Immune checkpoint inhibitors targeting the programmed cell death-1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene (p=0.012), which encodes a subunit of a SWI/SNF chromatin remodeling complex (the PBAF subtype). We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-(L)1 blockade therapy alone or in combination with anti-CTLA-4 therapies (p=0.0071). Gene expression analysis of PBAF-deficient ccRCC cell lines and PBRM1-deficient tumors revealed altered transcriptional output in JAK/STAT, hypoxia, and immune signaling pathways. PBRM1 loss in ccRCC may alter global tumor cell expression profiles to influence responsiveness to immune checkpoint therapy.

Objective Accumulating evidence links the intestinal microbiota and colorectal carcinogenesis. Fusobacterium nucleatum may promote colorectal tumour growth and inhibit T-cell-mediated immune responses against colorectal tumours. Thus, we hypothesized that the amount of Fusobacterium nucleatum in colorectal carcinoma might be associated with worse clinical outcome. Design We utilised molecular pathological epidemiology database of 1,069 rectal and colon cancer cases in the Nurses’ Health Study and the Health Professionals Follow-up Study, and measured Fusobacterium nucleatum DNA in carcinoma tissue. Cox proportional hazards model was used to compute hazard ratio (HR), controlling for potential confounders, including microsatellite instability (MSI, mismatch repair deficiency), CpG island methylator phenotype (CIMP), KRAS, BRAF, and PIK3CA mutations, and LINE-1 hypomethylation (low-level methylation). Results Compared to Fusobacterium nucleatum-negative cases, multivariable HRs (95% confidence interval) for colorectal cancer-specific mortality in Fusobacterium nucleatum-low cases and Fusobacterium nucleatum-high cases were 1.25 (0.82 to 1.92) and 1.58 (1.04 to 2.39), respectively (p for trend = 0.020). The amount of Fusobacterium nucleatum was associated with MSI-high (multivariable odds ratio, 5.22; 95% CI, 2.86 to 9.55) independent of CIMP and BRAF mutation status, whereas CIMP and BRAF mutation were associated with Fusobacterium nucleatum only in univariate analyses (p < 0.001) but not in multivariate analysis that adjusted for MSI status. Conclusions The amount of Fusobacterium nucleatum DNA in colorectal cancer tissue is associated with shorter survival, and may potentially serve as a prognostic biomarker. Our data may have implications in developing cancer prevention and treatment strategies through targeting gastrointestinal microflora by diet, probiotics, and antibiotics.