BRCA1 and BRCA2 germline mutations in Korean breast cancer patients at high risk of carrying mutations

A PARP inhibitor is a rationally designed targeted therapy for cancers with impaired DNA repair abilities. RAD51C is a paralog of RAD51 that has an important role in the DNA damage response. We found that cell lines sensitive to a novel oral PARP inhibitor, olaparib, had low levels of RAD51C expression using microarray analysis, and we therefore hypothesized that low expression of RAD51C may hamper the DNA repair process, resulting in increased sensitivity to olaparib. Compared with the cells with normal RAD51C expression levels, RAD51C-deficient cancer cells were more sensitive to olaparib, and a higher proportion underwent cell death by inducing G 2 -M cell-cycle arrest and apoptosis. The restoration of RAD51C in a sensitive cell line caused attenuation of olaparib sensitivity. In contrast, silencing of RAD51C in a resistant cell line enhanced the sensitivity to olaparib, and the number of RAD51 foci decreased with ablated RAD51C expression. We also found the expression of RAD51C was downregulated in cancer cells due to epigenetic changes and RAD51C expression was low in some gastric cancer tissues. Furthermore, olaparib significantly suppressed RAD51C-deficient tumor growth in a xenograft model. In summary, RAD51C-deficient cancer cells are highly sensitive to olaparib and offer preclinical proof-of-principle that RAD51C deficiency may be considered a biomarker for predicting the antitumor effects of olaparib. Mol Cancer Ther; 12(6); 865-77. Ó2013 AACR.

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“…The BRCA1 and BRCA2 mutations were analyzed using fluorescent-conformation sensitive gel electrophoresis (F-CSGE), as described previously (17).…”

Section: Brca1 and Brca2 Mutation Analysismentioning

confidence: 99%

RAD51C-Deficient Cancer Cells Are Highly Sensitive to the PARP Inhibitor Olaparib

Min

Yoon

et al. 2013

Molecular Cancer Therapeutics

123

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“…Of the reported studies conducted in China, Korea, Japan and Malaysia, germ-line BRCA1 mutation occurred in approximately 4-9% of breast cancer patients. [9][10][11][12] This is lower than the B10% reported in non-Jewish Caucasian women with early-onset or a familial history of breast cancer. 8 In Taiwan, two small studies found a few benign polymorphisms of BRCA1 without the identification of pathological mutants associated with breast cancer development.…”

Section: Introductionmentioning

confidence: 65%

“…10 One Korean study demonstrated 6.8% prevalence of germ-line BRCA1 mutation from 354 patients with familial breast cancer. 11 Possible reasons for the higher prevalence in our cohort are the small patient number and slightly different enrollment criteria used in the study. Also, VUS of BRCA1 was not characterized in the prior Chinese, Korean and Malaysia studies, and these studies only included frame-shift mutations and little known missense mutations as deleterious mutants.…”

Section: Discussionmentioning

confidence: 94%

Multimodel assessment of BRCA1 mutations in Taiwanese (ethnic Chinese) women with early-onset, bilateral or familial breast cancer

et al. 2012

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Although evidence suggests an importance of genetic factors in the development of breast cancer in Taiwanese (ethnic Chinese) women, including a high incidence of early-onset and secondary contralateral breast cancer, a major breast cancer predisposition gene, BRCA1, has not been well studied in this population. In fact, the carcinogenic impacts of many genetic variants of BRCA1 are unknown and classified as variants of uncertain significance (VUS). It is therefore important to establish a method to characterize the BRCA1 VUSs and understand their role in Taiwanese breast cancer patients. Accordingly, we developed a multimodel assessment strategy consisting of a prescreening portion and a validated functional assay to study breast cancer patients with early-onset, bilateral or familial breast cancer. We found germ-line BRCA1 mutations in 11.1% of our cohort and identified one novel missense mutation, c.5191C4A. Two genetic variants were initially classified as VUSs (c.1155C4T and c.5191C4A). c.1155C4T is not predicted to be deleterious in the prescreening portion of our assessment strategy. c.5191C4A, on the other hand, causes p.T1691K, which is predicted to have high deleterious probability because of significant structural alteration, a high deleterious score in the predictive programs and, clinically, triple negative characteristics in breast tumors. This mutant is confirmed by transcription activation and yeast growth-inhibition assays. In conclusion, we show as high a prevalence of germ-line BRCA1 mutation in high-risk Taiwanese patients as in Caucasians and demonstrate a useful strategy for studying BRCA1 VUSs. Keywords: BRCA1; breast cancer; structure modeling; variants of uncertain significance INTRODUCTION Breast cancer is one of the most common cancers and is the leading cause of cancer-related death in women throughout the world. Interestingly, the prevalence of breast cancer is lower in Taiwanese (ethnic Chinese) populations than in Caucasian populations, 1 and the epidemiological patterns are different in the two patient groups. First, the median age of breast cancer patients in Taiwan (45-49 years) is lesser than that in Western countries (70-74 years). 2 Second, a rise in incidence has been observed consistently in Asian countries, 2-4 and one age-period-cohort analysis showed that the increase in breast cancer incidence was largely due to a rise in young patients. 2 Third, a longitudinal cohort revealed that young breast cancer patients in

