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Background:  Tumor mutation burden (TMB) have been served as the most prevalent biomarkers to predict immunotherapy response.  LRP1B  (low-density lipoprotein receptor-related protein 1B) is frequently mutated in melanoma, non-small cell lung cancer (NSCLC) and other tumors; however, its association with TMB and survival in patients with immunotherapy remains unknown.   Methods:  We curated somatic mutation data and clinicopathologic information from 332 melanoma immunotherapy samples for discovery and 113 NSCLC samples for further corroboration. Bayesian variants non-negative matrix factorization was used to extract tumor mutational signatures. Multivariate Cox and logistic regression models were applied to adjust confounding factors. The CIBERSORT and GSEA algorithm were separately used to infer leukocyte relative abundance and significantly enriched pathways.   Results:  Patients with  LRP1B  mutation were identified to be associated with prolonged survival in both immunotherapy cohort. Higher tumor mutation burden was found in  LRP1B  mutated patients, and the association remained significant after controlling for age, gender, stage, mutations in  TP53  and  ATR , and mutational signatures. Immune response and cell cycle regulation circuits were among the top enriched pathways in samples with  LRP1B  mutations.   Conclusion:  Our studies suggested sequencing even a single, frequently mutated gene may provide insight into genome-wide mutational burden, and may serve as a biomarker to predict immune response.

frontiers in immunology

Association of LRP1B Mutation With Tumor Mutation Burden and Outcomes in Melanoma and Non-small Cell Lung Cancer Patients Treated With Immune Check-Point Blockades