Concordance of somatic mutation profiles (BRAF,NRAS, and TERT) and tumoral PD-L1 in matched primary cutaneous and metastatic melanoma samples.

Authors:
Dominick Leone, MPH, MS
Dominick Leone, MPH, MS
Boston University School of Public Health
Pre-Doctoral Candidate
Precision Approach to Population Health: Genomic and Infectious Disease Epidemiology
Boston, Massachusetts | United States

Hum Pathol 2018 12 16;82:206-214. Epub 2018 Aug 16.

Dermatopathology Section, VA Integrated Systems Network (VISN1), Department of Pathology and Laboratory Medicine, West Roxbury, MA 02132, USA. Electronic address:

Despite the efficacy of BRAF-targeted and PD-L1-related immune therapies in tackling metastatic melanoma, a significant number of patients exhibit resistance. Given this, the objective of the current study was to ascertain concordance of somatic mutations in BRAF/NRAS/TERT and immunohistochemical PD-L1 and CD8 in matched primary cutaneous and metastatic melanoma. A total of 43 archival paired samples with sufficient material for genetic and immunohistochemical analyses met the criteria for inclusion in the study. Immunohistochemistry was performed for PD-L1 and CD8 and direct-DNA Sanger sequencing for BRAF/NRAS/TERT promoter mutational analyses. Agreement between paired samples was assessed using Cohen κ. Poor concordance among primary and corresponding metastases was noted in BRAF (9/42 cases discordant, κ = 0.49; 95% confidence interval [CI], 0.21-0.77; P = .0013), TERT promoter mutations (13/41 cases discordant, κ = 0.33; 95% CI, 0.04-0.62; P = .033), tumoral PD-L1 immunoexpression (9/43 cases discordant, κ = 0.39; 95% CI, 0.07-0.72; P = .0099), and immunoexpression of CD8 T lymphocytes (12/43 cases discordant, κ = 0.44; 95% CI, 0.19-0.69; P = .002). Although NRAS1 and NRAS2 were highly concordant (42/43 and 39/43 cases, respectively), discordant NRAS2 mutational status was associated with a median time to metastasis of 90 versus 455 days for pairs with concordant status (P = .07). Although limited by sample size, our findings suggest that consideration be given to mutational analysis of metastatic tissue rather than the primary to guide BRAF-targeted therapy and question the roles of TERT promoter mutations and PD-L1 as predictive biomarkers in malignant melanoma.

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http://dx.doi.org/10.1016/j.humpath.2018.08.002DOI Listing
December 2018
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