bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2021–04–11
two papers selected by
Lara Paracchini, Humanitas Research
  1. Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy.
  2. Genome-wide enhancer maps link risk variants to disease genes.
  1. Nat Cancer. 2021 Dec;1(12): 1188-1203
    Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy.
    Robert M Samstein, Chirag Krishna, Xiaoxiao Ma, Xin Pei, Ken-Wing Lee, Vladimir Makarov, Fengshen Kuo, Jonathan Chung, Raghvendra M Srivastava, Tanaya A Purohit, Douglas R Hoen, Rajarsi Mandal, Jeremy Setton, Wei Wu, Rachna Shah, Besnik Qeriqi, Qing Chang, Sviatoslav Kendall, Lior Braunstein, Britta Weigelt, Pedro Blecua Carrillo Albornoz, Luc G T Morris, Diana L Mandelker, Jorge S Reis-Filho, Elisa de Stanchina, Simon N Powell, Timothy A Chan, Nadeem Riaz.
      Immune checkpoint blockade (ICB) has improved outcomes for patients with advanced cancer, but the determinants of response remain poorly understood. Here we report differential effects of mutations in the homologous recombination genes BRCA1 and BRCA2 on response to ICB in mouse and human tumors, and further show that truncating mutations in BRCA2 are associated with superior response compared to those in BRCA1. Mutations in BRCA1 and BRCA2 result in distinct mutational landscapes and differentially modulate the tumor-immune microenvironment, with gene expression programs related to both adaptive and innate immunity enriched in BRCA2-deficient tumors. Single-cell RNA sequencing further revealed distinct T cell, natural killer, macrophage, and dendritic cell populations enriched in BRCA2-deficient tumors. Taken together, our findings reveal the divergent effects of BRCA1 and BRCA2-deficiency on ICB outcome, and have significant implications for elucidating the genetic and microenvironmental determinants of response to immunotherapy.
    DOI:  https://doi.org/10.1038/s43018-020-00139-8
  2. Nature. 2021 Apr 07.
    Genome-wide enhancer maps link risk variants to disease genes.
    Joseph Nasser, Drew T Bergman, Charles P Fulco, Philine Guckelberger, Benjamin R Doughty, Tejal A Patwardhan, Thouis R Jones, Tung H Nguyen, Jacob C Ulirsch, Fritz Lekschas, Kristy Mualim, Heini M Natri, Elle M Weeks, Glen Munson, Michael Kane, Helen Y Kang, Ang Cui, John P Ray, Thomas M Eisenhaure, Ryan L Collins, Kushal Dey, Hanspeter Pfister, Alkes L Price, Charles B Epstein, Anshul Kundaje, Ramnik J Xavier, Mark J Daly, Hailiang Huang, Hilary K Finucane, Nir Hacohen, Eric S Lander, Jesse M Engreitz.
      Genome-wide association studies (GWAS) have identified thousands of noncoding loci that are associated with human diseases and complex traits, each of which could reveal insights into the mechanisms of disease1. Many of the underlying causal variants may affect enhancers2,3, but we lack accurate maps of enhancers and their target genes to interpret such variants. We recently developed the activity-by-contact (ABC) model to predict which enhancers regulate which genes and validated the model using CRISPR perturbations in several cell types4. Here we apply this ABC model to create enhancer-gene maps in 131 human cell types and tissues, and use these maps to interpret the functions of GWAS variants. Across 72 diseases and complex traits, ABC links 5,036 GWAS signals to 2,249 unique genes, including a class of 577 genes that appear to influence multiple phenotypes through variants in enhancers that act in different cell types. In inflammatory bowel disease (IBD), causal variants are enriched in predicted enhancers by more than 20-fold in particular cell types such as dendritic cells, and ABC achieves higher precision than other regulatory methods at connecting noncoding variants to target genes. These variant-to-function maps reveal an enhancer that contains an IBD risk variant and that regulates the expression of PPIF to alter the membrane potential of mitochondria in macrophages. Our study reveals principles of genome regulation, identifies genes that affect IBD and provides a resource and generalizable strategy to connect risk variants of common diseases to their molecular and cellular functions.
    DOI:  https://doi.org/10.1038/s41586-021-03446-x
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