Figure S3. Correlations between IGR burden, TMB, SCNA and Fusions in the ICGC Pan-cancer dataset. Scatter plots of ICGC tumors: (a) SCNA burden vs TMB, (b) SCNA burden vs IGR burden, (c) Fusion burden vs IGR burden, (d) Fusion burden vs SCNA burden, colored by T-inflamed signature are shown. Pearson’s correlation coefficients in a-d are 0.023, 0.22, 0.298 and 0.852 respectively.
Funding
National Cancer Institute (NCI)
United States Department of Health and Human Services
Find out more...DOD Peer Reviewed Cancer Research Program (PRCRP)
PA breast cancer coalition
Shear Family Foundation (Shear Family Foundation Inc)
Hillman Foundation
ARTICLE ABSTRACT
Immune checkpoint blockade (ICB) can induce durable cancer remission. However, only a small subset of patients gains benefits. While tumor mutation burden (TMB) differentiates responders from nonresponders in some cases, it is a weak predictor in tumor types with low mutation rates. Thus, there is an unmet need to discover a new class of genetic aberrations that predict ICB responses in these tumor types. Here, we report analyses of pan-cancer whole genomes which revealed that intragenic rearrangement (IGR) burden is significantly associated with immune infiltration in breast, ovarian, esophageal, and endometrial cancers, particularly with increased M1 macrophage and CD8+ T-cell signatures. Multivariate regression against spatially counted tumor-infiltrating lymphocytes in breast, endometrial, and ovarian cancers suggested that IGR burden is a more influential covariate than other genetic aberrations in these cancers. In the MEDI4736 trial evaluating durvalumab in esophageal adenocarcinoma, IGR burden correlated with patient benefits. In the IMVigor210 trial evaluating atezolizumab in urothelial carcinoma, IGR burden increased with platinum exposure and predicted patient benefit among TMB-low, platinum-exposed tumors. Altogether, we have demonstrated that IGR burden correlates with T-cell inflammation and predicts ICB benefit in TMB-low, IGR-dominant tumors, and in platinum-exposed tumors.
