Frequency of pathogenic germline mutation in CHEK2, PALB2, MRE11, and RAD50 in patients at high risk for hereditary breast cancer

Kim, Haeyoung; Cho, Daeyeon; Choi, Doo Ho; Oh, Min Seok; Shin, Insik; Park, Won; Huh, Seung Jae; Nam, Seok Jin; Lee, Jeong Eon; Kim, Seok Won

doi:10.1007/s10549-016-4034-2

Cited by 29 publications

(36 citation statements)

References 39 publications

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“…A total of 11 VUSs discovered here in ATM were reported previously. We found 1 deleterious germline mutation in CHEK2 (c.1245dupC), which was recently reported in Korean breast cancer patients . All 10 VUSs in CHEK2 were reported previously in ClinVar or Exome Aggregation Consortium.…”

Section: Discussioncontrasting

confidence: 85%

“…13 Deleterious PALB2 mutations were found in familial breast cancer with a prevalence of about 1% to 4% and .1% to 1% in unselected breast cancer. 30,40,41 In our study, only 1 novel deleterious mutation (.34%) was detected in PALB2. Although all PALB2 VUSs were predicted to be tolerant, there were 3 germline VUSs (PALB2 c.2673C>G, c.3054G>C and c.3139A>G) and 1 somatic VUS (PALB2 c.3139A>G) located in the WD40-repeat-containing domain of PALB2 that could affect PALB2 binding to the N-terminus of BRCA2.…”

Section: The Clinicopathological Characteristics Of Mutation Carrierscontrasting

confidence: 49%

“…PALB2 encodes a BRCA2‐interacting protein in the DNA repair process . Deleterious PALB2 mutations were found in familial breast cancer with a prevalence of about 1% to 4% and .1% to 1% in unselected breast cancer . In our study, only 1 novel deleterious mutation (.34%) was detected in PALB2 .…”

Section: Discussionmentioning

confidence: 43%

“…The PALB2 c.3054G>C variant was a recurrent mutation found in 3 cases (1.03%) in this study. This variant has also been observed in Australian patients (1/1998), Korean patients (1/235), Asian population in Malaysia and Singapore (1/122) . The prevalence of this variant ( PALB2 c.3054G>C) in Chinese population seemed to be higher than other ethnic groups.…”

Section: Discussionmentioning

confidence: 80%

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Mutation screening of 10 cancer susceptibility genes in unselected breast cancer patients

Xie

Chen

et al. 2017

Clinical Genetics

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Variants of cancer susceptibility genes other than BRCA1/2 have been proved to be associated with increased risks of breast cancer. This study was performed to investigate the spectrum and prevalence of mutations in 10 cancer susceptibility genes in paired tumor/normal tissues of 292 unselected Chinese breast cancer patients. We performed an analysis of germline and somatic variants in ATM, CDH1, CHEK2, ESR1, GATA3, MAP3K1, MSH2, PALB2, RB1 and STK11 genes by integrating microfluidic PCR-based target enrichment and next-generation sequencing technologies. In total, 3 germline and 25 somatic deleterious mutations were found among 27 patients (9.25%), and 17 of them were novel mutations. Most deleterious mutations were prevalent in luminal A invasive breast cancer (P = .014). We also observed 83 variants of uncertain significance (VUS) in 100 patients (34.25%), 23 of which were predicted to be deleterious by in silico prediction programs (MetaSVM and MetaLR). VUS carriers had higher positive rate of lymph node metastasis than non-carriers (P = .008) and were predominantly present in ER+ tumors (P = .018). Our findings would enhance the understanding of the molecular mechanisms of breast cancer in Chinese population.

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Section: Discussioncontrasting

confidence: 85%

Section: The Clinicopathological Characteristics Of Mutation Carrierscontrasting

confidence: 49%

Section: Discussionmentioning

confidence: 43%

Section: Discussionmentioning

confidence: 80%

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Mutation screening of 10 cancer susceptibility genes in unselected breast cancer patients

Xie

Chen

et al. 2017

Clinical Genetics

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“…evaluated the frequency of pathogenic RAD50 germline mutations among Korean patients at high risk for hereditary breast cancer. They reported a pathogenic RAD50 mutation rate of 0.85% in participating patients . In the current study, we found that 0.34% of our study population had a pathogenic RAD50 mutation, indicating that such mutations are infrequent.…”

Section: Discussionsupporting

confidence: 53%

RAD50 germline mutations are associated with poor survival in BRCA1/2–negative breast cancer patients

Fan

Zhang

Ouyang

et al. 2018

Intl Journal of Cancer

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RAD50 is a highly conserved DNA double-strand break (DSB) repair gene. However, the associations between RAD50 germline mutations and the survival and risk of breast cancer have not been fully elucidated. Here, we aimed to investigate the clinical impact of RAD50 germline mutations in a large cohort of unselected breast cancer patients. In our study, RAD50 germline mutations were determined using next-generation sequencing in 7657 consecutive unselected breast cancer patients without BRCA1/2 mutations. We also screened for RAD50 recurrent mutations (L719fs, K994fs, and H1269fs) in 5000 healthy controls using Sanger sequencing. We found that 26 out of 7,657 (0.34%) patients had RAD50 pathogenic mutations, and 16 patients carried one of the three recurrent mutations (L719fs, n = 6 cases; K994fs, n = 5 cases; and H1269fs, n = 5 cases); the recurrent mutation rate was 0.21%. The frequency of the three recurrent mutations in the 5,000 healthy controls was 0.18% (9/5,000). These mutations did not confer an increased risk of breast cancer in the studied patients [odds ratios (OR), 1.16; 95% confidence interval (CI), 0.51-2.63; p = 0.72]. Nevertheless, multivariate analysis revealed that RAD50 pathogenic mutations were an independent unfavourable predictor of recurrence-free survival (RFS) [adjusted hazard ratio (HR) 2.66; 95% CI, 1.18-5.98; p = 0.018] and disease-specific survival (DSS; adjusted HR 4.36; 95% CI, 1.58-12.03; p = 0.004) in the entire study cohort. Our study suggested that RAD50 germline mutations are not associated with an increased risk of breast cancer, but patients with RAD50 germline mutations have unfavourable survival compared to patients without these mutations.

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Germline mutations of PALB2 gene in a sequential series of Chinese patients with breast cancer

Zhang

Zhou

Zhu

et al. 2017

Breast Cancer Res Treat

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Frequency of pathogenic germline mutation in CHEK2, PALB2, MRE11, and RAD50 in patients at high risk for hereditary breast cancer

Abstract: Pathogenic variants in CHEK2, PALB2, MRE11, and RAD50 were detected in a small proportion of Korean patients with features of hereditary breast cancer.

Cited by 29 publications

References 39 publications

Mutation screening of 10 cancer susceptibility genes in unselected breast cancer patients

Mutation screening of 10 cancer susceptibility genes in unselected breast cancer patients

RAD50 germline mutations are associated with poor survival in BRCA1/2–negative breast cancer patients

Germline mutations of PALB2 gene in a sequential series of Chinese patients with breast cancer

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