Dataset Information

Genomic Diversity in Sporadic Breast Cancer in a Latin American Population.

ABSTRACT: Among Latin American women, breast cancer incidences vary across populations. Uruguay and Argentina have the highest rates in South America, which are mainly attributed to strong, genetic European contributions. Most genetic variants associated with breast cancer were described in European populations. However, the vast majority of genetic contributors to breast cancer risk remain unknown. Here, we report the results of a candidate gene association study of sporadic breast cancer in 176 cases and 183 controls in the Uruguayan population. We analyzed 141 variants from 98 loci that have been associated with overall breast cancer risk in European populations. We found weak evidence for the association of risk variants rs294174 (ESR1), rs16886165 (MAP3K1), rs2214681 (CNTNAP2), rs4237855 (VDR), rs9594579 (RANKL), rs8183919 (PTGIS), rs2981582 (FGFR2), and rs1799950 (BRCA1) with sporadic breast cancer. These results provide useful insight into the genetic susceptibility to sporadic breast cancer in the Uruguayan population and support the use of genetic risk scores for individualized screening and prevention.

SUBMITTER: Brignoni L

PROVIDER: S-EPMC7716199 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Genomic Diversity in Sporadic Breast Cancer in a Latin American Population.

Brignoni Lucía L Cappetta Mónica M Colistro Valentina V Sans Mónica M Artagaveytia Nora N Bonilla Carolina C Bertoni Bernardo B

Genes 20201028 11

Among Latin American women, breast cancer incidences vary across populations. Uruguay and Argentina have the highest rates in South America, which are mainly attributed to strong, genetic European contributions. Most genetic variants associated with breast cancer were described in European populations. However, the vast majority of genetic contributors to breast cancer risk remain unknown. Here, we report the results of a candidate gene association study of sporadic breast cancer in 176 cases an ...[more]

PMID: 33126731

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Project description: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 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.

Project description:IntroductionGenomic aberrations in the form of subchromosomal DNA copy number changes are a hallmark of epithelial cancers, including breast cancer. The goal of the present study was to analyze such aberrations in breast cancer at high resolution.MethodsWe employed high-resolution array comparative genomic hybridization with 4,134 bacterial artificial chromosomes that cover the genome at 0.9 megabase resolution to analyze 47 primary breast tumors and 18 breast cancer cell lines.ResultsCommon amplicons included 8q24.3 (amplified in 79% of tumors, with 5/47 exhibiting high level amplification), 1q32.1 and 16p13.3 (amplified in 66% and 57% of tumors, respectively). Moreover, we found several positive correlations between specific amplicons from different chromosomes, suggesting the existence of cooperating genetic loci. Queried by gene, the most frequently amplified kinase was PTK2 (79% of tumors), whereas the most frequently lost kinase was PTK2B (hemizygous loss in 34% of tumors). Amplification of ERBB2 as measured by comparative genomic hybridization (CGH) correlated closely with ERBB2 DNA and RNA levels measured by quantitative PCR as well as with ERBB2 protein levels. The overall frequency of recurrent losses was lower, with no region lost in more than 50% of tumors; the most frequently lost tumor suppressor gene was RB1 (hemizygous loss in 26% of tumors). Finally, we find that specific copy number changes in cell lines closely mimicked those in primary tumors, with an overall Pearson correlation coefficient of 0.843 for gains and 0.734 for losses.ConclusionHigh resolution CGH analysis of breast cancer reveals several regions where DNA copy number is commonly gained or lost, that non-random correlations between specific amplicons exist, and that specific genetic alterations are maintained in breast cancer cell lines despite repeat passage in tissue culture. These observations suggest that genes within these regions are critical to the malignant phenotype and may thus serve as future therapeutic targets.

Dataset Information

Genomic Diversity in Sporadic Breast Cancer in a Latin American Population.

Publications

Genomic Diversity in Sporadic Breast Cancer in a Latin American Population.

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