Homologous Recombination Deficiency and Tumor Mutational Burden as Clinical Biomarkers for Melanoma

Abstract

Abstract Introduction/Objective Homologous recombination deficiency (HRD) cancers have high levels of genetic instability, potentially being targets for platinum agents or poly-ADP ribose polymerase inhibitors. Tumor mutational burden (TMB), which is used to guide immunotherapy, is thought to be associated with HRD. This study aimed to evaluate the frequency of HRD and its correlation with other genomic parameters in melanoma. Methods/Case Report A total of 14 cases with the diagnosis of melanoma were found in the genomic database between March 1, 2021 to July 30, 2021. One case had an EWSR1-ATF1 translocation and was excluded. Copy number variations and absence of heterozygosity detection were analyzed by the NxClinical software (BioDiscovery, El Segundo, CA). HRD was scored by three DNA-based measures of genomic instability (loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale transitions (LST)). HRD-LOH is the number of LOH regions > 15 Mb and do not cross the centromere. HRD-TAI is the number of regions > 10 Mb with allelic imbalance that extend to one of the subtelomeres and do not cross the centromere. HRD-LST is the number of break points between regions > 10 Mb. A high HRD score and LOH percentage were defined as ≥ 42 and ≥ 16%, respectively. Results (if a Case Study enter NA) Of the 13 cases, 10 had a high TMB and 3 had a low TMB. A high HRD score was found in 3 cases; high LOH percentage was found in 4 cases. PDL-1 was expressed in 8 of the 11 cases tested. A high HRD score correlated with high LOH percentage by Pearson’s chi-squared test (p < 0.01). No significant association was found between TMB and HRD score or LOH percentage. Common alterations among cases with high TMB included mutations in NRAS (3/13; 23.1%), CDKN2A (2/13; 15.4%), BRAF (2/13; 15.4%), BRCA2 (2/13; 15.4%), RAF1 (2/13; 15.4%), RET (1/13; 7.7%), IDH1 (1/13; 7.7%), PALB2 (1/13; 7.7%), BRCA1 (1/13; 7.7%), ERBB2 (1/13; 7.7%), NF1 (1/13; 7.7%), MLH1 (1/13; 7.7%), ATM (1/13; 7.7%) and MET (1/13; 7.7%). One case had amplifications in CCND1, FGF 3/4/19 and MET. Among cases with low TMB, alterations included MYC amplification (1/3; 33.3%) and BRAF mutations (2/3; 66.6%). Conclusion In our study, HRD score is not associated with TMB status. There is a strong correlation between HRD score and LOH percentage, suggesting that LOH is a major component in the genomic scarring seen in HRD. HRD may be an independent biomarker of immunogenicity to guide immunotherapy.