Impact of genomic and epigenomic alterations of multigene on a multicancer pedigree

Author:

Gao Jingyu12,Wu Yongzhang23ORCID,Yu Jieming24,Qiu Yinbin2ORCID,Yi Tiantian12,Luo Chaochao2,Zhang Junxiao5,Lu Gary6,Li Xu7,Xiong Fu8,Wu Xuedong12,Pan Xinghua1239

Affiliation:

1. Department of Pediatrics Nanfang Hospital, Southern Medical University Guangzhou China

2. Guangdong Provincial Key Laboratory of Single Cell Technology and Application Southern Medical University Guangzhou China

3. Department of Biochemistry and Molecular Biology School of Basic Medical Sciences, Southern Medical University Guangzhou China

4. Affiliated Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University Shenzhen China

5. SequMed Institute of Biomedical Sciences Guangzhou China

6. Department of Fetal Medicine and Prenatal Diagnosis Zhujiang Hospital, Southern Medical University Guangzhou China

7. Kaiser Permanente Regional Genetics Laboratory, San Jose Medical Center San Jose California USA

8. Department of Medical Genetics School of Basic Medical Sciences, Southern Medical University Guangzhou China

9. Precision Regenerative Medicine Research Centre, Division of Medical Sciences Macau University of Science and Technology Macao China

Abstract

AbstractBackgroundGermline mutations have been identified in a small number of hereditary cancers, but the genetic predisposition for many familial cancers remains to be elucidated.MethodsThis 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.ResultsAccording 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.ConclusionsThese 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.

Funder

National Natural Science Foundation of China

Publisher

Wiley

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