Patterns of genomic evolution in advanced melanoma

Area of Science:

• Oncology
• Genetics
• Genomics

Background:

• Genomic alterations in melanoma progression and metastatic heterogeneity are not fully understood.
• Understanding these changes is crucial for developing effective melanoma treatments.

Purpose of the Study:

• To investigate the genomic landscape and heterogeneity of metastatic melanoma deposits.
• To identify key genomic events driving melanoma metastasis and progression.

Main Methods:

• Whole-exome sequencing (WES) was performed on 86 metastatic melanoma deposits from 53 patients.
• Analysis focused on mutation patterns, heterogeneity, and specific genetic events like BRAF mutations and whole-genome duplication (WGD).

Main Results:

• Metastatic melanoma exhibits low intermetastatic heterogeneity, with driver mutations largely shared across lesions.
• Early gain of mutated BRAF alleles and late-onset WGD (in ~40% of cases) were observed.
• UV damage signatures were noted in branch mutations, suggesting metastatic origins from distinct primary tumor subclones.
• One patient showed increased mutational diversity possibly due to chemotherapy and DNA repair defects.
• Radiotherapy exposure led to a detectable mutational signature in subsequent distant relapses.

Conclusions:

• Metastatic melanoma evolution is characterized by conserved driver mutations and limited heterogeneity.
• Specific genomic events, such as BRAF allele gain and WGD, play distinct roles in melanoma progression.
• External factors like chemotherapy and radiotherapy can influence melanoma's genomic landscape and metastatic potential.