Researchers Identify Mutations Underlying the Development of Rare Lymphoma

Researchers Identify Mutations Underlying the Development of Rare Lymphoma

A study recently published in the journal Nature Genetics, led by researchers at Stanford University, revealed a group of mutations responsible for the development of a rare blood cancer – cutaneous T cell lymphoma (CTCL). The study is entitled “Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2”.

Lymphoma is the most common blood cancer, affecting immune cells called lymphocytes, a type of white blood cells that defend the body from infections. In lymphoma, lymphocytes grow and multiply uncontrollably. Patients with lymphoma may experience swelling of the lymph nodes, fever, night sweats, itching, loss of appetite, sudden weight loss and fatigue.

There are two main types of lymphocytes that can develop into lymphomas: B-lymphocytes (B-cells) and T-lymphocytes (T-cells). CTCLs are one of the most common forms of T-cell lymphoma, and are diagnosed in about 3,000 patients each year in the United States. CTCLs are usually characterized by dry skin, itching, red rash and enlarged lymph nodes. Within CTCLs, the most common types are mycosis fungoides, which is characterized by skin patches, itchy, scaly, red skin eruptions that can cover the whole body, and the Sézary syndrome, which corresponds to an advanced, variant form of mycosis fungoides.

CTCL has no cure, it usually does not respond well to traditional chemotherapy and only a limited number of effective therapies are available. The genetic basis of CTCLs is still poorly elucidated. Now, researchers identified specific mutations that underlie CTCL development.

The team analyzed T cell’s DNA from 91 patients with CTLC and found 170 genes that had mutations related to the tumor. CTCL-associated mutations were found in genes that encode proteins involved in a T-cell-survival mechanism. When these mutations prevent the shutdown of this mechanism, T cells don’t die and keep on multiplying accumulating in the skin or circulating through the bloodstream.

These results suggested the development of new therapeutic strategies for CTCL based on the proteins involved in the cell’s survival mechanism. “We can now design drug trials in a smart, evidence-based way that is specific to the patient,” said the study’s co-author Dr. Youn Kim in a news release.

Specific mutations in a gene called tumor necrosis factor receptor 2 (TNFR2) were found in four of the patients analyzed. These mutations turned the receptor into an “always-on” state, preventing the cell-survival pathway from shutting down. Interestingly, it has been previously reported that patients with increased TNFR2 protein levels in their bloodstream exhibited a more aggressive form of cancer. Furthermore, researchers found that 10 patients in the cohort had multiple copies of the TNFR2 gene, which could explain the increased levels of the protein in the blood. Using in vitro cell cultures, the team observed that the cell-survival pathway is more active in cells with the mutation or duplication of the TNFR2 gene, compared to normal cells.

However, it is important to determine which mutations in the cell-survival pathway are present in the malignant T cells of each patient, as researchers found that in 60% of the CTCL cancers analyzed none of these mutations could be found.

“It really highlights that the future of many types of cancer treatment is going to be: first, know the cancer by sequencing it, and then tailor the therapy specifically,” said the study’s senior author Dr. Paul Khavari.

Furthermore, the team also identified mutations in the CTLA4 gene (which is also related to the cell-survival pathway) and may induce cell proliferation.

The authors concluded that the T cell-survival mechanism plays an important role in triggering certain CTCLs. The authors believe that their findings may offer new therapeutic strategies for CTCL patients with specific mutations.

“Before we had this data, it was trial and error — we were totally blind,” noted Dr. Kim. “We’re finally taking the blindfolds off.”

The team’s next goal is to evaluate the response of CTCL patients to different drug treatments based on their T cell genetic sequences. Researchers also expect to mimic these mutations in mice models to further study their effects.

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