Immunomodulatory germline variation associated with the development of multiple primary melanoma (MPM) (original) (raw)

Multiple primary melanoma (MPM) has been associated with a higher 10-year mortality risk compared to patients with single primary melanoma (SPM). Given that 3-8% of patients with SPM develop additional primary melanomas, new markers predictive of MPM risk are needed. Based on the evidence that the immune system may regulate melanoma progression, we explored whether germline genetic variants controlling the expression of 41 immunomodulatory genes modulate the risk of MPM compared to patients with SPM or healthy controls. By genotyping these 41 variants in 977 melanoma patients, we found that rs2071304, linked to the expression of SPI1, was strongly associated with MpM risk reduction (oR = 0.60; 95% CI = 0.45-0.81; p = 0.0007) when compared to patients with SPM. Furthermore, we showed that rs6695772, a variant affecting expression of BATF3, is also associated with MPM-specific survival (HR = 3.42; 95% CI = 1.57-7.42; p = 0.0019). These findings provide evidence that the genetic variation in immunomodulatory pathways may contribute to the development of secondary primary melanomas and also associates with MpM survival. the study suggests that inherited host immunity may play an important role in MpM development. Approximately 3-8% of patients diagnosed with cutaneous melanoma will develop additional primary melanomas during their lifetime 1,2 (referred to as multiple primary melanoma, or MPM), which, may confer a higher 10-year mortality risk when compared to patients with a single primary melanoma (SPM) 3. Despite an ongoing debate whether increased MPM incidence is due to improved surveillance, as we have also recently suggested 4 , the biological underpinning of MPM phenotype is poorly understood. While most patients with MPM present with two primary tumors 5 (~80%), the diagnoses of more than two multiple melanomas are not uncommon 6. To date, the known risk factors for MPM include a personal history of dysplastic nevi 7 and a family history of melanoma, which only account for approximately 20% of all MPM diagnoses 5 , leaving vast majority of MPM etiology unexplained. Several reports provided evidence that individuals with immunodeficiencies have a higher risk of cancer occurrence, including melanoma, as compared to the general population 8. Studies on immunodeficient HIV patients with prior diagnoses of skin cancer have shown that these patients are at greater risk of skin cancer recurrence 9. These observations, and the fact that melanomas are more immunogenic compared to other tumors, further suggest that the host immunity may impact melanomagenesis both in the context of metastatic progression as well as in its initial presentation and recurrence, hence increasing a risk for additional primary melanomas.