Comprehensive Analysis of Germline Variants in Mexican Patients with Hereditary Breast and Ovarian Cancer Susceptibility

Urban, Rosalía Quezada; Velásquez, Clara Estela Díaz; Gitler, Rina; Castillo, María Patricia Rojo; Toporek, Max Sirota; Morales, Andrea Figueroa; García, Oscar Moreno; Esquivel, Lizbeth García; Mejia, Gabriela Torres; Dean, Michael; Delgado‐Enciso, Iván; López, Héctor Ochoa Díaz; León, Fernando Rodríguez; Jan, Virginia; Barrientos, Víctor Hugo Garzón; Flores, Pablo; Silva, Perla Karina Espino; Cruz, Jorge Haro Santa; Gregorio, Héctor Martínez; Jiménez, Ernesto Rojas; Cruz, Luis Enrique Romero; Catalá, Claudia Fabiola Méndez; Gómez, Rosa María Álvarez; Ontiveros, Verónica Fragoso; Herrera, Luis A.; Romieu, Isabelle; Terrazas, Luis I.; Chirino, Yolanda I.; Frecha, Cecilia; Oliver, Javier; Pérdomo, Sandra; Paniagua, Felipe Vaca

doi:10.3390/cancers10100361

Cited by 25 publications

(51 citation statements)

References 65 publications

(61 reference statements)

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“…Variants in this genes have been associated with a deficiency in HR and increased sensitivity to DNA damage, classifying BARD1 as a gene of moderate penetrance to BC and OC [23,[77][78][79]. All three associated variants are described as VUS on ClinVar, but p.Asn255Ser (c.764A > G) and p.Lys423Arg (c.1268A > G) lack studies characterizing their effects on protein functions.…”

Section: Discussionmentioning

confidence: 99%

Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population

et al. 2020

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Background: The Hereditary Breast and Ovarian Cancer Syndrome (HBOC) occurs in families with a history of breast/ ovarian cancer, presenting an autosomal dominant inheritance pattern. BRCA1 and BRCA2 are high penetrance genes associated with an increased risk of up to 20-fold for breast and ovarian cancer. However, only 20-30% of HBOC cases present pathogenic variants in those genes, and other DNA repair genes have emerged as increasing the risk for HBOC. In Brazil, variants in ATM, ATR, CHEK2, MLH1, MSH2, MSH6, POLQ, PTEN, and TP53 genes have been reported in up to 7.35% of the studied cases. Here we screened and characterized variants in 21 DNA repair genes in HBOC patients. Methods:We systematically analyzed 708 amplicons encompassing the coding and flanking regions of 21 genes related to DNA repair pathways (ABRAXAS1, ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MRE11, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD50, RAD51, TP53 and UIMC1). A total of 95 individuals with HBOC syndrome clinical suspicion in Southeast Brazil were sequenced, and 25 samples were evaluated for insertions/deletions in BRCA1/BRCA2 genes. Identified variants were assessed in terms of population allele frequency and their functional effects were predicted through in silico algorithms. Results: We identified 80 variants in 19 genes. About 23.4% of the patients presented pathogenic variants in BRCA1, BRCA2 and TP53, a frequency higher than that identified among previous studies in Brazil. We identified a novel variant in ATR, which was predicted as pathogenic by in silico tools. The association analysis revealed 13 missense variants in ABRAXAS1, BARD1, BRCA2, CHEK2, CDH1, MLH1, PALB2, and PMS2 genes, as significantly associated with increased risk to HBOC, and the patients carrying those variants did not present large insertions or deletions in BRCA1/BRCA2 genes.

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Section: Discussionmentioning

confidence: 99%

Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population

et al. 2020

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“…Library preparation and sequencing of the Mexican, Argentinian and Guatemalan samples was performed with the GeneRead Cancer Predisposition V2 Kit (Qiagen), as previously described (18). Briefly, the kit targets 143 genes associated with inherited cancers.…”

Section: Library Preparation and Massive Parallel Sequencingmentioning

confidence: 99%

“…The variant reduction to identify pathogenic variants was done as reported previously (18). Briefly, FastQC files were aligned to the human genome reference hg19 with BWA-MEM; indels were realigned and the bases were recalibrated.…”

Section: Sequencing Normalization and Pathogenic Variant Detectionmentioning

confidence: 99%

“…The founder mutation consisting in a deletion in exons 9-12 was detected by PCR amplification of the mutant and wild-type alleles, using specific primers based the method published in Weitzel et al (18,27). The PCR products were resolved in 1.5% agarose gels to identify the amplification of the truncated allele and sequenced.…”

