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Unique Neoantigens Arise from Somatic Mutations in Patients with Gastrointestinal Cancers.

ABSTRACT: Immunotherapies can mediate regression of human tumors with high mutation rates, but responses are rarely observed in patients with common epithelial cancers. This raises the question of whether patients with these common cancers harbor T lymphocytes that recognize mutant proteins expressed by autologous tumors that may represent ideal targets for immunotherapy. Using high-throughput immunologic screening of mutant gene products identified via whole-exome sequencing, we identified neoantigen-reactive tumor-infiltrating lymphocytes (TIL) from 62 of 75 (83%) patients with common gastrointestinal cancers. In total, 124 neoantigen-reactive TIL populations were identified, and all but one of the neoantigenic determinants were unique. The results of in vitro T-cell recognition assays demonstrated that 1.6% of the gene products encoded by somatic nonsynonymous mutations were immunogenic. These findings demonstrate that the majority of common epithelial cancers elicit immune recognition and open possibilities for cell-based immunotherapies for patients bearing these cancers. SIGNIFICANCE: TILs cultured from 62 of 75 (83%) patients with gastrointestinal cancers recognized neoantigens encoded by 1.6% of somatic mutations expressed by autologous tumor cells, and 99% of the neoantigenic determinants appeared to be unique and not shared between patients.This article is highlighted in the In This Issue feature, p. 983.

SUBMITTER: Parkhurst MR

PROVIDER: S-EPMC7138461 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Unique Neoantigens Arise from Somatic Mutations in Patients with Gastrointestinal Cancers.

Parkhurst Maria R MR Robbins Paul F PF Tran Eric E Prickett Todd D TD Gartner Jared J JJ Jia Li L Ivey Gabriel G Li Yong F YF El-Gamil Mona M Lalani Almin A Crystal Jessica S JS Sachs Abraham A Groh Eric E Ray Satyajit S Ngo Lien T LT Kivitz Scott S Pasetto Anna A Yossef Rami R Lowery Frank J FJ Goff Stephanie L SL Lo Winifred W Cafri Gal G Deniger Drew C DC Malekzadeh Parisa P Ahmadzadeh Mojgan M Wunderlich John R JR Somerville Robert P T RPT Rosenberg Steven A SA

Cancer discovery 20190604 8

Immunotherapies can mediate regression of human tumors with high mutation rates, but responses are rarely observed in patients with common epithelial cancers. This raises the question of whether patients with these common cancers harbor T lymphocytes that recognize mutant proteins expressed by autologous tumors that may represent ideal targets for immunotherapy. Using high-throughput immunologic screening of mutant gene products identified via whole-exome sequencing, we identified neoantigen-rea ...[more]

PMID: 31164343

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Project description:Background & aimsPatients with Lynch syndrome carry germline mutations in single alleles of genes encoding the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2; when the second allele becomes mutated, cancer can develop. Increased screening for Lynch syndrome has identified patients with tumors that have deficiency in MMR, but no germline mutations in genes encoding MMR proteins. We investigated whether tumors with deficient MMR had acquired somatic mutations in patients without germline mutations in MMR genes using next-generation sequencing.MethodsWe analyzed blood and tumor samples from 32 patients with colorectal or endometrial cancer who participated in Lynch syndrome screening studies in Ohio and were found to have tumors with MMR deficiency (based on microsatellite instability and/or absence of MMR proteins in immunohistochemical analysis, without hypermethylation of MLH1), but no germline mutations in MMR genes. Tumor DNA was sequenced for MLH1, MSH2, MSH6, PMS2, EPCAM, POLE, and POLD1 with ColoSeq and mutation frequencies were established.ResultsTwenty-two of 32 patients (69%) were found to have 2 somatic (tumor) mutations in MMR genes encoding proteins that were lost from tumor samples, based on immunohistochemistry. Of the 10 remaining tumors 3 had one somatic mutation in a MMR gene, with possible loss of heterozygosity that could lead to MMR deficiency, 6 were found to be false-positive results (19%), and 1 had only one mutation in a MMR gene and remained unexplained. All of the tumors found to have somatic MMR mutations were of the hypermutated phenotype (>12 mutations/megabase); 6 had mutation frequencies >200/megabase, and 5 of these had somatic mutations in POLE, which encodes a DNA polymerase.ConclusionsSome patients are found to have tumors with MMR defects during screening for Lynch syndrome, yet have no identifiable germline mutations in MMR genes. We found that almost 70% of these patients acquire somatic mutations in MMR genes, leading to a hypermutated phenotype of tumor cells. Patients with colon or endometrial cancers with MMR deficiency not explained by germline mutations might undergo analysis for tumor mutations in MMR genes to guide future surveillance guidelines.

