PDF(Pubmed)
Abstract：
Germline mutations have been identified in a small number of hereditary cancers, but the genetic predisposition for many familial cancers remains to be elucidated.
This study identified a Chinese pedigree that presented different cancers (breast cancer, BRCA; adenocarcinoma of the esophagogastric junction, AEG; and B-cell acute lymphoblastic leukemia, B-ALL) in each of the three generations. Whole-genome sequencing and whole-exome sequencing were performed on peripheral blood or bone marrow and cancer biopsy samples. Whole-genome bisulfite sequencing was conducted on the monozygotic twin brothers, one of whom developed B-ALL.
According to the ACMG guidelines, bioinformatic analysis of the genome sequencing revealed 20 germline mutations, particularly mutations in the DNAH11 (c.9463G > A) and CFH (c.2314G > A) genes that were documented in the COSMIC database and validated by Sanger sequencing. Forty-one common somatic mutated genes were identified in the cancer samples, displaying the same type of single nucleotide substitution Signature 5. Meanwhile, hypomethylation of PLEK2, MRAS, and RXRA as well as hypermethylation of CpG island associated with WT1 was shown in the twin with B-ALL.
These findings reveal genomic alterations in a pedigree with multiple cancers. Mutations found in the DNAH11, CFH genes, and other genes predispose to malignancies in this family. Dysregulated methylation of WT1, PLEK2, MRAS, and RXRA in the twin with B-ALL increases cancer susceptibility. The similarity of the somatic genetic changes among the three cancers indicates a hereditary impact on the pedigree. These familial cancers with germline and somatic mutations, as well as epigenomic alterations, represent a common molecular basis for many multiple cancer pedigrees.
This study identified a Chinese pedigree that presented different cancers (breast cancer, BRCA; adenocarcinoma of the esophagogastric junction, AEG; and B-cell acute lymphoblastic leukemia, B-ALL) in each of the three generations. Whole-genome sequencing and whole-exome sequencing were performed on peripheral blood or bone marrow and cancer biopsy samples. Whole-genome bisulfite sequencing was conducted on the monozygotic twin brothers, one of whom developed B-ALL.
According to the ACMG guidelines, bioinformatic analysis of the genome sequencing revealed 20 germline mutations, particularly mutations in the DNAH11 (c.9463G > A) and CFH (c.2314G > A) genes that were documented in the COSMIC database and validated by Sanger sequencing. Forty-one common somatic mutated genes were identified in the cancer samples, displaying the same type of single nucleotide substitution Signature 5. Meanwhile, hypomethylation of PLEK2, MRAS, and RXRA as well as hypermethylation of CpG island associated with WT1 was shown in the twin with B-ALL.
These findings reveal genomic alterations in a pedigree with multiple cancers. Mutations found in the DNAH11, CFH genes, and other genes predispose to malignancies in this family. Dysregulated methylation of WT1, PLEK2, MRAS, and RXRA in the twin with B-ALL increases cancer susceptibility. The similarity of the somatic genetic changes among the three cancers indicates a hereditary impact on the pedigree. These familial cancers with germline and somatic mutations, as well as epigenomic alterations, represent a common molecular basis for many multiple cancer pedigrees.
摘要：
背景：已经在少数遗传性癌症中发现了种系突变，但是许多家族性癌症的遗传易感性仍有待阐明。
方法：这项研究确定了一个呈现不同癌症（乳腺癌，BRCA;食管胃结合部腺癌,AEG;和B细胞急性淋巴细胞白血病，B-ALL）在三代中的每一个中。对外周血或骨髓和癌症活检样品进行全基因组测序和全外显子组测序。对单卵孪生兄弟进行了全基因组亚硫酸氢盐测序，其中一人开发了B-ALL。
结果：根据ACMG指南，基因组测序的生物信息学分析揭示了20种系突变，特别是DNAH11(c.9463G>A)和CFH(c.2314G>A)基因中的突变,这些突变记录在COSMIC数据库中,并通过Sanger测序进行了验证.在癌症样本中鉴定出41个常见的体细胞突变基因，显示相同类型的单核苷酸取代特征5.同时,PLEK2，MRAS的低甲基化，和RXRA以及与WT1相关的CpG岛的超甲基化在具有B-ALL的双胞胎中显示。
结论：这些发现揭示了患有多种癌症的谱系中的基因组改变。在DNAH11，CFH基因中发现的突变，和其他基因易患这个家族的恶性肿瘤。WT1、PLEK2、MRAS、在B-ALL的双胞胎中，RXRA会增加癌症易感性。三种癌症之间的体细胞遗传变化的相似性表明对家系的遗传影响。这些具有种系和体细胞突变的家族性癌症，以及表观基因组改变，代表了许多多发性癌症家系的共同分子基础。
方法：这项研究确定了一个呈现不同癌症（乳腺癌，BRCA;食管胃结合部腺癌,AEG;和B细胞急性淋巴细胞白血病，B-ALL）在三代中的每一个中。对外周血或骨髓和癌症活检样品进行全基因组测序和全外显子组测序。对单卵孪生兄弟进行了全基因组亚硫酸氢盐测序，其中一人开发了B-ALL。
结果：根据ACMG指南，基因组测序的生物信息学分析揭示了20种系突变，特别是DNAH11(c.9463G>A)和CFH(c.2314G>A)基因中的突变,这些突变记录在COSMIC数据库中,并通过Sanger测序进行了验证.在癌症样本中鉴定出41个常见的体细胞突变基因，显示相同类型的单核苷酸取代特征5.同时,PLEK2，MRAS的低甲基化，和RXRA以及与WT1相关的CpG岛的超甲基化在具有B-ALL的双胞胎中显示。
结论：这些发现揭示了患有多种癌症的谱系中的基因组改变。在DNAH11，CFH基因中发现的突变，和其他基因易患这个家族的恶性肿瘤。WT1、PLEK2、MRAS、在B-ALL的双胞胎中，RXRA会增加癌症易感性。三种癌症之间的体细胞遗传变化的相似性表明对家系的遗传影响。这些具有种系和体细胞突变的家族性癌症，以及表观基因组改变，代表了许多多发性癌症家系的共同分子基础。
