Prevalence ofBRCA1/BRCA2pathogenic variation in Chinese Han population

Dong, Hongyan; Chandratre, Khyati; Qin, Ying; Zhang, Jing; Tian, Xiaodong; Rong, Ce; Wang, Ning; Guo, Maoni; Zhao, Guoping; Wang, San Ming

doi:10.1136/jmedgenet-2020-106970

Cited by 31 publications

(37 citation statements)

References 17 publications

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“…All the pathogenic variants identified in Taiwanese population are present in public BRCA databases. Similar situation exists for the pathogenic variants identified in other Asian populations (Bhaskaran et al, 2019;Bhaskaran et al, 2020;Dong et al, 2020;Qin et al, 2020;Zhang et al, 2020). In the meantime, 44.1% of the BRCA variants identified in Taiwanese population remain as novel, VUS, and unclassified variants.…”

Section: Discussionmentioning

confidence: 54%

“…This could be a factor contributing to higher prevalence of pathogenic variation in Taiwanese general population by increased probability of generating more pathogenic variants. The prevalence of 0.53% of pathogenic variation in the general Taiwanese population is the highest in Asian ethnic populations, comparing to 0.26% in Japanese ( Momozawa et al, 2018 ), 0.29% in southern Chinese ( Qin et al, 2020 ), 0.38% in mainland Chinese ( Dong et al, 2020 ), and 0.39% in Malaysia ( Wen et al, 2018 ), and has reached the same level of 0.53% as in Caucasian populations ( Kurian et al, 2019 ). One BRCA pathogenic variant carrier in every 189 Taiwanese individuals represents a serious threat for public health in Taiwanese population, justifying the inclusion of BRCA -related cancer diagnosis, treatment, and prevention in the healthcare system in Taiwan.…”

Section: Discussionmentioning

confidence: 92%

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BRCA1 and BRCA2 Variation in Taiwanese General Population and the Cancer Cohort

Chian¹,

Sinha²,

Qin³

et al. 2021

Front. Mol. Biosci.

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BRCA1 and BRCA2 (BRCA) play essential roles in maintaining genome stability. Rapidly evolving human BRCA generates oncogenic variants causing high cancer risk. BRCA variation is ethnic-specific in reflecting adaptation and/or effects of genetic drift. Taiwanese population of 23.8 million is an admixture of multiple ethnic origins; Taiwan’s subtropical and tropical climate and geographically islandic location provide a unique natural environment. Therefore, Taiwanese population provides a unique model to study human BRCA variation. Through collecting, standardizing, annotating, and classifying publicly available BRCA variants derived from Taiwanese general population and the cancer cohort, we identified 335 BRCA variants, of which 164 were from 1,517 non-cancer individuals, 126 from 2,665 cancer individuals, and 45 from both types of individuals. We compared the variant data with those from other ethnic populations such as mainland Chinese, Macau Chinese, Japanese, Korean, Indian, and non-Asians. We observed that the sharing rates with other Asian ethnic populations were correlated with its genetic relationship. Over 60% of the 335 Taiwanese BRCA variants were VUS, unclassified variants, or novel variants, reflecting the ethnic-specific features of Taiwanese BRCA variation. While it remains challenging to classify these variants, our structural and in silico analyses predicted their enrichment of BRCA deleterious variants. We further determined the 3.8% prevalence of BRCA pathogenic variants in the Taiwanese breast cancer cohort, and determined 0.53% prevalence of the BRCA pathogenic variants in Taiwanese general population, with the estimated 126,140 BRCA pathogenic variant carriers. We identified BRCA2 c.5164_5165delAG at BRCA2 BRC6 motif as a potential founder mutation in Taiwanese population. Our study on BRCA variation in Taiwanese and other East Asian populations demonstrates that ethnic specificity is a common phenomenon for BRCA variation in East Asian population; the data generated from the study provide a reference for clinical applications in BRCA-related cancer in Taiwanese population.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 92%

BRCA1 and BRCA2 Variation in Taiwanese General Population and the Cancer Cohort

Chian¹,

Sinha²,

Qin³

et al. 2021

Front. Mol. Biosci.