Project description:BackgroundWith the advent of whole-genome analysis for profiling tumor tissue, a pressing need has emerged for principled methods of organizing the large amounts of resulting genomic information. We propose the concept of multiplicity measures on cancer and gene networks to organize the information in a clinically meaningful manner. Multiplicity applied in this context extends Fearon and Vogelstein's multi-hit genetic model of colorectal carcinoma across multiple cancers.MethodsUsing the Catalogue of Somatic Mutations in Cancer (COSMIC), we construct networks of interacting cancers and genes. Multiplicity is calculated by evaluating the number of cancers and genes linked by the measurement of a somatic mutation. The Kamada-Kawai algorithm is used to find a two-dimensional minimum energy solution with multiplicity as an input similarity measure. Cancers and genes are positioned in two dimensions according to this similarity. A third dimension is added to the network by assigning a maximal multiplicity to each cancer or gene. Hierarchical clustering within this three-dimensional network is used to identify similar clusters in somatic mutation patterns across cancer types.ResultsThe clustering of genes in a three-dimensional network reveals a similarity in acquired mutations across different cancer types. Surprisingly, the clusters separate known causal mutations. The multiplicity clustering technique identifies a set of causal genes with an area under the ROC curve of 0.84 versus 0.57 when clustering on gene mutation rate alone. The cluster multiplicity value and number of causal genes are positively correlated via Spearman's Rank Order correlation (rs(8) = 0.894, Spearman's t = 17.48, p < 0.05). A clustering analysis of cancer types segregates different types of cancer. All blood tumors cluster together, and the cluster multiplicity values differ significantly (Kruskal-Wallis, H = 16.98, df = 2, p < 0.05).ConclusionWe demonstrate the principle of multiplicity for organizing somatic mutations and cancers in clinically relevant clusters. These clusters of cancers and mutations provide representations that identify segregations of cancer and genes driving cancer progression.

Project description:Gastrointestinal stromal tumors (GISTs) are rare but treatable soft tissue sarcomas. Nearly all GISTs have somatic mutations in either the KIT or PDGFRA gene, but there are no known inherited genetic risk factors. We assessed the relationship between KIT/PDGFRA mutations and select deletions or single nucleotide polymorphisms (SNPs) in 279 participants from a clinical trial of adjuvant imatinib mesylate. Given previous evidence that certain susceptibility loci and carcinogens are associated with characteristic mutations, or "signatures" in other cancers, we hypothesized that the characteristic somatic mutations in the KIT and PDGFRA genes in GIST tumors may similarly be mutational signatures that are causally linked to specific mutagens or susceptibility loci. As previous epidemiologic studies suggest environmental risk factors such as dioxin and radiation exposure may be linked to sarcomas, we chose 208 variants in 39 candidate genes related to DNA repair and dioxin metabolism or response. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between each variant and 7 categories of tumor mutation using logistic regression. We also evaluated gene-level effects using the sequence kernel association test (SKAT). Although none of the association p-values were statistically significant after adjustment for multiple comparisons, SNPs in CYP1B1 were strongly associated with KIT exon 11 codon 557-8 deletions (OR = 1.9, 95% CI: 1.3-2.9 for rs2855658 and OR = 1.8, 95% CI: 1.2-2.7 for rs1056836) and wild type GISTs (OR = 2.7, 95% CI: 1.5-4.8 for rs1800440 and OR = 0.5, 95% CI: 0.3-0.9 for rs1056836). CYP1B1 was also associated with these mutations categories in the SKAT analysis (p = 0.002 and p = 0.003, respectively). Other potential risk variants included GSTM1, RAD23B and ERCC2. This preliminary analysis of inherited genetic risk factors for GIST offers some clues about the disease's genetic origins and provides a starting point for future candidate gene or gene-environment research.

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Unique Neoantigens Arise from Somatic Mutations in Patients with Gastrointestinal Cancers.

Publications

Unique Neoantigens Arise from Somatic Mutations in Patients with Gastrointestinal Cancers.

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