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Genetic, Genomic Profiles Point to Potential Utility of Melanoma Xenograft Collection

NEW YORK (GenomeWeb) – In a pair of Cell Reports studies, researchers from the University of Pennsylvania and elsewhere described a collection of melanoma patient-derived xenografts — complete with preliminary genetic and genomic analyses for nearly 400 of the xenografts.

For the first of the new papers, researchers from the University of Pennsylvania and other centers in the US and Germany introduced 459 patient-derived xenografts established using samples from 384 individuals with melanoma. These xenografts were winnowed from a broader set of 694 melanoma samples collected at eight institutions from patients between 20 and 89 years old before, during, or after targeted treatment or immune checkpoint inhibitor therapy.

Along with xenografts derived from immune checkpoint responding and non-responding tumors, for example, the team noted that the patient-derived xenograft collection contains at least 57 xenografts representing tumors that have become resistant to targeted therapies. For its analyses of these xenografts, it considered everything from corresponding clinical data to molecular features in the patient-derived xenografts.

That study's senior author Meenhard Herlyn, a molecular and cellular oncogenesis researcher at Philadelphia's Wistar Institute, and his co-authors said the melanoma xenograft collection "is highly clinically annotated and includes rare body sites and subtypes such as brain metastasis, uveal, mucosal, and acral melanoma, as well as pre- and post-therapy samples from targeted inhibitor- and checkpoint-blockade-treated patients."

Herlyn was also part of a U Penn-led team reporting on genetic and genomic features of the melanoma patient-derived xenografts for another Cell Reports paper. In that study the team looked more closely at genetic and genomic patterns in 462 patient-derived xenograft, melanoma cell lines, and tumor samples — a set that included xenografts from 108 individuals with melanoma who received targeted treatment and/or immunotherapy and 263 treatment-naïve melanoma cases.

Using a custom capture panel, the researchers sequenced exon and intron sequences for 108 genes implicated in melanoma in the past. For a subset of 101 samples, including samples generated for three dozen new patients, they targeted a set of 119 genes.

"To account for the lack of matched normal samples, control samples were sequenced in each lane for normalization for copy number calling and to identify common variants, which were subtracted out," senior author Katherine Nathanson, a translational medicine and human genetics researcher at the University of Pennsylvania's Perelman School of Medicine, and her colleagues wrote. "We also removed sequences that more closely aligned to the mouse than human genome to decrease cross-contamination and increase accuracy of mutational and copy number calling."

From there, the team used its calling pipeline to find melanoma-related mutations and structural variations in the xenografts or cell lines, highlighting significant molecular heterogeneity in the patient-derived xenografts. In the process, the team uncovered xenograft features consistent with a range of melanoma subtypes, including subtypes beyond those considered for the Cancer Genome Atlas project.

"We have been able to identify all major and minor subtypes of melanoma," the authors concluded, "thus providing reagents that, in some cases, were previously unavailable for functional and biological studies."