Multigene panel analysis identified germline mutations of
            <scp>DNA</scp>
            repair genes in breast and ovarian cancer

Hirotsu, Yosuke; Nakagomi, Hiroshi; Sakamoto, Ikuko; Amemiya, Kenji; Oyama, Toshio; Mochizuki, Hitoshi; Omata, Masao

doi:10.1002/mgg3.157

Cited by 73 publications

(64 citation statements)

References 32 publications

(28 reference statements)

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“…In our study, no deleterious truncating variant was identified, and the allele counts of the observed missense variants were not statistically different from that in HGVD (Tables and ). Similar results are reported by Hirotsu and Nakagomi et al . They also detected no obvious deleterious truncating variants in Japanese familial breast cancer cases.…”

Section: Discussionsupporting

confidence: 90%

Mutation status of RAD51C,PALB2 and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations

et al. 2017

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In addition to BRCA1 and BRCA2, RAD51C,PALB2 and BRIP1 are known as breast cancer susceptibility genes. However, the mutation status of these genes in Japanese familial breast cancer cases has not yet been evaluated. To this end, we analyzed the exon sequence and genomic rearrangement of RAD51C,PALB2 and BRIP1 in 100 Japanese patients diagnosed with familial breast and ovarian cancer and without BRCA1 and BRCA2 mutations. We detected a large deletion from exons 6 to 9 in RAD51C, 4 novel BRIP1 missense variants containing 3 novel non‐synonymous variants, c.89A>C, c.736A>G and c.2131A>G, and a splice donor site variant c.918+2T>C. No deleterious variant of PALB2 was detected. The results of pedigree analysis showed that the proband with a large deletion on RAD51C had a family history of both breast and ovarian cancer, and the families of probands with novel BRIP1 missense variants included a male patient with breast cancer or many patients with breast cancer within the second‐degree relatives. We showed that the mutation frequency of RAD51C in Japanese familial breast cancer cases was similar to that in Western countries and that the prevalence of deleterious mutation of PALB2 was possibly lower. Furthermore, our results suggested that BRIP1 mutation frequency in Japan might differ from that in Western countries.

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Section: Discussionsupporting

confidence: 90%

Mutation status of RAD51C,PALB2 and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations

et al. 2017

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“…Germline mutations for BRCA1/2 and PALB2 were analyzed using targeted sequencing, as previously reported (4,19,22). Briefly, the Ion AmpliSeq™ BRCA1 and BRCA2 and the Ion AmpliSeq™ BRCA Reflex Hereditary Cancer Research panels (Thermo Fisher Scientific, Inc., Waltham, MA, USA) were used, targeting the whole exons of the BRCA1/2 genes and an additional 25 hereditary cancer-associated genes (22,23).…”

Section: Case Reportmentioning

confidence: 99%

“…Briefly, the Ion AmpliSeq™ BRCA1 and BRCA2 and the Ion AmpliSeq™ BRCA Reflex Hereditary Cancer Research panels (Thermo Fisher Scientific, Inc., Waltham, MA, USA) were used, targeting the whole exons of the BRCA1/2 genes and an additional 25 hereditary cancer-associated genes (22,23). Buffy coat DNA was used as a template, and the sequencing library was generated using an AmpliSeq Library kit 2.0 (Thermo Fisher Scientific, Inc.) (24-31).…”

