Intra- and intertumoral heterogeneity of liver metastases in a patient with uveal melanoma revealed by single-cell RNA sequencing

Weitao Lin; Aaron B Beasley; Nima Mesbah Ardakani; Elena Denisenko; Leslie Calapre; Matthew Jones; Benjamin A Wood; Lydia Warburton; Alistair R R Forrest; Elin S Gray

doi:10.1101/mcs.a006111

Intra- and intertumoral heterogeneity of liver metastases in a patient with uveal melanoma revealed by single-cell RNA sequencing

Cold Spring Harb Mol Case Stud. 2021 Oct 19;7(5):a006111. doi: 10.1101/mcs.a006111. Print 2021 Oct.

Authors

Weitao Lin^{1

2

3}, Aaron B Beasley^{1

2}, Nima Mesbah Ardakani^{4

5

6}, Elena Denisenko³, Leslie Calapre², Matthew Jones³, Benjamin A Wood^{4

5}, Lydia Warburton^{1

2

7

8}, Alistair R R Forrest³, Elin S Gray^{1

2}

Affiliations

¹ Centre for Precision Health, Edith Cowan University, Joondalup, Western Australia 6027, Australia.
² School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia 6027, Australia.
³ Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, Western Australia 6009, Australia.
⁴ Department of Anatomical Pathology, PathWest, QEII Medical Centre, Nedlands, Western Australia 6009, Australia.
⁵ School of Pathology and Laboratory Medicine, the University of Western Australia, Crawley, Western Australia 6009, Australia.
⁶ College of Science, Health, Engineering and Education, Murdoch University, Murdoch, Western Australia 6150, Australia.
⁷ Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia.
⁸ Department of Medical Oncology, Fiona Stanley Hospital, Murdoch, Western Australia 6150, Australia.

Abstract

Tumor heterogeneity is a major obstacle to the success of cancer treatment. An accurate understanding and recognition of tumor heterogeneity is critical in the clinical management of cancer patients. Here, we utilized single-cell RNA sequencing (scRNA-seq) to uncover the intra- and intertumoral heterogeneity of liver metastases from a patient with metastatic uveal melanoma. The two metastases analyzed were largely infiltrated by noncancerous cells with significant variability in the proportion of different cell types. Analysis of copy-number variations (CNVs) showed gain of 8q and loss of 6q in both tumors, but loss of Chromosome 3 was only detected in one of the tumors. Single-nucleotide polymorphism (SNP) array revealed a uniparental isodisomy 3 in the tumor with two copies of Chromosome 3, indicating a regain of Chromosome 3 during the development of the metastatic disease. In addition, both tumors harbored subclones with additional CNVs. Pathway enrichment analysis of differentially expressed genes revealed that cancer cells in the metastasis with isodisomy 3 showed up-regulation in epithelial-mesenchymal transition and myogenesis related genes. In contrast, up-regulation in interferon signaling was observed in the metastasis with monosomy 3 and increased T-cell infiltrate. This study highlights the complexity and heterogeneity of different metastases within an individual case of uveal melanoma.

Keywords: choroidal melanoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Liver Neoplasms* / genetics
Melanoma* / genetics
Sequence Analysis, RNA
Uveal Neoplasms* / genetics

Supplementary concepts

Uveal melanoma