Study Identifies Novel PD-L2 Variant as Possible Predisposition Indicator in Lymphoma

Whole-exome sequencing of a family with early-onset cancers found a novel variant in programmed cell death 1 ligand 2 that could potentially indicate germline predisposition to lymphoma.

Determining genetic predisposition to lymphoma, when possible, can significantly impact the management of patients and their relatives. First-degree relatives of lymphoma patients are known to be at an elevated risk, and a recent study published in Hematological Oncology identified a novel variant in programmed cell death 1 ligand 2 (PD-L2) that may indicate germline predisposition.

Thus far, a plethora of genes have been identified as potential indicators of germline predisposition to lymphoid cancers thanks to next-generation sequencing. In lymphoid and other malignancies, identifying as many relevant genes as possible has potential to improve patient management and benefit at-risk family members. Given the benefits for patients, the WHO recommends including specific underlying genetic defects and predisposition syndrome as part of diagnoses for myeloid malignancies, for example.

In the current study, researchers performed whole-exome sequencing on a family with early-onset lymphomas and other cancers — including a patient with follicular lymphoma and his son with Hodgkin’s lymphoma (HL) —who did not show pathogenic variants during clinical gene panel testing.

The primary patient was diagnosed with follicular lymphoma at 36 years old, his son was diagnosed with HL at 7 years old, and his mother, 2 maternal aunts, and other family members were diagnosed with cancer at young ages. When tested for 22 known lymphoma predisposition genes, no pathogenic or likely pathogenic variants were found in the initial patient with follicular lymphoma. However, a novel variant in PD-L2 (c.817-1G>T) was found in the initial patient and his son with HL. The variant was not found in the initial patient’s consanguineous partner, who did not have any symptoms at the time of the study.

The variant affects the canonical splice acceptor site of the last intron of PD-L2, intron 6, and has not previously been identified to the authors’ knowledge. The initial patient’s son and partner were both tested for PD-L2 expression via blood samples, and the affected son had elevated PD-L2 RNA expression compared with the asymptomatic partner who was used as a control. PD-L1 and Janus kinase 2 (JAK2) expression were also increased in the affected son but not the control, possibly because the novel variant was also embedded in a putative enhancer that interacts with PD-L1 and JAK2 promoters in blood cells. A 3’ rapid amplification of cDNA ends (3’ RACE) also showed an abnormal PD-L2 transcript in the affected son.

“Thus, the c.817-1G>T variant may result in the elevated PD-L2 expression due to the abnormal PD-L2 transcript and the elevated PD-L1 and JAK2 expression due to increased enhancer activity of PD-L1 and JAK2,” the authors wrote. The variant is therefore likely to underlie the genetic etiology of the lymphomas in this particular family. Family members with other cancer types were not available for further investigation, so whether PD-L2 mutations predispose family members to cancer types other than lymphomas is also yet to be determined.

As far as the authors are aware, this report is the first to identify the c.817-1G>T variant of PD-L2 as a potential indicator of germline predisposition to lymphoma. While the study was done on a single family and requires more research to confirm the findings, it suggests that PD-L2 has potential to reveal germline predisposition to lymphoma. Further studies are also needed to confirm the underlying mechanisms of the novel variant’s effects and investigate PD-L2 defects as possible therapeutic markers in lymphoma management.

Reference

Shao J, Gao L, Leung ML, et al. Exome sequencing identifies PD-L2 as a potential predisposition gene for lymphoma. Hematol Oncol. Published online May 25, 2022. doi:10.1002/hon.3033