Israeli Study Finds Women With Stomach Cancer Have Higher Mutation Burden Than Men, Especially Older Patients

A new Israeli study led by Dr. Dorit Shweiki, a bioinformatician at the Academic College of Tel Aviv-Yaffo, reveals that women with stomach cancer tend to have a higher tumor mutation burden (TMB) compared to men, particularly in older age groups. Published in BMC Cancer, the research analyzed genomic data from hundreds of stomach cancer patients across international databases, later expanding to thousands of tumor samples. The study aimed to identify genetic differences in tumor development between sexes and assess their clinical significance.

The key finding showed that women had a statistically significant higher average TMB than men, with 40.5 mutations per megabase in women versus 32.3 in men in the primary dataset of 441 patients. This disparity was most pronounced in patients over 60 years old, especially those above 70. The researchers linked this difference to the gene MLH1, which plays a critical role in DNA repair. Reduced MLH1 activity, often due to epigenetic methylation changes, correlated with increased mutation accumulation and impaired DNA repair mechanisms, particularly in women.

These findings have practical implications since TMB is already used to guide immunotherapy decisions, such as treatment with pembrolizumab (Keytruda), approved by the FDA in 2020. Dr. Shweiki suggests that future clinical thresholds for TMB might need to be sex-specific to optimize treatment. However, the study cautions that not all tumors differ by sex once molecular subtypes are accounted for; the overall gap likely results from a higher prevalence of a specific subtype with defective DNA repair in women.

The researchers emphasize the importance of considering sex differences in cancer research and clinical trials, noting that many current studies still treat patients as a homogeneous group. They call for increased awareness and separate analyses by sex to advance personalized medicine. While the findings do not yet change treatment protocols, they lay the groundwork for more tailored therapies that consider biological sex differences in stomach cancer.

Further validation in larger populations is needed, as additional international datasets showed similar trends but without statistical significance. Dr. Shweiki highlighted the need to move toward sex-adapted medicine to improve outcomes for both women and men with cancer.