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“…The study was conducted in accordance with the Declaration of Helsinki of 1975, as revised in 2000. Selection of patients was based on the following criteria as previously described 9,10 and at least one of the following: (F) at least one first-or seconddegree relative with breast and/or ovarian cancer diagnosed at any age, (E) early-onset breast cancer diagnosed at age 35 or before, (B) bilateral breast cancer and (M) multiple organ cancer, including breast cancer. The study subjects consisted of 134 unrelated Korean breast cancer patients who were identified as being at high risk of carrying BRCA1/BRCA2 mutations; 116 (87%) familial cases, 29 (22%) early-onset cancer cases, 13 (10%) bilateral cancer cases and 10 (7%) multiple organ cancer cases.…”

Section: Methodsmentioning

confidence: 99%

“…5 To date, only a few studies have examined the frequencies and spectra of mutations in large series of Korean breast cancer patients. [6][7][8][9][10] Several mutations are considered to be founder mutations, as they account for the majority of detected BRCA1/BRCA2 mutations in Korea. Although some of these recurrent mutations are unique to Koreans, their effects vary across studies.…”

Section: Introductionmentioning

confidence: 99%

Spectra of BRCA1 and BRCA2 mutations in Korean patients with breast cancer: the importance of whole-gene sequencing

et al. 2012

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The frequencies and spectra of germline mutations in the BRCA1 and BRCA2 genes vary among populations. In the present study, the mutation spectra of the BRCA1/BRCA2 genes in Korean breast cancer patients were investigated using whole-gene sequencing method. A total of 134 unrelated Korean breast cancer patients who were identified as being at high risk of carrying BRCA1/BRCA2 mutations were included. PCR amplification and direct sequencing were performed covering all exons and flanking intronic sequences of the BRCA1/BRCA2 genes. A total of 26 mutations were detected in 31 of 134 patients (23.1%). The mutation detection rate in the present study is higher than those of previous studies using screening methods (2.5-11.3%) and similar to that of a recent study, which used whole-gene sequencing (21.2%). The BRCA2: c.7480C4T mutation, which has been suggested to be a founder mutation in Koreans, was detected in only one patient. Five mutations were recurrent but observed in no more than two patients. Given that the mutation detection rates using whole-gene sequencing were much higher than for screening methods and that there were no consistent observations of founder mutations, whole-gene sequencing of both BRCA1 and BRCA2 genes should be the method of choice to identify mutations in high-risk Korean patients.

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BRCA1 and BRCA2 germline mutations in Korean breast cancer patients at high risk of carrying mutations

Cited by 52 publications

References 10 publications

RAD51C-Deficient Cancer Cells Are Highly Sensitive to the PARP Inhibitor Olaparib

RAD51C-Deficient Cancer Cells Are Highly Sensitive to the PARP Inhibitor Olaparib

Multimodel assessment of BRCA1 mutations in Taiwanese (ethnic Chinese) women with early-onset, bilateral or familial breast cancer

Spectra of BRCA1 and BRCA2 mutations in Korean patients with breast cancer: the importance of whole-gene sequencing

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