A Novel Germline Compound Heterozygous Mutation of BRCA2 Gene Associated With Familial Peripheral Neuroblastic Tumors in Two Siblings

Yeran Yang; Jiwei Chen; Hong Qin; Yaqiong Jin; Li Zhang; Shen Yang; Huanmin Wang; Libing Fu; Enyu Hong; Yongbo Yu; Jie Lu; Yan Chang; Xin Ni; Min Xu; Tieliu Shi; Yongli Guo

doi:10.3389/fgene.2021.652718

A Novel Germline Compound Heterozygous Mutation of BRCA2 Gene Associated With Familial Peripheral Neuroblastic Tumors in Two Siblings

Front Genet. 2021 Jul 23:12:652718. doi: 10.3389/fgene.2021.652718. eCollection 2021.

Authors

Yeran Yang^{1

2

3}, Jiwei Chen⁴, Hong Qin⁵, Yaqiong Jin^{1

2

3}, Li Zhang⁴, Shen Yang⁵, Huanmin Wang⁵, Libing Fu⁶, Enyu Hong^{1

2}, Yongbo Yu^{1

2

3}, Jie Lu^{1

2

3}, Yan Chang^{1

2

3}, Xin Ni^{1

2

3}, Min Xu⁷, Tieliu Shi⁴, Yongli Guo^{1

2

3}

Affiliations

¹ Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, National Center for Children's Health, Beijing Children's Hospital, Beijing Pediatric Research Institute, Capital Medical University, Beijing, China.
² Biobank for Clinical Data and Samples in Pediatric, National Center for Children's Health, Beijing Children's Hospital, Beijing Pediatric Research Institute, Capital Medical University, Beijing, China.
³ Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, Capital Medical University, Beijing, China.
⁴ Center for Bioinformatics and Computational Biology, School of Life Sciences, Institute of Biomedical Sciences, East China Normal University, Shanghai, China.
⁵ Department of Surgical Oncology, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China.
⁶ Department of Pathology, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China.
⁷ Department of Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Abstract

Objectives: To investigate the genetic variants that are responsible for peripheral neuroblastic tumors (PNTs) oncogenesis in one family case.

Materials and methods: One family was recruited, including the healthy parents, sister affected by neuroblastoma (NB), and brother who suffered from ganglioneuroma (GN). Whole-genome sequencing (WGS) of germline DNA from all the family members and RNA-seq of tumor RNA from the siblings were performed. Mutants were validated by Sanger sequencing and co-IP was performed to assess the impact of the mutant on chemosensitivity in the SH-SY5Y cell line.

Results: A novel compound heterozygous mutation of BRCA2 was locked as the cause of carcinogenesis. One allele was BRCA2-S871X (stop-gain) from the siblings' mother, the other was BRCA2-N372H (missense) from their father. This novel compound heterozygous mutations of the BRCA2 gene associated with PNTs by disordering DNA damage and response (DDR) signal pathway. Moreover, chemosensitivity was reduced in the NB cell line due to the BRCA2-N372H mutant.

Conclusion: In summary, these results revealed a novel germline compound heterozygous mutation of the BRCA2 gene associated with familial PNTs.

Keywords: BRCA2; RNA-Seq; cancer predisposition gene; ganglioneuroma; neuroblastoma; peripheral neuroblastic tumors; whole-genome sequencing.