Characterization of Clinical and Genomic Architecture of Pulmonary Tropism in Metastatic Melanoma

Abstract

Most melanoma-associated mortality occurs during the metastatic phase, yet our understanding of its clinical characteristics and molecular drivers remains limited. A growing body of literature is actively studying metastatic organotropism of melanoma from both basic and clinical perspectives. The active investigation of such phenomenon augments the risk stratification of patients and helps in the development of novel therapeutic approaches. In this investigation, we explore the clinicogenomic profile of pulmonary metastases of melanoma, an understudied challenging clinical entity. In this retrospective study, 1,142 melanoma patients who underwent next-generation sequencing of their tumors were included in the analyses. Patients were categorized based on the presence (n = 460) or absence (n = 682) of lung metastases. A comparative analysis between the study groups in terms of demographics, disease characteristics, and genomic profiles was conducted. The latter comparison utilized candidate genes originating from differential abundance analysis based on lung metastases status and overall survival (OS). Binary and Cox regression models were performed to identify possible associative and prognostic factors, respectively. The lung metastases sub-cohort had a mean age of 63.07 ± 14.3 years and was predominantly male (n = 292, 63.5%). The majority of patients with lung metastases were White, with cutaneous melanoma being the primary source of metastases. The median survival for patients with lung metastases was 38.41 months, and a significant difference in OS was observed between the lung metastases group and those without lung metastases (HR: 1.657, 95% CI: 1.362–2.016, P < .0001). Lung involvement was significantly associated concomitant metastases to the following sites: liver, bone, central nervous system, peripheral nervous system, intra-abdominal region, pleural, and kidneys. In addition, genomic alterations in SETD2 (OR: 2.074, 95% CI: 1.179–3.648, P = .011) and TSC1 (OR: 2.546, 95% CI: 1.225–5.295, P = .012) were significantly associated with lung metastases. Independent prognostic factors for melanoma lung metastases were microsatellite instability (HR: 2.873, 95% CI: 1.121–7.362, P = .028) and co-metastases to liver (HR: 2.184, 95% CI: 1.546–3.085, P < .001), bone (HR: 1.512, 95% CI: 1.091–2.095, P = .013), and central nervous system (HR: 1.904, 95% CI: 1.382–2.623, P < .001). On the other hand, none of the genomic alterations showed prognostic value. Melanoma pulmonary metastases are associated with poor survival and frequently co-occur with metastases to other sites. Genomic alterations in SETD2 and TSC1 might be linked to lung metastases, while microsatellite instability and co-metastases were independent prognostic factors. These findings highlight the need for further in-depth research with larger cohorts to confirm these findings.