%0 Journal Article %J Cancer Discov %D 2018 %T Genetic Mechanisms of Immune Evasion in Colorectal Cancer. %A Grasso, Catherine S %A Giannakis, Marios %A Wells, Daniel K %A Hamada, Tsuyoshi %A Mu, Xinmeng Jasmine %A Quist, Michael %A Nowak, Jonathan A %A Nishihara, Reiko %A Qian, Zhi Rong %A Inamura, Kentaro %A Morikawa, Teppei %A Nosho, Katsuhiko %A Abril-Rodriguez, Gabriel %A Connolly, Charles %A Escuin-Ordinas, Helena %A Geybels, Milan S %A Grady, William M %A Hsu, Li %A Hu-Lieskovan, Siwen %A Huyghe, Jeroen R %A Kim, Yeon Joo %A Krystofinski, Paige %A Leiserson, Mark D M %A Montoya, Dennis J %A Nadel, Brian B %A Pellegrini, Matteo %A Pritchard, Colin C %A Puig-Saus, Cristina %A Quist, Elleanor H %A Raphael, Ben J %A Salipante, Stephen J %A Shin, Daniel Sanghoon %A Shinbrot, Eve %A Shirts, Brian %A Shukla, Sachet %A Stanford, Janet L %A Sun, Wei %A Tsoi, Jennifer %A Upfill-Brown, Alexander %A Wheeler, David A %A Wu, Catherine J %A Yu, Ming %A Zaidi, Syed H %A Zaretsky, Jesse M %A Gabriel, Stacey B %A Lander, Eric S %A Garraway, Levi A %A Hudson, Thomas J %A Fuchs, Charles S %A Ribas, Antoni %A Ogino, Shuji %A Peters, Ulrike %K beta 2-Microglobulin %K Colorectal Neoplasms %K DNA Copy Number Variations %K DNA Methylation %K Germ-Line Mutation %K HLA Antigens %K Humans %K Loss of Heterozygosity %K Microsatellite Instability %K Tumor Escape %K Wnt Signaling Pathway %X

To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of and genes due to copy-number alterations and copy-neutral loss of heterozygosity. WNT/β-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion. This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. .

%B Cancer Discov %V 8 %P 730-749 %8 2018 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/29510987?dopt=Abstract %R 10.1158/2159-8290.CD-17-1327 %0 Journal Article %J Science %D 2013 %T Integrative annotation of variants from 1092 humans: application to cancer genomics. %A Khurana, Ekta %A Fu, Yao %A Colonna, Vincenza %A Mu, Xinmeng Jasmine %A Kang, Hyun Min %A Lappalainen, Tuuli %A Sboner, Andrea %A Lochovsky, Lucas %A Chen, Jieming %A Harmanci, Arif %A Das, Jishnu %A Abyzov, Alexej %A Balasubramanian, Suganthi %A Beal, Kathryn %A Chakravarty, Dimple %A Challis, Daniel %A Chen, Yuan %A Clarke, Declan %A Clarke, Laura %A Cunningham, Fiona %A Evani, Uday S %A Flicek, Paul %A Fragoza, Robert %A Garrison, Erik %A Richard A Gibbs %A Gümüş, Zeynep H %A Herrero, Javier %A Kitabayashi, Naoki %A Kong, Yong %A Lage, Kasper %A Liluashvili, Vaja %A Lipkin, Steven M %A MacArthur, Daniel G %A Marth, Gábor %A Donna M Muzny %A Pers, Tune H %A Ritchie, Graham R S %A Rosenfeld, Jeffrey A %A Sisu, Cristina %A Wei, Xiaomu %A Wilson, Michael %A Xue, Yali %A Yu, Fuli %A Dermitzakis, Emmanouil T %A Yu, Haiyuan %A Rubin, Mark A %A Tyler-Smith, Chris %A Gerstein, Mark %K Binding Sites %K Genetic Variation %K Genome, Human %K Genomics %K Humans %K Kruppel-Like Transcription Factors %K Molecular Sequence Annotation %K Mutation %K Neoplasms %K Polymorphism, Single Nucleotide %K Population %K RNA, Untranslated %K Selection, Genetic %X

Interpreting variants, especially noncoding ones, in the increasing number of personal genomes is challenging. We used patterns of polymorphisms in functionally annotated regions in 1092 humans to identify deleterious variants; then we experimentally validated candidates. We analyzed both coding and noncoding regions, with the former corroborating the latter. We found regions particularly sensitive to mutations ("ultrasensitive") and variants that are disruptive because of mechanistic effects on transcription-factor binding (that is, "motif-breakers"). We also found variants in regions with higher network centrality tend to be deleterious. Insertions and deletions followed a similar pattern to single-nucleotide variants, with some notable exceptions (e.g., certain deletions and enhancers). On the basis of these patterns, we developed a computational tool (FunSeq), whose application to ~90 cancer genomes reveals nearly a hundred candidate noncoding drivers.

%B Science %V 342 %P 1235587 %8 2013 Oct 04 %G eng %N 6154 %1 https://www.ncbi.nlm.nih.gov/pubmed/24092746?dopt=Abstract %R 10.1126/science.1235587 %0 Journal Article %J Science %D 2012 %T A systematic survey of loss-of-function variants in human protein-coding genes. %A MacArthur, Daniel G %A Balasubramanian, Suganthi %A Frankish, Adam %A Huang, Ni %A Morris, James %A Walter, Klaudia %A Jostins, Luke %A Habegger, Lukas %A Pickrell, Joseph K %A Montgomery, Stephen B %A Albers, Cornelis A %A Zhang, Zhengdong D %A Conrad, Donald F %A Lunter, Gerton %A Zheng, Hancheng %A Ayub, Qasim %A DePristo, Mark A %A Banks, Eric %A Hu, Min %A Handsaker, Robert E %A Rosenfeld, Jeffrey A %A Fromer, Menachem %A Jin, Mike %A Mu, Xinmeng Jasmine %A Khurana, Ekta %A Ye, Kai %A Kay, Mike %A Saunders, Gary Ian %A Suner, Marie-Marthe %A Hunt, Toby %A Barnes, If H A %A Amid, Clara %A Carvalho-Silva, Denise R %A Bignell, Alexandra H %A Snow, Catherine %A Yngvadottir, Bryndis %A Bumpstead, Suzannah %A Cooper, David N %A Xue, Yali %A Romero, Irene Gallego %A Wang, Jun %A Li, Yingrui %A Gibbs, Richard A %A McCarroll, Steven A %A Dermitzakis, Emmanouil T %A Pritchard, Jonathan K %A Barrett, Jeffrey C %A Harrow, Jennifer %A Hurles, Matthew E %A Gerstein, Mark B %A Tyler-Smith, Chris %K Disease %K Gene Expression %K Gene Frequency %K Genetic Variation %K Genome, Human %K Humans %K Phenotype %K Polymorphism, Single Nucleotide %K Proteins %K Selection, Genetic %X

Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated. We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease-causing variants, as well as common LoF variants in nonessential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies.

%B Science %V 335 %P 823-8 %8 2012 Feb 17 %G eng %N 6070 %1 https://www.ncbi.nlm.nih.gov/pubmed/22344438?dopt=Abstract %R 10.1126/science.1215040