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Exploratory analyses of consensus molecular subtype-dependent associations of TP53 mutations with immunomodulation and prognosis in colorectal cancer.

ABSTRACT: Background:Accumulating evidence suggests immunomodulatory and context-dependent effects of TP53 mutations in cancer. We performed an exploratory analysis of the transcriptional, immunobiological and prognostic associations of TP53 mutations within the gene expression-based consensus molecular subtypes (CMSs) of colorectal cancer (CRC). Materials and methods:In a single-hospital series of 401 stage I-IV primary CRCs, we sequenced the whole coding region of TP53 and analysed CMS-dependent transcriptional consequences of the mutations by gene expression profiling. Immunomodulatory associations were validated by multiplex, fluorescence-based immunohistochemistry of immune cell markers. Prognostic associations of TP53 mutations were analysed in an aggregated series of 635 patients classified according to CMS, including publicly available data from a French multicentre cohort (GSE39582). Results:TP53 mutations were found in 60% of the CRCs. However, gene set enrichment analyses indicated that their transcriptional consequences varied among the CMSs and were most pronounced in CMS1-immune and CMS4-mesenchymal. Subtype specificity was primarily seen as an upregulation of gene sets reflecting cell cycle progression in CMS4 and a downregulation of T cell activity in CMS1. The subtype-dependent immunomodulatory associations were reinforced by significant depletion of several immune cell populations in mutated tumours compared with wild-type (wt) tumours exclusively in CMS1, including cytotoxic lymphocytes (adjusted p value in CMS1=0.002?and CMS2-4>0.9, Microenvironment Cell Populations (MCP)-counter algorithm). This was validated by immunohistochemistry-based quantification of tumour infiltrating CD8+ cells. Within CMS1, the immunomodulatory association of TP53 mutations was strongest among microsatellite stable (MSS) tumours, and this translated into a propensity for metastatic disease and poor prognostic value of the mutations specifically in the CMS1/MSS subtype (both series overall survival: TP53 mutation vs wt: HR 5.52, p=0.028). Conclusions:Integration of TP53 mutation status with the CMS framework in primary CRC suggested subtype-dependent immunobiological associations with prognostic and potentially immunotherapeutic implications, warranting independent validation.

SUBMITTER: Smeby J

PROVIDER: S-EPMC6598553 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Exploratory analyses of consensus molecular subtype-dependent associations of <i>TP53</i> mutations with immunomodulation and prognosis in colorectal cancer.

Smeby Jørgen J Sveen Anita A Bergsland Christian H CH Eilertsen Ina A IA Danielsen Stine A SA Eide Peter W PW Hektoen Merete M Guren Marianne G MG Nesbakken Arild A Bruun Jarle J Lothe Ragnhild A RA

ESMO open 20190624 3

<h4>Background</h4>Accumulating evidence suggests immunomodulatory and context-dependent effects of <i>TP53</i> mutations in cancer. We performed an exploratory analysis of the transcriptional, immunobiological and prognostic associations of <i>TP53</i> mutations within the gene expression-based consensus molecular subtypes (CMSs) of colorectal cancer (CRC).<h4>Materials and methods</h4>In a single-hospital series of 401 stage I-IV primary CRCs, we sequenced the whole coding region of <i>TP53</i ...[more]

