Whole-Exome Sequencing and cfDNA Analysis Uncover Genetic Determinants of Melanoma Therapy Response in a Real-World Setting.

Autor: Vanni I; Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy., Pastorino L; Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy.; Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy., Tanda ET; Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy.; Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy., Andreotti V; Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy., Dalmasso B; Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy., Solari N; Surgical Oncology, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy., Mascherini M; Surgical Clinic Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy., Cabiddu F; Anatomic Pathology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy., Guadagno A; Anatomic Pathology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy., Coco S; Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy., Allavena E; Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy., Bruno W; Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy.; Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy., Pietra G; IRCCS Ospedale Policlinico San Martino, U.O. Immunologia, 16132 Genoa, Italy.; Department of Experimental Medicine (DiMES), University of Genoa, 16132 Genoa, Italy., Croce M; Bioterapie, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy., Gangemi R; Bioterapie, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy., Piana M; Dipartimento di Matematica (MIDA), University of Genoa, 16132 Genoa, Italy.; Life Science Computational Laboratory (LISCOMP), IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy., Zoppoli G; Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy.; Clinica di Medicina Interna a Indirizzo Oncologico, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy., Ferrando L; Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy.; Clinica di Medicina Interna a Indirizzo Oncologico, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy., Spagnolo F; Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy.; Dipartimento di Scienze Chirurgiche e Diagnostiche Integrate (DISC), University of Genoa, 16132 Genoa, Italy., Queirolo P; Melanoma, Sarcoma & Rare Tumors Division, European Institute of Oncology (IEO), 20141 Milan, Italy., Ghiorzo P; Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy.; Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2023 Feb 21; Vol. 24 (5). Date of Electronic Publication: 2023 Feb 21.
DOI: 10.3390/ijms24054302
Abstrakt: Although several studies have explored the molecular landscape of metastatic melanoma, the genetic determinants of therapy resistance are still largely unknown. Here, we aimed to determine the contribution of whole-exome sequencing and circulating free DNA (cfDNA) analysis in predicting response to therapy in a consecutive real-world cohort of 36 patients, undergoing fresh tissue biopsy and followed during treatment. Although the underpowered sample size limited statistical analysis, samples from non-responders had higher copy number variations and mutations in melanoma driver genes compared to responders in the BRAF V600+ subset. In the BRAF V600- subset, Tumor Mutational Burden (TMB) was twice that in responders vs. non-responders. Genomic layout revealed commonly known and novel potential intrinsic/acquired resistance driver gene variants. Among these, RAC1 , FBXW7 , GNAQ mutations, and BRAF / PTEN amplification/deletion were present in 42% and 67% of patients, respectively. Both Loss of Heterozygosity (LOH) load and tumor ploidy were inversely associated with TMB. In immunotherapy-treated patients, samples from responders showed higher TMB and lower LOH and were more frequently diploid compared to non-responders. Secondary germline testing and cfDNA analysis proved their efficacy in finding germline predisposing variants carriers (8.3%) and following dynamic changes during treatment as a surrogate of tissue biopsy, respectively.
Databáze: MEDLINE
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