Section: Case Reportmentioning

confidence: 99%

PALB2 mutation in a woman with bilateral breast cancer: A case report

Nakagomi

Hirotsu

Okimoto

et al. 2017

Molecular and Clinical Oncology

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Abstract. Partner and localizer of breast cancer 2 (PALB2) was identified as a moderate-risk gene of breast and pancreas cancer. The present authors previously reported that no PALB2 germline mutations with a deleterious frameshift or stop codons were identified in 155 Japanese patients with breast and/or ovarian cancer who were estimated to be at risk of hereditary cancer, according to the National Comprehensive Cancer Network (NCCN) criteria. In the present study, one patient with a deleterious mutation of PALB2 (c. 2834+2 T>C) has been identified from a study of an additional 128 cases. Therefore, the prevalence of PALB2 among Japanese patients is now estimated to be 0.35% (1/283). The proband was a 63-year-old woman with bilateral breast cancer, although she had experienced no other cancers. The proband had two elder sisters, the eldest of whom died from pancreatic cancer at 60 years of age. The proband's 40-year-old daughter was affected, but did not show any malignancies. There are only a few reports concerning PALB2 mutations in Japan. To the best of our knowledge, this is the first case study to reveal the significance of DNA-repair genes in the development of malignancies in Japanese patients with breast cancer. IntroductionThe significance of the breast cancer 1 (BRCA1) and BRCA2 mutations in familial breast and ovarian cancer has been well established (1,2). However, the mutations of these genes are estimated to cause, at most, 20-30% of cases of hereditary breast cancer (3). The present authors studied the BRCA1/2 mutations in 191 patients in a previous study, but the prevalence was shown to be unexpectedly low (4,5). In fact, it was only 7% among the analyzed patients who had a family history of breast cancers.Partner and localizer of BRCA2 (PALB2) was identified as a moderate-risk gene in breast and pancreas cancer (6). PALB2 is located on chromosome 16p12.2 containing 13 exons and 12 introns, and is involved in BRCA2-associated pathways (6). Recently, Antoniou et al (7) reported that PALB2 carriers have a high risk of developing breast cancer, and concluded that the cumulative risk of mutation carrier was 34% by the age of 70 in their prospective follow-up study on 154 families.The prevalence of the PALB2 mutation was reported to be 1.2-3.4% in European countries, whereas it is very rare in Asian countries (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). To the best of our knowledge, no study has been performed that has identified the PALB2 deleterious mutation in Japanese patients with breast cancer. From our first cohort data, no deleterious PALB2 mutations were identified in 155 patients with breast and/or ovarian cancer who were estimated to be at risk of hereditary cancer according to the National Comprehensive Cancer Network (NCCN) criteria (19). In the present case study, an additional 128 cases having breast and/or ovarian cancer were studied, and the case of a patient with bilateral breast cancer is presented who harbors the deleterious mutation in PALB2. Factoring in the first cohort of 155 c...

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“…The current medicine strategy against ovarian cancer emphasizes targeting the dominant factor(s) during the clinical trials. One of the efficient approaches is developed by trying to identify the germline and sporadic key mutations in the primary site of the tumors [67–69]. The study here not only reveals the DNA damage as a potential driver of ovarian tumorigenesis, but also provides possible gene targets for clinical treatment.…”

Section: Resultsmentioning

confidence: 99%

Increasing sensitivity to DNA damage is a potential driver for human ovarian cancer

Jin

Wang

et al. 2016

Oncotarget

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Ovarian cancer is one of the most common cancers among women, accounting for more deaths than any other gynecological diseases. However, the survival rate for ovarian cancer has not essentially improved over the past thirty years. Thus, to understand the molecular mechanism of ovarian tumorigenesis is important for optimizing the early diagnosis and treating this disease. In this study, we observed obvious DNA lesions, especially DNA double strand breaks (DSBs) accompanying cell cycle checkpoint activation, in the human epithelial ovarian cancer samples, which could be due to the impaired DNA response machinery. Following this line, we found that these DNA damage response-deficient primary cancer cells were hypersensitive to DNA damage and lost their ability to repair the DNA breaks, leading to genomic instability. Of note, three key DNA damage response factors, RNF8, Ku70, and FEN1 exhibited dramatically decreased expression level, implying the dysfunctional DNA repair pathways. Re-expression of wild type RNF8, Ku70, or FEN1 in these cells restored the DNA lesions and also partially rescued the cells from death. Our current study therefore proposes that accumulated DNA lesions might be a potential driver of ovarian cancer and the impaired DNA damage responders could be the targets for clinical treatment.

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Multigene panel analysis identified germline mutations of DNA repair genes in breast and ovarian cancer

Cited by 73 publications

References 32 publications

Mutation status of RAD51C,PALB2 and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations

Mutation status of RAD51C,PALB2 and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations

PALB2 mutation in a woman with bilateral breast cancer: A case report

Increasing sensitivity to DNA damage is a potential driver for human ovarian cancer

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