Correlation of mutated <i>B2M</i> , an immune-related gene, with overall survival in renal cell carcinoma.

Abstract

555 Background: Renal cell carcinoma (RCC) is the most common renal malignancy and although most cases are sporadic, certain hereditary disorders and genes are associated with its development and response to various immunotherapies. One identified gene implicated in malignant and neoplastic progression and therapeutic resistance is Beta-2-microglobulin (B2M), a component of MHC I class molecules. Our study aimed to explore other gene mutations potentially associated with B2M and any significant findings in survival outcomes with RCC immunotherapy. Methods: NextGen sequencing of DNA (592-gene/whole exome) and RNA (whole transcriptome) was performed on kidney cancer specimens (N = 7104) at Caris Life Sciences (Phoenix, AZ). B2M likely pathogenic/pathogenic (LP/P) mutated patients were used to identify common co-alterations. B2M -high/low expression was defined as &gt; 75 th / &lt; 25 th quartile RNA transcripts per million (TPM). Overall survival (OS) was defined as the time of collection or first of immune checkpoint inhibitor (ICI) to death/last follow-up. Results: Specimens were derived from primary (N = 2950, 41.5%) and metastatic sites (N = 4154, 58.5%) and included all histologies. The most prevalent co-mutations in B2M -mutated tumors include VHL , BAP1 , PBRM1 , NF2 , and SETD2 . Patients with B2M -mutant tumors were found to have worse overall survival, from collection of the specimen to last contact, compared to B2M wild-type tumors (HR = 1.977, 95% CI: 1.47-2.659, P &lt; 0.00001). Additionally, patients with high B2M expression (&gt; 75 th ) had improved survival from start of ICI to last contact compared to patients with low B2M expression (&lt; 25 th ) (HR = 1.34, 95% CI: 1.127-1.593, P &lt; 0.001). BAP1 LP/P mutations were found to be significantly enriched in the high expressors, while B2M LP/P mutations were found to be significantly enriched in the low expressors. While the prevalence of TMB and MSI were not found to be significantly different between the high and low expressors, PD-L1 (SP142) positive frequency (&gt; = 2+ intensity, &gt; = 5% cells stained) was enriched in the higher expressors. Conclusions: Our study demonstrates that Beta-2-microglobulin (B2M) mutation and expression levels, along with numerous other co-mutations, potentially have prognostic and predictive implications in renal cell carcinoma. It remains unclear how these additional genetic mutations interact with each other and with B2M in RCC; however, multiple genes may influence B2M, thereby affecting its expression or the response to treatment. These findings underscore the complex molecular landscape of RCC and highlight B2M and other genetic mutation status as a potential biomarker for predicting therapeutic outcomes and offering new avenues for personalized immunotherapy strategies. Further research may help elucidate the interactions among co-alterations in B2M-mutated RCC and clarify their significance in other cancer types.