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Genetic Disorders That Raise Lymphoma Risk

Medically reviewed by Mark Levin, M.D.
Written by Nyaka Mwanza
Posted on February 4, 2022

Almost all diseases are associated with genetic factors. A genetic disorder is caused by a change in (or damage to) a person’s DNA. Certain genetic disorders have been shown to increase a person’s risk of lymphoma. Inherited genetic mutations play a major role in about 5 percent to 10 percent of all types of cancer, including lymphoma.

Is Lymphoma Hereditary?

Lymphoma is not a type of cancer that is inherited directly from a parent or other family member. Having a history of lymphoma in your family does, however, increase your risk of developing the disease. If a person has a family history of lymphoma, they are at three to four times greater risk of some non-Hodgkin lymphoma some non-Hodgkin lymphoma (NHL) subtypes, such as:

  • Diffuse large B-cell lymphoma
  • Follicular lymphoma
  • Plasma cell myeloma
  • Chronic lymphocytic leukemia

People whose parents, siblings, or children (first-degree relatives) have had chronic lymphocytic leukemia have a risk twice as high as those with no immediate family members who’ve had the disease.

About Genetic Mutations

There are two primary types of genetic mutation: inherited (germline) and acquired (somatic). Acquired gene mutations occur throughout our lives, especially as we age. This type of mutation can be caused by environmental factors (such as a viral infection, radiation, or toxins) or can happen at random (spontaneous or de novo mutation). Inherited genetic mutations are embedded in cells’ DNA and passed down from parents to their children. Therefore, germline mutations are present in all cells in the body.

How Genetics Factor Into Lymphomas

Certain acquired and inherited mutations are genetic risk factors for the two main types of lymphoma: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma. Some mutations increase a person’s risk slightly, and others might put them at high risk. A risk factor is not the same as a cause. A risk factor statistically increases a person’s chance of getting a disease but does not cause it.

Why Do Some Genetic Mutations Increase Risk of Lymphoma?

Scientists do not yet know exactly how or why genetic risk factors lead to lymphoma in some people but not in others. Research is ongoing to fully understand the mechanisms behind genetic risk factors of lymphoma.

Inflammation and Immune Functioning

Like most lymphomas, autoimmune diseases are thought to be the result of both genetic factors and environmental factors. A groundbreaking study found that half of the newly discovered genetic changes linked to HL are the same as those linked to an increased risk of autoimmune diseases like multiple sclerosis and rheumatoid arthritis (RA).

People who have genetic mutations to specific genes or genetic disorders that alter the way their immune system functions are at increased risk of HL. Autoimmune diseases compromise the immune system and cause systemic inflammation. Data suggest that inflammation may increase gene mutations in lymphocytes and help mutated cells survive.

Specific Genes or Gene Functions Are Affected

Certain genes and certain parts of genes are responsible for all the various things cells need to do to survive and to work together to make our bodies function. Mutations affect the ability to properly function. Genes that control cell growth (switching them on and off and controlling the pace) are often implicated in the rapid growth of cancer cells and formation of tumors. Mutations in tumor necrosis factor (TNF) and interleukin (IL)-10 genes specifically, were shown to increase a person’s risk of NHLs by 25 percent and an aggressive NHL subtype called diffuse large B-cell lymphoma by 65 percent.

The BRCA genes are commonly discussed in the context of breast cancer and ovarian cancer susceptibility. Researchers recently discovered that BRCA1 and BRCA2 variants are linked to several other cancers. Inherited BRCA1 and BRCA2 mutations also seem to substantially increase a person’s risk of lymphoma, especially in children and adolescents.

Germline Mutations That Increase Lymphoma Risk

Certain inherited genetic disorders and gene mutations (germline variants) are linked to an increased risk of developing some types of lymphoma. A germline mutation occurs in the DNA of a sperm or egg cell (reproductive cell) and is passed from parent to a child at conception.

Ataxia-Telangiectasia

Ataxia-telangiectasia is a rare, genetic condition that affects both the nervous and immune systems. The condition is usually passed down from parent to child. However, in 7 percent to 20 percent of people with ataxia-telangiectasia, the variant is caused by a random mutation in the DNA of reproductive cells that occurs during the developmental process.

Klinefelter Syndrome

Klinefelter syndrome is a genetic condition that causes males to be born with one or more extra X chromosomes. The condition is usually due to a spontaneous genetic mutation during the development of sex cells, the egg, and the sperm. The association between Klinefelter syndrome and lymphoma is a topic of debate in scientific circles. However, some data suggest an increased risk of lymphoma in males with the condition. This risk appears to increase with every extra X chromosome the person has.