PMID: 31321083

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Project description:Consensus molecular subtyping is an RNA expression-based classification system for colorectal cancer (CRC). Genomic alterations accumulate during CRC pathogenesis, including the premalignant adenoma stage, leading to changes in RNA expression. Only a minority of adenomas progress to malignancies, a transition that is associated with specific DNA copy number aberrations or microsatellite instability (MSI). We aimed to investigate whether colorectal adenomas can already be stratified into consensus molecular subtype (CMS) classes, and whether specific CMS classes are related to the presence of specific DNA copy number aberrations associated with progression to malignancy. RNA sequencing was performed on 62 adenomas and 59 CRCs. MSI status was determined with polymerase chain reaction-based methodology. DNA copy number was assessed by low-coverage DNA sequencing (n?=?30) or array-comparative genomic hybridisation (n?=?32). Adenomas were classified into CMS classes together with CRCs from the study cohort and from The Cancer Genome Atlas (n?=?556), by use of the established CMS classifier. As a result, 54 of 62 (87%) adenomas were classified according to the CMS. The CMS3 'metabolic subtype', which was least common among CRCs, was most prevalent among adenomas (n?=?45; 73%). One of the two adenomas showing MSI was classified as CMS1 (2%), the 'MSI immune' subtype. Eight adenomas (13%) were classified as the 'canonical' CMS2. No adenomas were classified as the 'mesenchymal' CMS4, consistent with the fact that adenomas lack invasion-associated stroma. The distribution of the CMS classes among adenomas was confirmed in an independent series. CMS3 was enriched with adenomas at low risk of progressing to CRC, whereas relatively more high-risk adenomas were observed in CMS2. We conclude that adenomas can be stratified into the CMS classes. Considering that CMS1 and CMS2 expression signatures may mark adenomas at increased risk of progression, the distribution of the CMS classes among adenomas is consistent with the proportion of adenomas expected to progress to CRC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Project description:BackgroundApproximately 15% of primary colorectal cancers have DNA mismatch repair deficiency, causing a complex genome with thousands of small mutations-the microsatellite instability (MSI) phenotype. We investigated molecular heterogeneity and tumor immunogenicity in relation to clinical endpoints within this distinct subtype of colorectal cancers.MethodsA total of 333 primary MSI+ colorectal tumors from multiple cohorts were analyzed by multilevel genomics and computational modeling-including mutation profiling, clonality modeling, and neoantigen prediction in a subset of the tumors, as well as gene expression profiling for consensus molecular subtypes (CMS) and immune cell infiltration.ResultsNovel, frequent frameshift mutations in four cancer-critical genes were identified by deep exome sequencing, including in CRTC1, BCL9, JAK1, and PTCH1. JAK1 loss-of-function mutations were validated with an overall frequency of 20% in Norwegian and British patients, and mutated tumors had up-regulation of transcriptional signatures associated with resistance to anti-PD-1 treatment. Clonality analyses revealed a high level of intra-tumor heterogeneity; however, this was not associated with disease progression. Among the MSI+ tumors, the total mutation load correlated with the number of predicted neoantigens (P = 4 × 10-5), but not with immune cell infiltration-this was dependent on the CMS class; MSI+ tumors in CMS1 were highly immunogenic compared to MSI+ tumors in CMS2-4. Both JAK1 mutations and CMS1 were favorable prognostic factors (hazard ratios 0.2 [0.05-0.9] and 0.4 [0.2-0.9], respectively, P = 0.03 and 0.02).ConclusionsMultilevel genomic analyses of MSI+ colorectal cancer revealed molecular heterogeneity with clinical relevance, including tumor immunogenicity and a favorable patient outcome associated with JAK1 mutations and the transcriptomic subgroup CMS1, emphasizing the potential for prognostic stratification of this clinically important subtype. See related research highlight by Samstein and Chan 10.1186/s13073-017-0438-9.

