Clinical Evaluation of BRCA1/2 Mutation in Mexican Ovarian Cancer Patients

Gallardo‐Rincón, Dolores; Álvarez-Gómez, Rosa María; Montes-Servín, Edgar; Toledo-Leyva, Alfredo; Michel-Tello, David; Alamilla-García, Gabriela; Bahena-González, Antonio; Hernández-Nava, Elizabeth; Fragoso-Ontiveros, Verónica; Espinosa-Romero, Raquel; Cetina, Lucely

doi:10.1016/j.tranon.2019.11.003

Cited by 14 publications

(21 citation statements)

References 35 publications

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“… 29 Another study on patients with ovarian cancer in Mexico found that the incidence of BRCA1/2 mutations was 33%, of which 66.1% was BRCA1 and 33.9% was BRCA2 . 30 These differences may be related to the geographical distribution of the selected population. The prevalence of BRCA mutations among Spanish patients with ovarian cancer was 16%, of which the prevalence of BRCA2 mutations was 63%, which is contrary to most studies.…”

Section: Discussionmentioning

confidence: 99%

“… 46 Another study showed that the most common mutation was BRCA1 ex9-12del, a Mexican founder mutation. 30 Mutational data show that the most frequently recorded BRCA1 c.5266dupC mutation is the founder mutation in Italian, 47 Northeastern Romanian, 48 and Turkish populations. 49 Slavic BRCA1 and BRCA2 founder mutations include BRCA1 c.5266dupC, BRCA1 c.4034delA, and BRCA1 c.68_69delAG.…”

Section: Discussionmentioning

confidence: 99%

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The Features of BRCA1 and BRCA2 Germline Mutations in Hakka Ovarian Cancer Patients: BRCA1 C.536 A>T Maybe a Founder Mutation in This Population

Luo

Huang

et al. 2022

IJGM

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Objective To investigate the frequencies of BRCA1 and BRCA2 mutations in Chinese Hakka patients with ovarian cancer. Methods The protein coding regions and exon intron boundary regions of the BRCA gene were sequenced using genomic DNA isolated from the lymphocytes of patients with next-generation sequencing. The patients’ family history and clinical records were collected. Results A total of 195 patients with ovarian cancer were included in the study, and 52 distinct variants of the BRCA gene were identified. It was found that 64 patients (64/195, 32.8%) had BRCA gene mutations, including 32 patients (50.0%) with BRCA1 mutation, 27 patients (42.2%) with BRCA2 mutation, and 5 patients (7.8%) with both mutations. Furthermore, 22 pathogenic mutations were detected in 26 patients, 2 likely pathogenic variants in 2 patients, 12 variants of uncertain significance in 20 patients, and 16 likely benign variants in 24 patients. The mutations were mainly found to occur in exons 8, 14, and 17 of BRCA1 and exons 10, 11, 14, and 15 of BRCA2 . The results showed that the BRCA genes possess different mutation hotspots in different ethnic groups. In addition, recurrent mutations were noted in many patients. BRCA1 c.536 A>T, considered a founder mutation, was identified in 10 patients (15.63%, 10/64), followed by BRCA1 c.2635 G>T (6.25%, 4/64) and BRCA2 c.2566 T>C (6.25%, 4/64). Conclusion The BRCA1 c.536 A>T could be considered to be a founder mutation in this ovarian cancer population. This recurrent BRCA1 mutation has rarely been observed in other ethnic groups. Our findings are expected to provide valuable data for clinical consultation and for designing individualized treatment for ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Features of BRCA1 and BRCA2 Germline Mutations in Hakka Ovarian Cancer Patients: BRCA1 C.536 A>T Maybe a Founder Mutation in This Population

Luo

Huang

et al. 2022

IJGM

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“…One of the limitations of this study was the absence of CNV data for the Russian population because in some countries, large rearrangements (mainly equal to copy number variations, CNVs) are known to be recurrent in BRCA1/2 genes, e.g. in Mexica (BRCA1 ex9-12del) [42], and this limitation should be eliminated in the future.…”

Section: Discussionmentioning

confidence: 99%

A spectrum of BRCA1 and BRCA2 germline deleterious variants in ovarian cancer in Russia