Section: Detection Of Exon 9-12 Deletion In Brca1mentioning

confidence: 99%

“…Currently, there is a limited volume of studies of genetic susceptibility to HBOC in Latin America, and the majority of them are focused on the BRCA1/2 genes. Only a few publications have described the association of pathogenic variants in genes other than BRCA1/2 in selected HBOC cases in patients from Colombia (17), Mexico (18), Brazil (19,20), and Chile (21). Therefore, a network of collaborators and cancer specialists in LA joined common efforts to create a The Latin American consortium for HBOC-LACAM.…”

Section: Introductionmentioning

confidence: 99%

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Latin American Study of Hereditary Breast and Ovarian Cancer LACAM: A Genomic Epidemiology Approach

et al. 2019

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Purpose: Hereditary Breast and Ovarian Cancer (HBOC) syndrome is responsible for ∼5-10% of all diagnosed breast and ovarian cancers. Breast cancer is the most common malignancy and the leading cause of cancer-related mortality among women in Latin America (LA). The main objective of this study was to develop a comprehensive understanding of the genomic epidemiology of HBOC throughout the establishment Oliver et al. Latin American HBOC Study of The Latin American consortium for HBOC-LACAM, consisting of specialists from 5 countries in LA and the description of the genomic results from the first phase of the study. Methods: We have recruited 403 individuals that fulfilled the criteria for HBOC from 11 health institutions of Argentina, Colombia, Guatemala, Mexico and Peru. A pilot cohort of 222 individuals was analyzed by NGS gene panels. One hundred forty-three genes were selected on the basis of their putative role in susceptibility to different hereditary cancers. Libraries were sequenced in MiSeq (Illumina, Inc.) and PGM (Ion Torrent-Thermo Fisher Scientific) platforms. Results: The overall prevalence of pathogenic variants was 17% (38/222); the distribution spanned 14 genes and varied by country. The highest relative prevalence of pathogenic variants was found in patients from Argentina (25%, 14/57), followed by Mexico (18%, 12/68), Guatemala (16%, 3/19), and Colombia (13%, 10/78). Pathogenic variants were found in BRCA1 (20%) and BRCA2 (29%) genes. Pathogenic variants were found in other 12 genes, including high and moderate risk genes such as MSH2, MSH6, MUTYH, and PALB2. Additional pathogenic variants were found in HBOC unrelated genes such as DCLRE1C, WRN, PDE11A, and PDGFB. Conclusion: In this first phase of the project, we recruited 403 individuals and evaluated the germline genetic alterations in an initial cohort of 222 patients among 4 countries. Our data show for the first time in LA the distribution of pathogenic variants in a broad set of cancer susceptibility genes in HBOC. Even though we used extended gene panels, there was still a high proportion of patients without any detectable pathogenic variant, which emphasizes the larger, unexplored genetic nature of the disease in these populations.

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Ancestry‐specific hereditary cancer panel yields: Moving toward more personalized risk assessment

Roberts¹,

Susswein²,

Cheng

et al. 2020

Journal of Genetic Counseling

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Healthcare disparities in genomic medicine are well described. Despite some improvements, we continue to see fewer individuals of African American, Asian, and Hispanic ancestry undergo genetic counseling and testing compared to those of European ancestry. It is well established that variant of uncertain significance (VUS) rates are higher among non‐European ancestral groups undergoing multi‐gene hereditary cancer panel testing. However, pathogenic variant (PV) yields, and genomic data in general, are often reported in aggregate and derived from cohorts largely comprised of individuals of European ancestry. We performed a retrospective review of clinical and ancestral data for individuals undergoing multi‐gene hereditary cancer panel testing to determine ancestry‐specific PV and VUS rates. An ancestry other than European was reported in 29,042/104,851 (27.7%) of individuals. Compared to Europeans (9.4%), individuals of Middle Eastern ancestry were more likely to test positive for one or more pathogenic variants (12.1%, p = .0025), while African Americans were less likely (7.9%, p < .0001). Asian and Middle Eastern individuals were most likely (34.8% and 33.2%, respectively) to receive a report with an overall classification of VUS, while individuals of Ashkenazi Jewish and European ancestry were least likely (17.1% and 20.4%, respectively). These data suggest that in addition to higher VUS rates, there may be ancestry‐specific PV yields. Providing aggregate data derived from cohorts saturated with European individuals does not adequately reflect genetic testing outcomes in minority groups, and interrogation of ancestry‐specific data is a step toward a more personalized risk assessment.

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Comprehensive Analysis of Germline Variants in Mexican Patients with Hereditary Breast and Ovarian Cancer Susceptibility

Cited by 25 publications

References 65 publications

Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population

Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population

Latin American Study of Hereditary Breast and Ovarian Cancer LACAM: A Genomic Epidemiology Approach

Ancestry‐specific hereditary cancer panel yields: Moving toward more personalized risk assessment

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