Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination

Abstract

Melanoma is difficult to treat once it becomes metastatic. However, the precise ancestral relationship between primary tumors and their metastases is not well understood. We performed whole-exome sequencing of primary melanomas and multiple matched metastases from eight patients to elucidate their phylogenetic relationships. In six of eight patients, we found that genetically distinct cell populations in the primary tumor metastasized in parallel to different anatomic sites, rather than sequentially from one site to the next. In five of these six patients, the metastasizing cells had themselves arisen from a common parental subpopulation in the primary, indicating that the ability to establish metastases is a late-evolving trait. Interestingly, we discovered that individual metastases were sometimes founded by multiple cell populations of the primary that were genetically distinct. Such establishment of metastases by multiple tumor subpopulations could help explain why identical resistance variants are identified in different sites after initial response to systemic therapy. One primary tumor harbored two subclones with different oncogenic mutations in CTNNB1, which were both propagated to the same metastasis, raising the possibility that activation of wingless-type mouse mammary tumor virus integration site (WNT) signaling may be involved, as has been suggested by experimental models.A s in many other solid tumors, melanoma metastases often first present in lymph nodes in the draining area of the primary, whereas distant metastases tend to appear later (1). The conclusion that melanoma follows a linear progression from primary tumor to regional to distant metastases has supported preemptive surgical removal of regional lymph nodes with curative intent (2). However, several observations suggest that distant metastases are seeded early, contemporaneously with regional metastases. Patients who undergo resection of lymph node basins harboring metastasis do not experience a significantly extended life expectancy (3, 4). Furthermore, circulating melanoma cells were detected in the blood of 26% of patients who only have metastases detected regionally (5, 6).Melanoma, like other cancers, arises and evolves through the accumulation of genetic alterations within tumor cells (7-9). Comparing somatic mutations in primary tumor and regional and distant metastases from the same patient can provide insight into the phylogenetic relationships between these distinct tumor cell populations and the order of metastatic dissemination (8, 10). These analyses may also establish whether cells in the primary tumor that metastasize acquired this ability to disseminate and seed other anatomic sites by a newly acquired genetic alteration, or whether metastatic colonization is simply a stochastic process of which all cells in the primary are capable but few succeed.Using whole-exome sequencing (for discovery) and targeted sequencing (for validation), we analyzed mutation patterns of primary melanomas and two or more metastases in each of e...

Interlesional diversity of T cell receptors in melanoma with immune checkpoints enriched in tissue-resident memory T cells

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Multiregion Whole-Exome Sequencing Uncovers the Genetic Evolution and Mutational Heterogeneity of Early-Stage Metastatic Melanoma

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Tumor cells PD-L1 expression as a favorable prognosis factor in nasopharyngeal carcinoma patients with pre-existing intratumor-infiltrating lymphocytes

“…26 Advances in genetics have helped reveal the genetic complexity of melanoma and intratumoral heterogeneity. 27,28 In addition, TCR sequencing has shown that differences in T cell receptor residents within these lesions are greater than the genetic differences between individual metastases. 29 This discovery stimulates us to investigate whether the spatial discordance of PD-L1 and TILs in the primary lesion microenvironment has a different meaning.…”