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“…However, the majority of studies to date focused on the clinical manifestation of BRCA mutations are from European, North American, African or African-American populations. Although the number of reports from Asian populations have been increasing, most are focused on the prevalence and epidemiology of BRCA [2,3,[14][15][16][17][18]. The clinical characteristics, pathologic features, prognosis, and risk of CBC remain uncertain in Asian patients with BRCA mutated breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Impact of BRCA Mutation on the Survival and Risk of Contralateral Breast Cancer in Asian Breast Cancer Patients

Lin¹,

Chen²,

Tseng³

et al. 2021

Preprint

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Purpose Breast cancer is increasing around the globe, including Asia. We aimed to examine the survival and risk of contralateral breast cancer (CBC) in Asian breast cancer patients with BRCA mutations. MethodsA total of 128 breast cancer patients with germline BRCA mutations and 4,754 control breast cancer patients were enrolled. Data on clinical pathologic characteristics, survival and CBC were collected from the medical record. The rates of survival and CBC were estimated by Kaplan-Meier method. Results The mean age of onset in BRCA mutation carriers was significantly younger than control patients (BRCA vs. Non-BRCA: 43.9 vs. 53.2 years-old). BRCA mutation carriers had a higher proportion of triple-negative breast cancer (TNBC) (52%) than control patients (12%, p<0.001). The risk of CBC was significantly higher in BRCA mutation patients than in control cases (hazard ratio (HR) = 3.95, 95% CI 2.71-5.75); when stratified by genotype, the HRs (95%CI) were 4.84 (3.00-7.82) for BRCA1 and 3.13 (1.78-5.49) for BRCA2 carriers, respectively. Moreover, BRCA1 mutation patients with triple-negative breast cancer (TNBC) as their first breast cancer had the highest risk of CBC (HR = 5.55, 95% CI 3.29-9.34). However, we did not observe any differences in relapse-free survival and overall survival between mutation carriers and control patients. ConclusionOur study suggest that BRCA patients had a significantly higher risk of developing CBC, particularly for BRCA1 mutation carriers with TNBC as the first breast cancer.

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“…While recent population-based studies have estimated the frequency of germline BRCA1/2 PV to be as high as 1 in 200 [47, 60], outside of strong founder populations such as the Icelandic and Jewish, this is insufficient to account for more than 20% of the heritable component of breast cancer and only about 2% of all breast cancers [61, 62]. The discrepancy has become even greater with the recognition that many women with germline mutations in either BRCA1 or BRCA2 have an average lifetime risk of developing breast cancer (“penetrance”) of around 65–70% or less rather than the 85–90% originally generated from high-risk families.…”

Section: Missing Heritability Of Breast Cancer Predispositionmentioning

confidence: 99%

From BRCA1 to Polygenic Risk Scores: Mutation-Associated Risks in Breast Cancer-Related Genes

2021

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Background: There has been huge progress over the last 30 years in identifying the familial component of breast cancer. Summary: Currently around 20% is explained by the high-risk genes BRCA1 and BRCA2, a further 2% by other high-penetrance genes, and around 5% by the moderate risk genes ATM and CHEK2. In contrast, the more than 300 low-penetrance single-nucleotide polymorphisms (SNP) now account for around 28% and they are predicted to account for most of the remaining 45% yet to be found. Even for high-risk genes which confer a 40–90% risk of breast cancer, these SNP can substantially affect the level of breast cancer risk. Indeed, the strength of family history and hormonal and reproductive factors is very important in assessing risk even for a BRCA carrier. The risks of contralateral breast cancer are also affected by SNP as well as by the presence of high or moderate risk genes. Genetic testing using gene panels is now commonplace. Key-Messages: There is a need for a more parsimonious approach to panels only testing those genes with a definite 2-fold increased risk and only testing those genes with challenging management implications, such as CDH1 and TP53, when there is strong clinical indication to do so. Testing of SNP alongside genes is likely to provide a more accurate risk assessment.

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Prevalence ofBRCA1/BRCA2pathogenic variation in Chinese Han population

Cited by 31 publications

References 17 publications

BRCA1 and BRCA2 Variation in Taiwanese General Population and the Cancer Cohort

BRCA1 and BRCA2 Variation in Taiwanese General Population and the Cancer Cohort

Impact of BRCA Mutation on the Survival and Risk of Contralateral Breast Cancer in Asian Breast Cancer Patients

From <b><i>BRCA1</i></b> to Polygenic Risk Scores: Mutation-Associated Risks in Breast Cancer-Related Genes

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