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

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.