The links between smoking and various forms of cancer have been well established over the years. However, a team of scientists at Weill Cornell Medicine has uncovered strong evidence linking smoking and age-related hematopoiesis to a rare form of lymphoma. Findings from the new study—published recently in eLife through an article titled, “Mutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smoking”—may lead to new ways to diagnose, treat, or prevent rare blood cancers and to identify patients who could go on to develop a second type of blood cancer.

Peripheral T cell lymphoma (PTCL) and angioimmunoblastic T cell lymphoma (AITL) are two uncommon cancers that affect immune T cells. “AITL can be very aggressive, with only about one-third of patients surviving at least five years after their diagnosis,” explained lead study investigator Shuhua Cheng, PhD, a senior research associate in the department of pathology and laboratory medicine at Weill Cornell Medicine. “To develop more effective therapies against AITL and PTCL, we need to learn more about what causes them.”

Cheng and the team used next-generation genome sequencing to analyze 537 genes in 27 patients with AITL or PTCL for genetic changes that might lead to these T-cell tumors and secondary cancers in some patients.

“We generated and analyzed the mutation profiles through 537-gene targeted sequencing of the primary tumors and matched bone marrow/peripheral blood samples in 25 patients with AITL and 2 with PTCL-NOS,” the authors wrote.

They found that in about 70% of the patients, there were mutations in precursor cells, most likely stem cells, in the bone marrow that can lead to the production of growing numbers of blood cells with these mutations and early development of the T-cell tumors. These mutations in the precursor cells have been thought to be related to aging.

“Clonal hematopoiesis (CH)-associated genomic alterations, found in 70.4% of the AITL/PTCL-NOS patients, were shared among CH and T-cell lymphoma, as well as concomitant myeloid neoplasms or diffuse large B-cell lymphoma (DLBCL) that developed before or after AITL,” the authors penned. “Aberrant AID/APOBEC activity-associated and tobacco smoking-associated mutational signatures were respectively enriched in the early CH-associated mutations and late non-CH associated mutations during AITL/PTCL-NOS development.”

In addition, the team found that the mutations associated with the progression of these tumors might be linked to smoking or exposure to second-hand smoke. This suggests that the cessation of smoking or avoiding exposure to second-hand smoke may have beneficial effects in preventing the development of these T-cell tumors. They also found that patients with a higher mutation burden of one of the genes associated with the early development of these tumors were at a higher risk of developing additional types of tumors.

“Our results provide new information on how exposure to smoking may cooperate with early mutations in blood precursor cells to lead to the development of certain T-cell cancers,” concluded senior study investigator Wayne Tam, PhD, a professor of pathology and laboratory medicine at Weill Cornell Medicine. “The findings suggest a potential new way to identify patients with AITL or PTCL who are most at risk of developing secondary tumors and may also help scientists and clinicians improve how these cancers are prevented, diagnosed, and treated.”