SETBP1 mutation determines sensitivity to immune checkpoint inhibitors in melanoma and NSCLC

Abstract

SET binding protein 1 (SETBP1) plays crucial roles in various biological processes; however, its involvement in cancer immune checkpoint inhibitor (ICI) treatments has never been studied. In this study, we collected a total of 631 melanoma and 109 non-small cell lung cancer (NSCLC) samples treated with ICI agents (i.e., anti-CTLA-4, anti-PD-1/PD-L1, or combination therapy). Additionally, we obtained their corresponding somatic mutational profiles. We observed that SETBP1 mutated (SETBP1-MUT) melanoma patients exhibited significantly prolonged ICI survival outcomes compared to wild-type patients (HR: 0.56, 95% CI: 0.38-0.81, P = 0.002). Consistently, an elevated ICI response rate was also noticed in the SETBP1-MUT group (42.9% vs. 29.1%, P = 0.016). The Association of SETBP1 mutations with favorable immunotherapeutic prognosis and response was further supported by an independent NSCLC cohort (both P < 0.05). Additional immunological analyses revealed that favorable immune infiltration, tumor immunogenicity, and immune response circuits were enriched in SETBP1-MUT patients. Overall, our findings suggest that SETBP1 mutations may serve as a new biomarker for stratifying beneficiaries of ICI treatments in melanoma and NSCLC, which provides possible evidence for tailoring clinical immunotherapeutic strategies.

The impact of telomere length on prostate cancer aggressiveness, genomic instability and health disparities

“…Shared between the ancestries, we found shortened TTL to be associated with acquired variation within the DNA replication tumour-associated gene SETBP1 . Having previously reported SETBP1 to be significantly mutated in African-derived tumours 9 , this new PCa driver 36 showing favourable outcomes in response to immune checkpoint inhibitor treatment in melanoma patients 37 , warrants further investigation on the clinical impact for patients presenting with shortened TTL and SETBP1 mutant prostate tumours. European specific correlations with shortened TTL most notably included: the DNA mismatch repair gene MSH2 , known to be associated with telomere shortening 38 ; PTEN and TP53 tumour suppressor gene deficiencies, consistent with 2012 findings showing their critical roles in telomere dysfunction which aggravates aggressive PCa progression 39 ; while the association with the newly described African-predominant PCa driver DDX11L1 9 remains unexplained.…”