Kechin

Boyarskikh

Barinov

et al. 2021

Preprint

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Pathogenic mutations in BRCA1 and BRCA2 genes are essential biomarkers of an increased breast and ovarian cancer risk and tumor sensitivity to poly ADP ribose (PARP) inhibitors. In many countries, their detection includes patient prescreening with quantitative PCR (qPCR) identifying several founder mutations. In Russia, eight mutations are included in such tests, among which c.5266dup (5382insC) is the most frequently identified one. Here, we showed the distribution of 1406 pathogenic or likely pathogenic mutations in BRCA1/2 genes identified in ovarian cancer patients recruited into the study from 72 Russian regions in 2015-2021. The most of mutations were detected with qPCR, for qPCR mutation negative samples, targeted next-generation sequencing (NGS) covering whole coding sequences of the genes was applied. As expected, the most abundant mutations were c.5266dupC (41.0%), c.4035delA (7.0%), c.1961delA (6.3%), c.181T>G (5.2%), c.3756_3759delGTCT (1.8%), c.3700_3704delGTAAA (1.5%), and c.68_69delAG (1.5%). However, we identified several mutations which were more frequent than the founder c.5946delT mutation (also known as 6174delT, 0.5% of participants): c.5152+1G>T (1.2%), c.1687C>T (1.0%), c.4689C>G (0.9%), c.1510delC (0.6%), c.2285_2286delGA (0.6%) in the BRCA1 gene; and c.5286T>G (1.2%), c.2808_2811delACAA (0.8%), c.658_659delGT (0.7%), c.7879A>T (0.6%), c.3847_3848delGT (0.6%) in the BRCA2 gene. Having developed an NGS-targeted panel on SNPs flanking BRCA2 c.5286T>G, we showed the founder effect for this mutation and suggested that it arose about 700 years ago that is twice later that it is thought for the c.5266dupC. The total occurrence of mutations identified in at least 10 participants (13 mutations) was only 70%. To our knowledge, eighty-nine mutations (identified in 8% of participants) have not been described previously. Thus, this study may help in improving prescreening qPCR tests and extend our knowledge about the BRCA1 and BRCA2 genes variability in ovarian cancer patients.

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“…Hollis and colleagues summarized the evidence regarding the implications of different germline BRCA PVs in ovarian cancer and concluded that aberrations at particular BRCA sites could confer differential sensitivity to platinum-based chemotherapy and PARPi (14). Furthermore, a study of patients with ovarian cancer showed that the presence of BRCA PVs in the ovarian cancer cluster region was associated with a better RFS than those in breast cancer cluster regions and not-related risk regions (25). Drost and colleagues investigated mice carrying the BRCA1185stop and BRCA15382stop alleles (which mimic the most common human BRCA founder mutations) and showed that the BRCA1185stop mice responded markedly worse to HRR deficiency-targeting therapies (13).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it was reported in a small study that patients with ovarian cancer harboring the Mexican BRCA founder CNVs had a better RFS than those with other types of BRCA PVs (25). However, the prognostic role of CNV such as the Mexican BRCA founder mutation on BC had not been previously reported.…”

Section: Discussionmentioning

confidence: 99%

Influence of Germline BRCA Genotype on the Survival of Patients with Triple-Negative Breast Cancer

Villarreal‐Garza

Ferrigno

Aranda-Gutierrez

et al. 2021

Cancer Research Communications

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The presence of BRCA pathogenic variants (PV) in triple-negative breast cancer (TNBC) is associated with a distinctive genomic profile that makes the tumor particularly susceptible to DNA-damaging treatments. However, patients with BRCA PVs can develop treatment resistance through the appearance of reversion mutations and restored BRCA expression. As copy-number variants (CNV) could be less susceptible to reversion mutations than point mutations, we hypothesize that carriers of BRCA CNVs may have improved survival after treatment compared with carriers of other BRCA PVs or BRCA wild-type. Women diagnosed with stage I–III TNBC at ≤50 years at a cancer center in Mexico City were screened for BRCA PVs using a recurrent PV assay (HISPANEL; 77% sensitivity). Recurrence-free survival (RFS) and overall survival (OS) were compared according to the mutational status. Among 180 women, 17 (9%) were carriers of BRCA1 ex9–12del CNVs and 26 (14%) of other BRCA PVs. RFS at ten years for the whole cohort was 79.2% [95% confidence interval (CI), 72.3–84.6], with no significant differences according to mutational status. 10-year OS for the entire cohort was 85.3% (95% CI, 78.7–90.0), with BRCA CNV carriers demonstrating numerically superior OS rates other PV carriers and noncarriers (100% vs. 78.6% and 84.7%; log-rank P = 0.037 and P = 0.051, respectively). This study suggests that BRCA1 ex9–12del CNV carriers with TNBC may have a better OS, and supports the hypothesis that the genotype of BRCA PVs may influence survival by limiting treatment resistance mediated by reversion mutations among CNV carriers. Significance: Large CNV BRCA carriers in a cohort of young Mexican patients with TNBC had superior OS rates than carriers of other BRCA pathogenic variants (i.e., small indels or point mutations). We hypothesize that this is due to the resistance of CNVs to reversion mutations mediating resistance to therapy. If validated, these findings have important prognostic and clinical treatment implications for BRCA-associated breast cancers.

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Clinical Evaluation of BRCA1/2 Mutation in Mexican Ovarian Cancer Patients

Cited by 14 publications

References 35 publications

The Features of BRCA1 and BRCA2 Germline Mutations in Hakka Ovarian Cancer Patients: BRCA1 C.536 A>T Maybe a Founder Mutation in This Population

The Features of BRCA1 and BRCA2 Germline Mutations in Hakka Ovarian Cancer Patients: BRCA1 C.536 A>T Maybe a Founder Mutation in This Population

A spectrum of BRCA1 and BRCA2 germline deleterious variants in ovarian cancer in Russia

Influence of Germline BRCA Genotype on the Survival of Patients with Triple-Negative Breast Cancer

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