An international research team has shown that a specific subtype of diffuse large B-cell lymphoma (DLBCL) is associated with higher mortality risk in women than in men. The study was led by the laboratory of Ari Melnick, MD, Director of the Josep Carreras Leukaemia Research Institute and the Gebroe Family Professor of Hematology/Oncology at Weill Cornell Medicine, along with the laboratories of Wendy Béguelin, PhD, of the New York University Grossman School of Medicine, and Leandro Venturutti, PhD, of the University of British Columbia. Researchers identified the biological reason for this disparity and discussed an existing class of drugs that may benefit female patients. Findings were published by Pelzer et al in Cancer Discovery.
SPEN and NOTCH2 Variants
DLBCL affects hundreds of thousands of people worldwide each year. Although outcomes vary widely between patients, sex had never previously been identified as a driver of survival differences in this disease. By analyzing data from nearly 5,000 patients across 14 independent studies, the team found that women who carry simultaneous faults in two genes called SPEN and NOTCH2 had a more than fourfold higher mortality risk than men with the same mutations. Benedikt Pelzer, MD, of Weill Cornell Medicine, the first author of the study, commented, "When we noted that women were doing far worse than men with these specific mutations, we knew we had to understand why. What we found was unexpected, that the X chromosome itself was the key."
The researchers explained that the reason for this is due to fundamental differences in male and female biology. Women carry two copies of the X chromosome, and one is normally kept permanently switched off, a process partly controlled by the SPEN gene. When SPEN is damaged alongside NOTCH2, that silencing becomes unstable. Genes on the supposedly dormant X chromosome begin to wake up, including TLR7, a gene that when overactive acts like a jammed accelerator for cancer cell growth and survival. In men, who carry only one X chromosome, this mechanism cannot occur.
Importantly, the researchers showed this is not driven by female hormones. The effect persisted in animals even after removal of the ovaries, confirming that the vulnerability is built into the chromosomes themselves.
"Sex differences in cancer have too often been attributed to lifestyle or hormones. This study shows the biology itself can be fundamentally different between men and women at the molecular level, and that this can be invisible unless you specifically look for it,” said Dr. Venturutti.
Potential Therapeutic Options
According to investigators, the overactive TLR7 pathway that drives tumor growth in female patients can be blocked by IRAK inhibitors, which are in clinical development for other conditions. In laboratory experiments and animal models, these drugs were significantly more effective at killing female tumor cells than male ones. A tumor model derived directly from a female patient with DLBCL responded well, with growth slowing substantially over the course of treatment. Combining the IRAK inhibitor with standard chemotherapy enhanced the effect further.
“IRAK inhibitors are already in clinical trials. The path from this discovery to a treatment option for patients is shorter than it usually is in cancer research, and that urgency is something we feel strongly,” said Dr. Béguelin.
The study also upends another long-held assumption about how this cancer develops, noted the investigators. It had been thought that this subtype of DLBCL originates deep within the immune system's active response centers. The new data show it likely begins from a cell type that accumulates with aging and exposure to infections, and is closely associated with autoimmune diseases, consistent with a different developmental path, and potentially explaining why the disease is more common in older patients who may have had an undetected precursor condition for years.
"This work reframes the X chromosome from a bystander to an active driver of cancer biology in women. Combined with the discovery of a druggable target, it is a genuine paradigm shift, and a compelling argument for making biological sex a standard variable in how we design cancer trials going forward," said Dr. Melnick.
DISCLOSURE: For full disclosures of the study authors, visit aacrjournals.org/cancerdiscovery.