Project description:BackgroundColorectal cancer (CRC) has been ranked as the second most deadly cancer and the third most diagnosed cancer cases for the year 2020. Specifically for Romania, the number of CRC-related deaths in 2019 was estimated at 6307 people, with a standardized mortality rate of 33.8 per 100,000 inhabitants. Although the tumor protein 53 (TP53) gene is intensively studied, there are few data on TP53 mutations in Romanian CRC. Furthermore, since genetic alterations may show geographical differences, our study aimed to analyze the clinical status and TP53 somatic variation in Romanian CRC patients.Subjects and methodsDNA from 40 randomly selected cases of CRC was extracted from formalin-fixed paraffin-embedded tissues and sequenced using direct Sanger sequencing techniques, and variants were annotated according to the recommendations of the Human Genome Variation Society. Novel variants were analyzed using MutationTaster2021 to predict their effects.ResultsThe mean age was 63.6 years (range 33-85 years) with a male to female ratio of 2.3. More than 45% (18/40) had an advanced cancer stage (≥ stage III). Mutations were found in 21/40 cases (52.5%), with one case having two mutations, giving a total of twenty-two mutations in the TP53 coding DNA. These mutations include 3 (13.6%) insertion-deletion mutations, two of which are novel frameshift mutations: c.165delT (in exon 4) and c.928_935dup (in exon 9), both of which are predicted to lead to nonsense-mediated mRNA decay and are classified as deleterious. The remaining 19 (86.36%) were substitution mutations: 1 nonsense and 18 (81.8%) missense mutations, with G > A (n = 7/19; 36.8%) and C > T (n = 6/19; 31.5%) transitions being the most common. The G > T transversion was found in 21.05% (4/19) of the substitution mutations.ConclusionWe have described two novel frameshift mutations in TP53. The discovery of novel mutations following the efforts of The Cancer Genome Atlas and other large-scale cancer genome sequencing projects may be further evidence of the heterogeneous nature of mutations in cancer and may indicate that the identification of carcinogenic mutations is not yet saturated. Further sequencing is therefore needed, especially in less studied populations. Importantly, consideration of their geographical environment will shed light on population-specific carcinogenesis.

Project description:BackgroundTP53 mutations have a prognostic significance in relapsed and refractory diffuse large B-cell lymphoma (rrDLBCL) patients, and their treatment still faces a great challenge. This study aimed to evaluate the prognosis of patients with TP53 mutations (TP53mut) in the context of CAR-T therapy (Chimeric antigen receptor T-cell therapy) as well as explore the heterogeneity in their cohort and identify the possible risk factors.MethodsA retrospective study was conducted to investigate the clinical characteristics of rrDLBCL patients with TP53 mutations and their prognostic factors, receiving CAR-T therapy. And the expression level of TP53 and DDX3X, which was an important co-mutation of TP53 revealed in the cohort, were explored in public databases and cell lines.ResultsThe median overall survival time of 40 patients with TP53 mutations was 24.5 months, while their median progression-free survival time after CAR-T was 6.8 months. There were no significant differences in the ORR (objective remission rate, X2 = 3.0498, p > 0.05) and PFS (after CAR-T therapy) between the patients with wild-type and mutated TP53 genes after CAR-T therapy, while the OS of patients with TP53 mutations was significantly worse (p < 0.01). In patients with TP53 mutations, the performance status (ECOG score) was identified as the most important prognostic factor, while the efficacies of induction and salvage treatments were also correlated with the prognosis. Among molecular indicators, the co-mutations of Chr-17 and those located on the exon 5 of the TP53 gene showed a tendency for a worse prognosis. Moreover, the patients with TP53-DDX3X co-mutations were identified as a subgroup with an extremely bad prognosis. The expression levels of DDX3X and TP53 were explored in a public database and the cell lines with their co-mutations, which indicated that inhibiting the DDX3X gene could affect the proliferation of rrDLBCL cells and the expression of TP53.ConclusionsThis study indicated rrDLBCL patients with TP53 mutations was still the group of poor prognosis in the CAR-T therapy era. CAR-T therapy can benefit some TP53mut patients, and the performance status (ECOG) might help predict their prognosis. The study also revealed a subgroup of TP53-DDX3X co-mutations in rrDLBCL, which showed a strong clinical significance.

Dataset Information

Exploratory analyses of consensus molecular subtype-dependent associations of TP53 mutations with immunomodulation and prognosis in colorectal cancer.

Publications

Exploratory analyses of consensus molecular subtype-dependent associations of <i>TP53</i> mutations with immunomodulation and prognosis in colorectal cancer.

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