Li-Fraumeni Syndrome and Li-Fraumeni-Like Syndrome

Li-Fraumeni syndrome and Li-Fraumeni-like syndrome are rare genetic disorders that increase the risk of several types of cancer including lymphomas — especially lymphomas diagnosed in children and young adults. Approximately 90 percent of people with Li-Fraumeni syndrome develop cancer by the time they are 60 years old. Between 2 percent and 8 percent of people with Li-Fraumeni syndrome develop HL.

Nijmegen Breakage Syndrome

Nijmegen breakage syndrome is a rare genetic disease that includes immune deficiency among its symptoms. The disease increases a person’s risk of developing NHL, specifically B-cell and T-cell types of NHL. Around 50 percent of people with Nijmegen breakage syndrome develop NHL, often during childhood or early teens, before age 15.

Wiskott-Aldrich Syndrome

Wiskott-Aldrich syndrome is a rare genetic disease characterized by immunodeficiency and problems forming blood clots. Wiskott-Aldrich syndrome increases a person’s risk of autoimmune disorders — a known lymphoma risk factor — and of lymphoma itself. Between 5 percent and 29 percent of people born with Wiskot-Aldrich syndrome go on to develop lymphoma.

X-Linked Severe Combined Immunodeficiency

X-linked severe combined immunodeficiency is a genetic disorder, mostly seen in male children, which severely affects the immune system. Between 1 percent and 5 percent of those born with X-linked severe combined immunodeficiency develop lymphoma.

Autoimmune Disorders

Although the previously mentioned syndromes have a direct genetic cause, autoimmune diseases occur when environmental factors trigger disease in people whose genes make them more likely to have them. These diseases include Sjögren’s syndrome, RA, and lupus. Autoimmune disease is also a known lymphoma risk factor, associated with several subtypes. People with Sjögren’s syndrome are about five times more likely to get NHL. RA and systemic lupus erythematosus are linked to splenic marginal zone lymphoma and diffuse large B-cell lymphoma. RA is also strongly associated with T-cell large granular lymphocytic leukemia. Some medications used in autoimmune treatment have also been linked to an increased risk of lymphoma.

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References
  1. Facts and Statistics Overview — Leukemia & Lymphoma Society
  2. X-Linked Severe Combined Immunodeficiency — Genetic and Rare Diseases Information Center
  3. Wiskott Aldrich Syndrome — Genetic and Rare Diseases Information Center
  4. Nijmegen Breakage Syndrome — Genetic and Rare Diseases Information Center
  5. Hereditary Cancer Syndromes and Risk Assessment — The American College of Obstetricians and Gynecologists
  6. Klinefelter Syndrome and Cancer: From Childhood to Adulthood — Pediatric Endocrinology Reviews
  7. Klinefelter Syndrome — Genetic and Rare Diseases Information Center
  8. Sjogren Syndrome — Genetic and Rare Diseases Information Center
  9. Complications: Sjögren’s Syndrome — NHS
  10. Lymphoma — Non-Hodgkin: Risk Factors — Cancer.Net
  11. Large Granular Lymphocytic Leukaemia (LGLL) — Leukaemia Care
  12. Hodgkin Lymphoma Risk Factors — American Cancer Society
  13. Ataxia Telangiectasia — Genetic and Rare Diseases Information Center
  14. Genetic Susceptibility to Lymphoma — Haematologica
  15. Genome-Wide Association Study of Classical Hodgkin Lymphoma Identifies Key Regulators of Disease Susceptibility — Nature Communications
  16. Genetic Factors of Autoimmune Diseases 2017 — Journal of Immunology Research
  17. Understanding Genetics — Leukemia & Lymphoma Society
  18. Genetic Disorders — Health National Human Genome Research Institute
  19. What Causes Non-Hodgkin Lymphoma? — American Cancer Society
  20. NHL Subtypes — Leukemia & Lymphoma Society
  21. Germline and Somatic Mutations: What Is the Difference? — ONS Voice
  22. Lymphoma, Non-Hodgkin, Familial — OMIM
  23. Association of Germline BRCA2 Mutations With the Risk of Pediatric or Adolescent Non–Hodgkin Lymphoma — JAMA Oncology
  24. Causes and Risk Factors for Lymphoma — Lymphoma Action UK
  25. The Genetics of Cancer — National Cancer Institute
Posted on February 4, 2022
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Mark Levin, M.D. is a hematology and oncology specialist with over 37 years of experience in internal medicine. Review provided by VeriMed Healthcare Network. Learn more about him here
Nyaka Mwanza has worked with large global health nonprofits focused on improving health outcomes for women and children. Learn more about her here

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