<i>BRCA1</i> c.5470_5477del, a founder mutation in Chinese Han breast cancer patients

Meng, Hua; Yao, Lu; Yuan, Hua; Xu, Ye; Ouyang, Tao; Li, Jinfeng; Wang, Tianfeng; Fan, Zhaoqing; Fan, Tie; Lin, Benyao; Xie, Yuntao

doi:10.1002/ijc.32877

Cited by 21 publications

(19 citation statements)

References 28 publications

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“…Haplotype analysis was carried out on 31 unrelated patients and 50 unrelated controls without the mutation. The haplotype analysis was performed independent of the work of Meng et al [6]; similar to their findings, our haplotype analysis suggested strong founder effect (supplementaryTable S1) of the mutation. Moreover, carriers of this variant are distributed throughout the country (Figure 4), except provinces with sampling size < 100 (regions colored in gray; total sample size: 7919).…”

Section: Resultssupporting

confidence: 81%

“…For example, Ashkenazi Jewish generally have higher risk of being BRCA1/2 carriers because of the highly prevalent founder mutations BRCA 185delAG, BRCA1 5382insC and BRCA2 6174delT [1]. Several Chinese founder mutations have also been reported previously [2][3][4][5][6]. Moreover, it is recognized that great differences in cancer risks even present within BRCA1/2 mutation carriers, depending on the location and type of mutation they bear.…”

Section: Introductionmentioning

confidence: 99%

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Assessing the variations in breast/ovarian cancer risk for Chinese BRCA1/2 carriers

Luo

et al. 2020

Preprint

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Background: Cancer risks vary in different BRCA1/2 mutations. Previous studies based on Caucasian population have identified regions associated with elevated/reduced risks of breast/ovarian cancers. Since ethnic differences are known to affect BRCA1/2 mutation spectra, we are interested in defining Chinese-specific ovarian/breast cancer cluster regions (OCCR/BCCR) and comparing with previously reported Caucasian-based cluster regions. We also aim to characterize the distribution and estimate the cancer risks of different Chinese recurrent mutations. Methods: 7,919 (3,641 unselected cancer-free women + 4,278 female cancer patients) individuals were included in the study. Germline BRCA1/2 status were detected with amplicon-based next-generation sequencing. BRCA1/2 carriers were defined as bearing likely pathogenic or pathogenic mutations. We calculated odds ratio (OR) of breast cancer and OR of ovarian cancer, and their ratio of the two ORs (ROR) for each region. ROR > 1 indicated elevated odds of breast cancer and/or decreasing odds of ovarian cancer; ROR < 1 indicated increasing odds of ovarian cancer and/or decreasing breast cancer odds. The frequency, distribution and penetrance of six known Chinese founder mutations were characterize respectively. Haplotype analysis and age estimation were performed on the most prevalent and widely-spread founder mutation BRCA1:c.5470_5477del. Results: A total of 729 subjects were detected with germline BRCA1/2 deleterious mutations, including 236 BRCA1 and 122 BRCA2 mutations. The putative Chinese OCCR/BCCR are partially overlapped with Caucasian-based OCCR/BCCR and shared structural-functional characteristics. The six known Chinese founder mutations vary greatly in both distribution and penetrance. The two most prevalent and widely-spread mutations are estimated to convey low penetrance, while the area-restricted founder mutations seemed to confer higher or nearly complete penetrance. The most prevalent founder mutation BRCA1:c.5470_5477del accounting for 9.5% - 18% of BRCA1 carriers is estimated to have emerged ~2,090 years ago (70 B.C.) during the Han Dynasty, about 290 years (~14.5 generations) prior to the Three Kingdoms Period when a major population migration occurred. Conclusion: BRCA1/2 carriers with different genotypes have significantly different cancer risks. Hence ideally risk assessment should be mutation-specific, rather than concerning a single figure. The probably most ancient Chinese founder mutation may have originated more than 2,000 years ago.

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Section: Resultssupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Assessing the variations in breast/ovarian cancer risk for Chinese BRCA1/2 carriers

Luo

et al. 2020

Preprint

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“…The conserved region from chr17:42627978 to 43223568 was only partially shared by BRCA1 :c.981_982del carriers, which is probably caused by genomic rearrangement or other aberrations that occurred during the course of heredity. Recently, BRCA1 :c.5470_5477del was also revealed as a founder mutation in a cohort of 9505 Han breast cancer patients, which made our conclusion more solid ( 24 ). Of note, studies carried out in the southern part of China identified different founder mutations, i.e.…”

Section: Discussionmentioning

confidence: 65%

Identification of BRCA1:c.5470_5477del as a Founder Mutation in Chinese Ovarian Cancer Patients

Han

Zhang

et al. 2021

Front. Oncol.

