Abstract 2846: Stereotypic patterns and genomic correlates of organotropism in metastatic melanoma
Authors: Ge William H. , Tarantino Giuseppe , Robitschek Emily , Manos Michael P. , Eastman Lauren , Ouyang Olivia , Ott Patrick , Silk Ann W. , Rahma Osama E. , Gusev Alexander , Haq Rizwan , Buchbinder Elizabeth I. , Insco Megan L. , Hodi Stephen , Van Allen Eliezer , Liu David 
Published: July 2021

Despite the major role that metastasis plays in the morbidity and mortality of melanoma, stereotyped patterns of metastasis and drivers of its organotropism in melanoma are still not well characterized, limited by a dearth of sequencing data in well-annotated clinical melanoma samples. To address these open questions, we performed an integrative analysis of clinical and genomic features from 243 patients with metastatic melanoma treated at Dana Farber Cancer Institute (DFCI). Tumor biopsies were sequenced with OncoPanel, a next-generation sequencing panel that identifies mutations in 331 cancer genes. Presence of site metastases was evaluated radiographically pre-treatment for each patient; sites include lymph node (64% of cohort), soft tissue (59%), lung (57%), liver (32%), brain (24%), bone (22%), mesentery (12%), adrenal gland (9%), spleen (7%), and other metastatic sites (13%).

Metastases showed significant co-occurrences (e.g. bone and lung, OR 2.8, 95% CI = [2.3, 3.3], p &lt; 0.01; adrenal and mesentery, OR 4.4, 95% CI = [3.8, 5.0], p &lt; 0.01) and exclusions (lymph node and brain, OR 0.5, 95% CI = [0.2, 0.8], p = 0.02). We performed unsupervised hierarchical clustering of patients with cutaneous melanoma (n = 203) by metastatic site pattern using a Euclidean distance metric weighted to favor uncommon metastatic sites, yielding five stereotypic patterns of metastasis, characterized by: (1) co-occurrence of adrenal, mesenteric, and abdominal metastases (n=19); (2) liver metastases (n=33); (3) low metastatic burden (n=80); (4) co-occurrence of lung, brain, and mesentery metastases (n=42); and (5) co-occurrence of bone and lung metastases (n=29). Clustering is stable, with highly concordant cluster assignments in repeated subsampling of the data.

Patients with cutaneous melanoma (n=203) exhibited both site-specific and pattern-specific genomic correlates of metastatic organotropism that persist after correction for mutational burden. Tumors from patients with liver metastases showed significantly higher prevalence (p &lt; 0.05) of mutation compared to patients without liver metastases in KMT2D (56% vs 18%), BCL6 (22% vs 0%), TMPRSS2 (22% vs 0%), ARID1B (33% vs 4%), MET (33% vs 4%), and AXL (44% vs 11%), with similar enrichment in the liver met-predominant metastatic cluster, implicating dysregulation of histone and protein deacetylation pathways in liver metastatic organotropism (p &lt; 0.01). Numerous additional mutational correlates were found for the remaining nine metastatic sites and all five metastatic patterns, and validation in an orthogonal dataset is ongoing.

We present robust stereotypic patterns of metastasis and both site- and pattern-specific genomic correlates of organotropism in metastatic melanoma. By leveraging a valuable clinical/genomic data set, we nominate genetic correlates of organotropism for functional validation and potential therapeutic targets.

Citation Format: William H. Ge, Giuseppe Tarantino, Emily Robitschek, Michael P. Manos, Lauren Eastman, Olivia Ouyang, Patrick Ott, Ann W. Silk, Osama E. Rahma, Alexander Gusev, Rizwan Haq, Elizabeth I. Buchbinder, Megan L. Insco, Stephen Hodi, Eliezer Van Allen, David Liu. Stereotypic patterns and genomic correlates of organotropism in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2846.