Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica, Perfiérico Sur, 4809, Arenal Tepepan, 14610, Mexico City, CP, Mexico.
Instituto de Enfermedades la Mama FUCAM, Avenida El Bordo 100, Santa Ursula Coapa, 04980, Mexico City, CP, Mexico.
Hum Genomics. 2019 Jan 10;13(1):3. doi: 10.1186/s40246-018-0188-9.
Interpretation of variants of unknown significance (VUS) in genetic tests is complicated in ethnically diverse populations, given the lack of information regarding the common spectrum of genetic variation in clinically relevant genes. Public availability of data obtained from high-throughput genotyping and/or exome massive parallel sequencing (MPS)-based projects from several thousands of outbred samples might become useful tools to evaluate the pathogenicity of a VUS, based on its frequency in different populations. In the case of the Mexican and other Latino populations, several thousands of samples have been genotyped or sequenced during the last few years as part of different efforts to identify common variants associated to common diseases. In this report, we analyzed Mexican population data from a sample of 3985 outbred individuals, and additional 66 hereditary breast cancer patients were analyzed in order to better define the spectrum of common genomic variation of the BRCA1 and BRCA2 genes. Our analyses identified the most common genetic variants in these clinically relevant genes as well as the presence and frequency of specific pathogenic mutations present in the Mexican population. Analysis of the 3985 population samples by MPS identified three pathogenic mutations in BRCA1, only one population sample showed a BRCA1 exon 16-17 deletion by MLPA. This resulted in a basal prevalence of deleterious mutations of 0.10% (1:996) for BRCA1 and 11 pathogenic mutations in BRCA2, resulting in a basal prevalence of deleterious mutations of 0.276% (1:362) for BRCA2, combined of 0.376% (1:265). Separate analysis of the breast cancer patients identified the presence of pathogenic mutations in 18% (12 pathogenic mutations in 66 patients) of the samples by MPS and 13 additional alterations by MLPA. These results will support a better interpretation of clinical studies focused on the detection of BRCA mutations in Mexican and Latino populations and will help to define the general prevalence of deleterious mutations within these populations.
在遗传检测中，对于具有不同种族背景的人群，解释意义不明的变异（VUS）较为复杂，因为在临床上相关的基因中，缺乏常见遗传变异的信息。从高通量基因分型和/或外显子大规模平行测序（MPS）的项目中获得的公开数据，可能会成为评估 VUS 致病性的有用工具，其依据是不同人群中 VUS 的频率。在墨西哥和其他拉丁裔人群中，在过去几年中，作为确定与常见疾病相关的常见变体的不同努力的一部分，已经对数千个样本进行了基因分型或测序。在本报告中，我们分析了来自 3985 名随机个体的墨西哥人群数据，并对另外 66 名遗传性乳腺癌患者进行了分析，以便更好地定义 BRCA1 和 BRCA2 基因常见基因组变异的范围。我们的分析确定了这些临床上相关基因中最常见的遗传变体，以及在墨西哥人群中存在的特定致病性突变的频率。通过 MPS 对 3985 个人群样本的分析，发现 BRCA1 中有 3 种致病性突变，仅一个人群样本通过 MLPA 显示 BRCA1 外显子 16-17 缺失。这导致 BRCA1 中有害突变的基础患病率为 0.10%（1:996），BRCA2 中有 11 种致病性突变，BRCA2 中有害突变的基础患病率为 0.276%（1:362），合并患病率为 0.376%（1:265）。对乳腺癌患者的单独分析，通过 MPS 在 18%（66 名患者中有 12 种致病性突变）的样本中发现了致病性突变，通过 MLPA 还发现了 13 种额外的改变。这些结果将有助于更好地解释针对墨西哥和拉丁裔人群中 BRCA 突变检测的临床研究，并有助于确定这些人群中有害突变的总体患病率。
