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Peng M, Bakker JL, Dicioccio RA, et al. Inactivating Mutations in GT198 in Familial and Early-Onset Breast and Ovarian Cancers. Genes Cancer. 2013;4(1):15-25doi: 10.1177/1947601913486344.
Peng, M., Bakker, J. L., Dicioccio, R. A., Gille, J. J., Zhao, H., Odunsi, K., Sucheston, L., Jaafar, L., Mivechi, N. F., Waisfisz, Q., & Ko, L. (2013). Inactivating Mutations in GT198 in Familial and Early-Onset Breast and Ovarian Cancers. Genes & cancer, 4(1), 15-25. https://doi.org/10.1177/1947601913486344
Peng, Min, et al. "Inactivating Mutations in GT198 in Familial and Early-Onset Breast and Ovarian Cancers." Genes & cancer vol. 4,1 (2013): 15-25. doi: https://doi.org/10.1177/1947601913486344
Peng M, Bakker JL, Dicioccio RA, Gille JJ, Zhao H, Odunsi K, Sucheston L, Jaafar L, Mivechi NF, Waisfisz Q, Ko L. Inactivating Mutations in GT198 in Familial and Early-Onset Breast and Ovarian Cancers. Genes Cancer. 2013 Jan;4(1):15-25. doi: 10.1177/1947601913486344. PMID: 23946868; PMCID: PMC3743154.
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Genes Cancer. 2013 Jan;4(1):15-25. doi: 10.1177/1947601913486344.

Inactivating Mutations in GT198 in Familial and Early-Onset Breast and Ovarian Cancers.

Genes & cancer

Min Peng, Janine L Bakker, Richard A Dicioccio, Johan J P Gille, Hua Zhao, Kunle Odunsi, Lara Sucheston, Lahcen Jaafar, Nahid F Mivechi, Quinten Waisfisz, Lan Ko

Affiliations

  1. Cancer Center, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.

PMID: 23946868 PMCID: PMC3743154 DOI: 10.1177/1947601913486344

Abstract

The human GT198 gene (gene symbol PSMC3IP) is located at chromosome 17q21, 470 kb proximal to BRCA1, a locus previously linked to breast and ovarian cancer predisposition. Its protein product (also known as TBPIP and Hop2) has been shown to regulate steroid hormone receptor-mediated gene activation and to stimulate homologous recombination in DNA repair. Here, we screened germline mutations in GT198 in familial and early-onset breast and ovarian cancer patients. We have identified 8 germline variants in a total of 212 index patients including reoccurring nonsense mutation c.310C>T (p.Q104X) and 5' UTR mutation c.-37A>T, each found in 2 unrelated families. Most identified index patients from cancer families had early onsets with a median age of 35 years. c.310C>T was absent in a total of 564 control individuals analyzed. GT198 gene amplification with an imbalanced mutant copy gain was identified in the blood DNA of one of the patients carrying c.310C>T. When tested, this truncating mutation abolished DNA damage-induced Rad51 foci formation. In addition, we have identified 15 somatic mutations in 2 tumors from 1 patient carrying germline mutation c.-37A>T. The presence of a somatic mutation on the wild-type allele showed that GT198 was biallelically mutated in the tumor. The somatic mutations identified near a splicing junction site caused defective alternative splicing and truncated the open reading frame. Therefore, distinct mutations may cause a similar consequence by truncating the full-length protein and inducing a loss of the wild type. Our study provides the first evidence of the presence of inactivating mutations in GT198 in familial and early-onset breast and ovarian cancer patients. Mutations in GT198, a gene regulating DNA repair, potentially contribute to an increased risk in familial breast and ovarian cancers.

Keywords: GT198; breast and ovarian cancer; gene amplification; mutation

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