We performed WES on a pair of siblings who developed HL in adulthood as well as on their parents to identify potential genetic sequence variations associated with hereditary predisposition to HL. In this family, the parents were consanguineously married, and the paternal grandmother and maternal grandmother were biological sisters. The siblings were diagnosed with nodular sclerosis classic HL in their early twenties, which is younger than the peak age of HL incidence in China (approximately 40 years of age). Both siblings presented with lymph node involvement in the neck and mediastinum, poor response to frontline treatment, or short-term relapse, and exhibited similar clinical manifestations.
HL displays a strong hereditary component when compared with many other diseases, with the risk of lymphoma being particularly high among relatives of affected patients [13]. A retrospective analysis of 31 families with lymphoma in first-degree relatives identified 20 HL/HL, 8 non-Hodgkin’s lymphoma (NHL)/HL, and 8 NHL/NHL pairs, indicating that the highest incidence of HL genetic susceptibility, with a relatively young median age of diagnosis at 27 years, and a predominance of sibling cases [14]. Altieri et al. reported on the familial risk of HL in Sweden, confirming the familial aggregation of HL, and finding that the risk was significantly higher for brothers of affected males or sisters of affected females relative to that for opposite-sex siblings [15], suggesting that a gene for HL might reside in either of the pseudoautosomal regions of the sex chromosomes [16]. Inbreeding may lead to the presence of recessive alleles for HL, resulting in increased expression of harmful recessive genes within a population [17]. Although several studies have demonstrated a clear genetic predisposition for familial HL, the specific genes involved have rarely been reported.
Collecting biological materials from family cases is an important method for conducting genetic research. In our study, the screening of the two patients and their parents revealed a homozygous p.R140W mutation in CD38, consistent with an autosomal recessive inheritance pattern, thus adding a new variant to the HL gene mutation database. The CD38 gene is located on the short arm of chromosome 4 (4p15) and has a length of over 80 kb, with more than 98% represented by intronic sequences [18, 19]. R140W is located in the CD38 Rib_hydrolase domain, where the arginine (R) at codon 140 is replaced by tryptophan (W). Although this germline mutation has been reported to be associated with an increased risk of neonatal disorders (PMID: 26025338) [20] and autism spectrum disorders (PMID: 22366648) [21], this is the first report of its association with hematologic malignancies.
CD38 gene polymorphism is associated with genetic susceptibility to hematological malignancies, particularly B-cell chronic lymphocytic leukemia (B-CLL). There are two single nucleotide polymorphisms (SNPs) in intron 1 (182C/G) and exon 3 (418C/T) of the CD38 gene, and the allele frequencies and distributions of these SNPs differ significantly between B-CLL patients and healthy controls. The presence of alternative alleles increases the risk of developing B-CLL [22]. The C > G variation in the regulatory region of intron 1 may be related to Richter syndrome transformation [23]. Talaat et al. found that CD38 (184C/G; rs6449182) is associated with susceptibility to DLBCL in Egyptians [24]. CD38 gene polymorphism may affect lymphoma development by influencing biological processes such as B-cell apoptosis and proliferation [25]. Variations at certain sites are associated with altered CD38 protein expression levels and enzymatic activity [22]. CD38 is a type II transmembrane glycoprotein belonging to the ADP-ribosyl cyclase family and has a molecular mass of 46 kDa. It is expressed in human T cells, B cells, dendritic cells, and NK cells, among others. CD38 functions as an extracellular enzyme with roles in transmembrane signal transduction and cell adhesion, along with the regulation of cell migration, receptor-mediated adhesion, extracellular metabolite generation, and intracellular Ca2+ signaling [26, 27]. Over recent years, multiple studies have supported a potential role for CD38 as a powerful immune regulatory molecule. It has been shown that CD38 can inhibit T cell activity by degrading extracellular NAD+ [28], and CD38 is highly expressed in partially dysfunctional T cells [29], which suppresses immune responses and increases susceptibility to lymphoma. CD38 can serve as a marker for adaptive immune resistance to tumor-specific T-cell infiltration and its upregulation contributes to resistance to PD-1/PD-L1 blockade therapy [26, 30]. Despite these reports, research on the association between CD38 gene polymorphism and lymphoma susceptibility is still relatively limited, and further studies are needed to validate these findings and explore the underlying molecular mechanisms.