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Germline variants of DNA repair genes in early onset mantle cell lymphoma

Oncogene volume 40, pages 551–563 (2021)Cite this article

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Abstract

Although somatic mutations of DNA repair genes are frequent in mantle cell lymphoma (MCL), our understanding of their germline defects is limited. In a Chinese family with maternal Lynch syndrome and paternal B cell non-Hodgkin lymphoma, one sibling developed both Lynch syndrome and MCL. Lynch syndrome is caused by heterozygous mutations in mismatch repair (MMR) genes. To understand the genetic predispositions in the family, we performed exome sequencing and analyses of affected individuals and their tumor samples. A novel germline indel, MLH1 Gly101fsX1, was identified as the cause of Lynch syndrome, and unstable microsatellite loci and mutational signatures as evidence of defective MMR were revealed in the MCL sample. Furthermore, we included additional 15 MCL patients with early onset, and found by exome sequencing that 11 patients carried heterozygous germline variants of 20 DNA repair genes, including MSH2 in MMR. In the MCL with MSH2 Arg359fsX16, unstable microsatellite loci and defective MMR signatures were also found. In addition, five patients also had heterozygous germline variants of genes involved in B cell functions. Thus, our study found germline variants of genes in single-strand break repair, double-strand break repair, and Fanconi anemia pathway in early onset MCL; and for the first time we identified germline defects of MMR in two MCLs.

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Fig. 1: The pedigree of a family with Lynch syndrome and B-NHL.
Fig. 2: MLH1 Gly101fsX1 and mutational signatures of the MCL.
Fig. 3: MSH2 Arg359fsX16, aberrant splicing and mutational signatures of the MCL.

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Acknowledgements

This work was supported by grants from the Key Research Program of the Chinese Academy of Sciences (KJZD-EW-L06-2) (CZ), the National Natural Science Foundation of China (81972807, 81670187 and 81470368) (YS and JZ), the National High Technology Research and Development Program (863 Program) of China (2012AA022502) (CZ), the Beijing Natural Science Foundation (7202025) (YS), and the China Postdoctoral Science Foundation (2013M541009) (XW). We thank Sheng Li for the help in the interview of relatives of the family and collection of their samples. We are grateful to Yunfei Shi for pathological review. Further thanks are due to Wen Zheng, Ningjing Lin, Meifeng Tu, Xiaopei Wang, Lingyan Ping, Zhitao Ying, Lijuan Deng, Chen Zhang, Tingting Du, Meng Wu, Xin Len, and Feier Feng for their help in collection of clinical information. We are grateful to Caixia Guo for advice and help in revision.

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  1. These authors contributed equally: Xiaogan Wang, Yuqin Song

Authors and Affiliations

  1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, China

    Xiaogan Wang, Yuqin Song, Ning Ding, Weiping Liu, Yan Xie & Jun Zhu

  2. CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China

    Xiaogan Wang, Wei Chen & Changqing Zeng

  3. China National Center for Bioinformation, Beijing, China

    Wei Chen & Changqing Zeng

  4. Hebei Tangshan People’s Hospital, Tangshan, Hebei, China

    Yinan Wang

  5. University of Chinese Academy of Sciences, Beijing, China

    Changqing Zeng

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Wang, X., Song, Y., Chen, W. et al. Germline variants of DNA repair genes in early onset mantle cell lymphoma. Oncogene 40, 551–563 (2021). https://doi.org/10.1038/s41388-020-01542-2

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