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Predisposition of germline BRCA1/2 mutations (gBRCAMUT) increases the risk of breast and ovarian cancer in females, but the mutation prevalence and spectrum are highly ethnicity-specific with different recurrent mutations being reported in different populations. Hereby, we performed hybridization-based target sequencing of BRCA1/2 in 530 ovarian cancer patients from Henan, the central region of China, followed by haplotype analysis of six short tandem repeat (STR) markers in the patients with recurrent mutations to determine their founder effect. About 28.3% (150/530) of the OC patients in our cohort harbored gBRCAMUT; of the 151 mutations, 117 in BRCA1 and 34 in BRCA2, identified in this study, BRCA1:c.5470_5477del, c.981_982del, and c.4065_4068del are the top three mutants, recurrently detected in eight, seven, and six independent patients respectively. Haplotype analysis identified a region of 0.6 MB genomic length covering BRCA1 highly conserved across all eight carriers of BRCA1:c.5470_5477del, but not c.981_982del, suggesting a consequence of founder effect. Retrospective analysis in a subgroup of serous ovarian cancer patients revealed gBRCAMUT status was not associated with the progression-free survival (PFS); instead, an expression of Ki-67% ≥50% was associated with a shorter PFS (p = 0.041). In conclusion, patients with pathogenic or likely pathogenic gBRCAMUT account for 28.3% of the OC cases from Henan, and BRCA1:c.5470_5477del, the most frequently detected mutation in Henan patients, is a founder mutation in the population.

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“…It is also known that race/ethnic differences are presented in the mutation spectrum, the prevalence of mutations, and in the recurrently mutated positions, which are likely to reflect the so-called “founder effects.” For example, Ashkenazi Jews generally have a higher risk of being BRCA1/2 carriers because of the highly prevalent founder mutations BRCA1 185delAG , BRCA1 5382insC, and BRCA2 6174delT [ 1 ]. Several Chinese founder mutations have also been previously reported [ 2 – 6 ].…”

Section: Introductionmentioning

confidence: 99%

Assessing the Variations in Breast/Ovarian Cancer Risk for Chinese BRCA1/2 Carriers

Hao

Luo

et al. 2022

Journal of Oncology

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Background. Cancer risks vary in different BRCA1/2 mutations. We are interested in identifying regions associated with elevated/reduced risks of breast/ovarian cancers in the Chinese population and comparing with previously reported Caucasian-based breast/ovarian cancer cluster regions (OCCR/BCCR). We also aim to characterize the distribution and estimate the cancer risks of different Chinese recurrent mutations. Methods. A total of 3,641 cancer-free women and 4,278 female cancer patients were included in the study. Germline BRCA1/2 status was detected with amplicon-based next-generation sequencing. We calculated the odds ratio (OR) of breast cancer and OR of ovarian cancer, and their ratio of the two ORs (ROR) for each region. ROR >1 indicated elevated odds of breast cancer and/or decreasing odds of ovarian cancer, and vice versa. The frequency, distribution, and penetrance of six known Chinese founder mutations were characterized, respectively. Haplotype analysis and age estimation were performed on the most prevalent founder mutation BRCA1: c.5470_5477del. Results. A total of 729 subjects were detected with germline BRCA1/2 deleterious mutations. The putative Chinese OCCR/BCCR partially overlapped with Caucasian-based OCCR/BCCR and shared structural-functional characteristics. The six known Chinese founder mutations greatly vary in both distribution and penetrance. The two widely spread mutations are estimated to convey low penetrance, while the area-restricted founder mutations seemed to confer higher/complete penetrance. BRCA1: c.5470_5477del is estimated to have emerged ∼2,090 years ago (70 B.C.) during the Han dynasty. Conclusions. BRCA1/2 carriers with different genotypes have significantly different cancer risks. An optimal risk assessment should be mutation specific, rather than concerning a single figure.

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BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients

Cited by 21 publications

References 28 publications

Assessing the variations in breast/ovarian cancer risk for Chinese BRCA1/2 carriers

Assessing the variations in breast/ovarian cancer risk for Chinese BRCA1/2 carriers

Identification of BRCA1:c.5470_5477del as a Founder Mutation in Chinese Ovarian Cancer Patients

Assessing the Variations in Breast/Ovarian Cancer Risk for Chinese BRCA1/2 Carriers

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