Prevalence of Homologous Recombination Pathway Gene Mutations in Melanoma: Rationale for a New Targeted Therapeutic Approach

Abstract

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PARP Inhibitors in Melanoma—An Expanding Therapeutic Option?

“…While cells that have intact capable of repairing the double-stranded breaks that are created by PARP inhibito with mutations in HR, such as defective BRCA1 or BRCA2 or other DDR genes, are to effectively perform HR, thereby causing cell death with synthetic lethality [21,2 ure 1). Although BRCA1 and BRCA2 mutant tumours are the best-known associations of HR deficiency and intrinsically sensitive to PARP inhibitors, there are a wide range of other non-BRCA DNA repair genes associated with HR deficiency, including but not limited to ARID1A, ATM, PALB2, CHEK2 and FANCA [23]. Thus, PARP inhibitors may have utility beyond the small proportion (5-10%) of patients carrying BRCA mutations [24].…”

“…Although BRCA1 and BRCA2 mutant tumours are the best-known associations of HR deficiency and intrinsically sensitive to PARP inhibitors, there are a wide range of other non- BRCA DNA repair genes associated with HR deficiency, including but not limited to ARID1A, ATM, PALB2, CHEK2 and FANCA [ 23 ]. Thus, PARP inhibitors may have utility beyond the small proportion (5–10%) of patients carrying BRCA mutations [ 24 ].…”

“…Thus, PARP inhibitors may have utility beyond the small proportion (5–10%) of patients carrying BRCA mutations [ 24 ]. To date, PARP inhibitors have established a role in treatment of patients with HR deficiency and/or BRCA mutant tumours such as prostate, breast and ovarian cancers [ 23 ].…”

“…The prevalence of HR-DDR amongst tumour lineages is poorly characterised even though various solid tumours have been treated with PARP inhibitors [ 25 ]. There is a need to understand the clinical characteristics of melanoma patients with HR-DDR gene mutations and their impact on treatment decisions [ 23 ].…”

“…Homologous recombination deficiency can be found in almost all types of cancers. There have been varying reports of frequency in cutaneous melanoma, such as Kim et al which reported that 21.4% harboured a HR-DDR gene pathway mutation [ 23 ]. In this cohort, the presence of an HR-DDR pathway gene mutation was associated with a significantly higher proportion of thinner primary tumours, head and neck primary tumours, higher tumour mutational burden (TMB) and concurrent NF1 mutation [ 23 ].…”