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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)15-25
Number of pages11
JournalGenes and Cancer
Volume4
Issue number1-2
DOIs
StatePublished - Mar 1 2013

Fingerprint

Ovarian Neoplasms
Breast Neoplasms
Mutation
Germ-Line Mutation
Genes
Recombinational DNA Repair
Neoplasms
Gene Amplification
Nonsense Codon
Steroid Receptors
5' Untranslated Regions
Alternative Splicing
DNA Repair
Transcriptional Activation
Open Reading Frames
DNA Damage
Proteins
Chromosomes
Alleles
Hormones

Keywords

  • GT198
  • breast and ovarian cancer
  • gene amplification
  • mutation

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

Cite this

Peng, M., Bakker, J. L., DiCioccio, R. A., Gille, J. J. P., Zhao, H., Odunsi, K., ... Ko, L. (2013). Inactivating Mutations in GT198 in Familial and Early-Onset Breast and Ovarian Cancers. Genes and Cancer, 4(1-2), 15-25. https://doi.org/10.1177/1947601913486344

Inactivating Mutations in GT198 in Familial and Early-Onset Breast and Ovarian Cancers. / Peng, Min; Bakker, Janine L.; DiCioccio, Richard A.; Gille, Johan J.P.; Zhao, Hua; Odunsi, Kunle; Sucheston, Lara; Jaafar, Lahcen; Mivechi, Nahid F; Waisfisz, Quinten; Ko, Lan.

In: Genes and Cancer, Vol. 4, No. 1-2, 01.03.2013, p. 15-25.

Research output: Contribution to journalArticle

Peng, M, Bakker, JL, DiCioccio, RA, Gille, JJP, Zhao, H, Odunsi, K, Sucheston, L, Jaafar, L, Mivechi, NF, Waisfisz, Q & Ko, L 2013, 'Inactivating Mutations in GT198 in Familial and Early-Onset Breast and Ovarian Cancers', Genes and Cancer, vol. 4, no. 1-2, pp. 15-25. https://doi.org/10.1177/1947601913486344
Peng M, Bakker JL, DiCioccio RA, Gille JJP, Zhao H, Odunsi K et al. Inactivating Mutations in GT198 in Familial and Early-Onset Breast and Ovarian Cancers. Genes and Cancer. 2013 Mar 1;4(1-2):15-25. https://doi.org/10.1177/1947601913486344
Peng, Min ; Bakker, Janine L. ; DiCioccio, Richard A. ; Gille, Johan J.P. ; Zhao, Hua ; Odunsi, Kunle ; Sucheston, Lara ; Jaafar, Lahcen ; Mivechi, Nahid F ; Waisfisz, Quinten ; Ko, Lan. / Inactivating Mutations in GT198 in Familial and Early-Onset Breast and Ovarian Cancers. In: Genes and Cancer. 2013 ; Vol. 4, No. 1-2. pp. 15-25.
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