Unfolding the enigma of familial Hodgkin lymphoma: Current insights

Abstract

Hodgkin lymphoma (HL) is a heterogenous lymphoproliferative disorder of B-cell origin and represents one of the most common malignancies in children and young adults. In addition to well-known underlying factors - such as Epstein-Barr virus infection - the familial aggregation demonstrated in large population studies suggested a genetic predisposition. First-degree relatives of patients with HL have an approximately threefold increased risk of developing the disease compared to the general population. These observations have recently prompted several whole-genome studies in affected families, identifying variants possibly implicated in lymphomagenesis, including alterations in DICER1 (a member of the ribonuclease III family), POT1 (protection of telomeres 1), KDR (kinase insert domain receptor), KLHDC8B (kelch domain-containing protein 8B), PAX5 (paired box protein 5), GATA3 (GATA binding protein 3), IRF7 (interferon regulatory factor 7), EEF2KMT (eukaryotic elongation factor 2 lysine methyltransferase), and POLR1E (RNA polymerase I subunit E). In this article, we review current insights into the etiopathogenesis and risks of familial HL, and present case reports involving two sisters diagnosed with HL nearly 17 years apart. Recognizing the risk for first-degree relatives may potentially increase awareness of early symptoms among family members of HL patients, leading to earlier diagnosis and better outcomes. Conversely, understanding that the hereditary risk, though higher than in the general population, remains relatively low may provide reassurance for affected families.

Keywords: Hodgkin lymphoma; Familial Hodgkin lymphoma; Genetic analysis; Whole genome sequencing; Pathogenic variants

Core Tip: Hodgkin lymphoma (HL), although rare, is one of the most common pediatric malignancies. Familial clustering points to genetic susceptibility, especially in young-onset cases. Recently, whole-genome sequencing studies of affected families have identified several predisposing genetic variants, contributing to unraveling the complex etiopathogenesis of HL. New insights into tumor biology and the identification of germline mutations may facilitate genetic counselling, raising awareness among first-degree relatives of HL patients about potential symptoms and leading to earlier diagnosis and better outcomes. Emphasizing that the hereditary risk of HL remains low can provide significant psychological relief for affected families.