped SNPs: rs3754127 [-8.85 (-15.01 to -2.70), P<0.01]; rs3765501 [-8.98 (-15.61 to -2.36), P<0.01]; rs4658973 [-8.70 (-14.94 to -2.46), P<0.01]. These values correspond to those obtained assuming a dominant model. This study shows for the first time that WDR3 can modulate genome stability.

SUBMITTER: Garcia-Quispes WA

PROVIDER: S-EPMC3458856 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Possible role of the WDR3 gene on genome stability in thyroid cancer patients.

García-Quispes Wilser Andrés WA Pastor Susana S Galofré Pere P Biarnés Josefina J Castell Joan J Velázquez Antonia A Marcos Ricard R

PloS one 20120926 9

The role of the WDR3 gene on genomic instability has been evaluated in a group of 115 differentiated thyroid cancer (DTC) patients. Genomic instability has been measured according to the response of peripheral blood lymphocytes to ionizing radiation (0.5 Gy). The response has been measured with the micronucleus (MN) test evaluating the frequency of binucleated cells with MN (BNMN), both before and after the irradiation. No differences between genotypes, for the BNMN frequencies previous the irra ...[more]

PMID: 23049746

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Project description:Familial inheritance in non-medullary thyroid cancer (NMTC) is an area that has yet to be adequately explored. Despite evidence suggesting strong familial clustering of non-syndromic NMTC, known variants still account for a very small percentage of the genetic burden. In a recent whole genome sequencing (WGS) study of five families with several NMTCs, we shortlisted promising variants with the help of our in-house developed Familial Cancer Variant Prioritization Pipeline (FCVPPv2). Here, we report potentially disease-causing variants in checkpoint kinase 2 (CHEK2), Ewing sarcoma breakpoint region 1 (EWSR1) and T-lymphoma invasion and metastasis-inducing protein 1 (TIAM1) in one family. Performing WGS on three cases, one probable case and one healthy individual in a family with familial NMTC left us with 112254 variants with a minor allele frequency of less than 0.1%, which was reduced by pedigree-based filtering to 6368. Application of the pipeline led to the prioritization of seven coding and nine non-coding variants from this family. The variant identified in CHEK2, a known tumor suppressor gene involved in DNA damage-induced DNA repair, cell cycle arrest, and apoptosis, has been previously identified as a germline variant in breast and prostate cancer and has been functionally validated by Roeb et al. in a yeast-based assay to have an intermediate effect on protein function. We thus hypothesized that this family may harbor additional disease-causing variants in other functionally related genes. We evaluated two further variants in EWSR1 and TIAM1 with promising in silico results and reported interaction in the DNA-damage repair pathway. Hence, we propose a polygenic mode of inheritance in this family. As familial NMTC is considered to be more aggressive than its sporadic counterpart, it is important to identify such susceptibility genes and their associated pathways. In this way, the advancement of personalized medicine in NMTC patients can be fostered. We also wish to reopen the discussion on monogenic vs polygenic inheritance in NMTC and instigate further development in this area of research.

Dataset Information

Possible role of the WDR3 gene on genome stability in thyroid cancer patients.

Publications

Possible role of the WDR3 gene on genome stability in thyroid cancer patients.

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