Is Cutaneous T-Cell Lymphoma Hereditary?

Patients often question whether various lymphoma types run in families, concerned that their own diagnosis may indicate cancer risk for their loved ones, as well. When an inquiry regarding the possibility of genetic predisposition in cutaneous T-cell lymphoma (CTCL) recently came through our clinic, we sat down with expert Jia Ruan, MD, PhD, to break down what we know and what we don’t know about the cause of this rare and complex condition.Dr. Ruan at computer

T-cell lymphomas are a form of non-Hodgkin lymphoma caused by abnormal growth of mature T-cell lymphocytes, a type of white blood cell found in the immune system. In healthy people, T-cell lymphocytes are responsible for attacking foreign antigens and viruses, and aiding B-cell lymphocytes in antibody production – but by the process of clonal evolution, the T-cell lymphocytes mutate and produce abnormal offspring that become lymphoma. When T-cell lymphomas affect the skin, they are known as cutaneous T-cell lymphomas (CTCL).

The most common subtype of CTCL, mycosis fungoides (MF), occurs when malignant cells develop from CD4+CD45RO+ T-lymphocytes and migrate to the skin. Symptoms include scaly and itchy rash-like patches that may thicken over time and develop into a plaque or a tumor. If the cancer then makes its way from the skin to the lymphatic and blood system, MF becomes the more aggressive Sézary syndrome (SS). MF patients with limited skin symptoms do very well with skin-directed treatment, such as light therapy and topical medicines including steroids, while those with more extensive skin involvement or SS often require systemic treatment.

Although mycosis fungoides and Sézary syndrome are the most common types of cutaneous T-cell lymphoma, they are still quite rare, occurring in only 4-5 percent of non-Hodgkin lymphoma cases, with about 3,000 new diagnoses per year. The median age at diagnosis is 50-70, with a prevalence in men and African Americans.

It is in part due to their rarity that doctors and researchers have yet to understand what causes MF/SS. While there is no definitive evidence of familial risk of CTCL, scientists are continually evaluating whether genetics play a role in the disease formation.

Human leukocyte antigen (HLA) genes, which enable the immune system to discern between proteins native and foreign to the body, possess specific variations, or alleles, that are inherited via the family germline and passed through generations. When a certain HLA class II allele (specifically DQB1*04) was measured in a study of six families, each with occurrences of mycosis fungoides in two first-degree relatives, researchers found the allele to appear more frequently in patients than in the healthy control population, thus suggesting an association of the allele with familial MF. It is worth noting, however, that although some familial clusters of MF have been reported, the vast majority of CTCL cases occur without a familial link.

Additionally, deep genetic sequencing (whole exome) of mycosis fungoides samples, in which the patients’ DNA was analyzed to identify genetic variants, revealed recurrent mutations that seem to be acquired during a lifetime, rather than inherited – also known as somatic mutations. Somatic mutations are believed to be a leading factor in the unchecked cell division in most cancers. The examples of alterations included genes involved in: T-cell activation and programmed cell death (apoptosis), NF-κB signaling that plays a role in cell proliferation and survival, remodeling of chromatin (the DNA and proteins from which chromosomes are derived), and DNA damage response.

Without any strong scientific evidence of hereditary susceptibility, CTCL will likely continue to be thought of as an acquired disorder. Those with skin rash who are concerned about risk and family history are encouraged to see a dermatologist, who can refer to an oncologist or other specialist if the CTCL diagnosis is confirmed.

References:

Journal of the American Academy of Dermatology, 2005 Mar; 52: 393–402.

Nature Genetics, 2015 Sep; 47(9): 1011-9.

Lymphoma in the News: Family History May Be a Risk Factor for Non-Hodgkin Lymphoma

By Peter Martin, MD

A recently published study from investigators at Stanford University and in Lund University in Sweden used data from a large Swedish cohort study, birth records, and cancer registries to look for risk factors associated with development of non-Hodgkin lymphoma (NHL). The investigators evaluated the records of over 3.5 million people, including 936 with NHL, born between 1973 and 2008.

They reported that family history of NHL was associated with development of NHL in early life. Specifically, history of NHL in a sibling increased the risk of developing NHL roughly nine-fold while having a parent with NHL increased the risk of NHL roughly two-fold. Importantly, the overall incidence rate of NHL was 1.4 per 100,000 person-years (the number of people x the number of years of follow-up per person). Therefore, a two-fold increase, although statistically significant, would only have increased the rate to roughly 3 per 100,000 person years. Moreover, only 4 of the 936 cases had a sibling with NHL and 10 had a parent with NHL.

These small numbers, although statistically significant, make it difficult to make any definitive conclusions regarding the degree of risk. The lack of data regarding environmental exposures, infections, and other co-existing conditions (e.g., immunodeficiencies) make it difficult to determine whether the familial association of NHL is due to an inherited condition or some other unmeasured factor. Despite the issues, the results are consistent with the concept that genetic factors may contribute to NHL. It is possible that contemporary studies using next generation sequencing of the genomes of patients and family members could yield more conclusive results. The risks and benefits of such studies, however, need to be weighed very carefully.