Multiplatform Analysis of Intratumoral PTEN Heterogeneity in Melanoma

Authors

Sharmeen Chagani
Mariana P De Macedo
Fernando Carapeto
Feng Wang
Diego M Marzese
Khalida Wani
Lauren E Haydu
Weiyi Peng
Giang T Ong
Sarah E Warren
Joseph M Beechem
Dave S B Hoon
Gordon B Mills
Michael T Tetzlaff
Alexander J Lazar
Lawrence N Kwong
Michael A Davies

Publication Date

9-1-2023

Journal

Journal of Investigative Dermatology

Abstract

Loss of protein expression of the tumor suppressor PTEN is associated with increased cancer aggressiveness, decreased tumor immune infiltration, and resistance to immune and targeted therapies in melanoma. We assessed a unique cohort of eight melanoma samples with focal loss of PTEN protein expression to understand the features and mechanisms of PTEN loss in this disease. We compared the PTEN-negative (PTEN[-]) areas to their adjacent PTEN-positive (PTEN[+]) areas using DNA sequencing, DNA methylation, RNA expression, digital spatial profiling, and immunohistochemical platforms. Variations or homozygous deletions of PTEN were identified in PTEN(-) areas that were not detected in the adjacent PTEN(+) areas in three cases (37.5%), but no clear genomic or DNA methylation basis for loss was identified in the remaining PTEN(-) samples. RNA expression data from two independent platforms identified a consistent increase in chromosome segregation gene expression in PTEN(-) versus adjacent PTEN(+) areas. Proteomic analysis showed a relative paucity of tumor-infiltrating lymphocytes in PTEN(-) versus adjacent PTEN(+) areas. The findings add to our understanding of potential molecular intratumoral heterogeneity in melanoma and the features associated with the loss of PTEN protein in this disease.

Keywords

PTEN, melanoma, intratumoral heterogeneity, tumor suppressor genes, immune infiltration

Comments

Supplementary Materials

PMID: 36871660