Hodgkin lymphoma (HL) is a cancer originating in the lymphatic system, part of the body’s immune defense. It affects lymphocytes, a type of white blood cell, leading to their uncontrolled growth. While HL’s exact cause is complex, genetic factors significantly influence its development and progression. This article explores the genetic aspects of Hodgkin lymphoma, from inherited predispositions to acquired changes within cancer cells.
Understanding Genetic Influences
Genetic influences on Hodgkin lymphoma can be broadly categorized into two types: inherited genetic predispositions and acquired genetic changes. Inherited genetic predispositions, also known as germline mutations, are genetic alterations passed down from parents and are present in nearly every cell of a person’s body. Acquired genetic changes, or somatic mutations, occur during a person’s lifetime and are not inherited; these changes happen when DNA becomes damaged, often due to environmental factors or random errors during cell division. Most cases of Hodgkin lymphoma are not directly inherited, with only about 5% of cases having a clear genetic connection.
Having a first-degree relative, such as a parent or sibling, with Hodgkin lymphoma can increase an individual’s risk, even though it’s not strictly hereditary. This increased risk is thought to stem from shared genetic variants within families, with the highest risk observed in identical twins. Rare genetic syndromes, such as Ataxia-telangiectasia, which affects DNA repair, or Wiskott-Aldrich syndrome, affecting immune cells, have also been linked to a slightly increased risk of lymphoma. These syndromes are uncommon, and their association with HL development is infrequent.
Specific Genetic Changes in Hodgkin Lymphoma Cells
Hodgkin lymphoma develops due to specific genetic alterations within cancerous Hodgkin and Reed-Sternberg (HRS) cells. HRS cells often show dysregulation in key signaling pathways, such as the NF-κB and JAK/STAT pathways, which promote uncontrolled cell growth and survival.
Genetic alterations activating these pathways include mutations in genes like SOCS1 and TNFAIP3, which normally regulate these signaling cascades. Amplifications of CD274 (PD-L1) and PDCD1LG2 (PD-L2) genes are also frequently observed in HRS cells. These amplifications increase PD-L1 and PD-L2 protein expression, allowing cancer cells to evade the immune system. Other recurrent genetic alterations in HRS cells include mutations in B2M, STAT6, GNA13, and XPO1. The Epstein-Barr virus (EBV) is also implicated in a significant proportion of HL cases, contributing to the activation of both NF-κB and JAK/STAT pathways.
How Genetics Guides Diagnosis and Treatment
Understanding Hodgkin lymphoma’s genetic landscape provides valuable insights for diagnosis and treatment. Specific genetic markers and protein expressions help confirm a diagnosis. For example, the protein CD30 is a characteristic cell surface marker on Hodgkin and Reed-Sternberg cells, making it a central diagnostic tool for classical Hodgkin lymphoma. Its identification is performed through immunohistochemistry.
Genetic insights also help understand disease behavior and predict prognosis. For instance, high-level amplifications of the 9p24.1 region are associated with shorter progression-free survival. This genetic information increasingly influences targeted therapies, which aim to attack cancer cells based on their unique genetic vulnerabilities.
Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have shown effectiveness in treating Hodgkin lymphoma. These therapies work by blocking the interaction between PD-1 on immune cells and PD-L1 on cancer cells, allowing the immune system to recognize and attack lymphoma cells. Understanding these genetic alterations paves the way for future personalized medicine approaches.