Dataset Information

Presence of Concurrent TP53 Mutations Is Necessary to Predict Poor Outcomes within the SMAD4 Mutated Subgroup of Metastatic Colorectal Cancer.

ABSTRACT: Prior studies have resulted in conflicting conclusions on the value of SMAD4 mutations as a prognostic biomarker in metastatic colorectal cancer. In this study, the impact of coexisting mutations with SMAD4 on overall survival was evaluated retrospectively in 433 patients with metastatic colorectal cancer. SMAD4 mutation was found in 16.2% (70/433) of tumors. A systemic univariate and multivariate survival analysis model including age, gender, sidedness of primary tumor, RAS, BRAF^V600E, APC, TP53 and SMAD4 status showed that SMAD4 mutations were not associated with worse prognosis (multivariate HR = 1.25, 95% CI 0.90-1.73, p = 0.18). However, coexisting mutations in SMAD4 and TP53 were significantly associated with worse overall survival (multivariate HR = 2.5, 95% CI 1.44-4.36, p = 0.001). The median overall survival of patients with coexisting SMAD4 and TP53 mutation was 24.2 months, compared to 42.2 months for the rest of the population (p = 0.002). Concurrent SMAD4 and TP53 defines a new subgroup of patients of metastatic colorectal cancer with poor clinical outcomes.

SUBMITTER: Wang C

PROVIDER: S-EPMC9332822 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Presence of Concurrent TP53 Mutations Is Necessary to Predict Poor Outcomes within the SMAD4 Mutated Subgroup of Metastatic Colorectal Cancer.

Wang Chongkai C Sandhu Jaideep J Tsao Amber A Fakih Marwan M

Cancers 20220727 15

Prior studies have resulted in conflicting conclusions on the value of SMAD4 mutations as a prognostic biomarker in metastatic colorectal cancer. In this study, the impact of coexisting mutations with SMAD4 on overall survival was evaluated retrospectively in 433 patients with metastatic colorectal cancer. SMAD4 mutation was found in 16.2% (70/433) of tumors. A systemic univariate and multivariate survival analysis model including age, gender, sidedness of primary tumor, ...[more]

PMID: 35892903

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Project description:BackgroundTP53 is the most commonly mutated gene across all cancer types. R175H mutation was considered structural mutation where the mutation causes misfolding of the protein and leads to a significant conformational alterations within p53's DNA binding domain. The aim of this study was to explain the reason why R175H worse the response to immunotherapy by analyzing tumor immune microenvironment through the expression of immune cells and PD-1.Materials and methodsPatients diagnosed with metastatic carcinoma, including colorectal cancer (CRC), breast cancer (BRCA), gastric cancer (GC), non-small cell lung cancer (NSCLC), and 20 other cancer types, treated in a palliative setting at Samsung Medical Center between October 2019 and April 2021, were enrolled. Of these patients, those who underwent TDS analysis (TruSight™ Oncology 500 assay [TSO 500]) were finally analyzed.ResultsOf 1770 patients, 1012 (57.2%) harbored genetic alterations in TP53. All mutations were single nucleotide variants (SNVs), and the most frequent SNV was R175H (n = 84, 7.5%) which was known as one of the most common hotspot TP53 mutation. The overall survival of patients with TP53 R175H mutations was significantly worse following chemotherapy (606 vs. 456 days, p < 0.001) or immunotherapy (822 vs. 350 days, p < 0.001) compared to those with TP53 mutation in other loci. RNA sequencing indicated that the immune response-related pathways were downregulated in tumors harboring TP53 R175H mutation. Moreover, the expression of CD8(+) T cells PD-1 were lowered in R175H mutation tumors. In the analysis of TP53 structural domain, compared to those having TP53 mutation in other domain, patients with mutations occurring in the nuclear exporter signal (NES) and E4F1-binding domains had significantly worse overall survival following chemotherapy (NES: 606 vs. 451 days, p = 0.043; E4F1: 606 vs. 469 days, p = 0.046) and immunotherapy (NES: 822 vs. 403 days, p < 0.001; E4F1: 822 vs. 413 days, p < 0.001). In addition, tumors with TP53 mutation and co-existing copy number amplification of CCND1, FGF4, and FGF19 in chromosome 11 conferred worse prognosis than those with only TP53 mutation (p < 0.050).DiscussionEach TP53 mutations indicated differential treatment outcomes following chemotherapy or immunotherapy in patients with metastatic cancer. Functional analysis including RNASeq suggested that TP53 mutation downregulated immune response.ConclusionOverall, we found each TP53 mutation to indicate different prognoses in patients with metastatic tumors undergoing chemotherapy and ICI treatment. Further validations, including a prospective cohort study or a functional study, would be particularly valuable in advancing the knowledge on this aspect and developing improved prognostic parameters.

Project description:Background: Survival of metastatic colorectal cancer (mCRC) patients has improved, but mainly for trial patients. New predictive and prognostic biomarkers validated in the general mCRC population are needed. Caudal-type homeobox 2 (CDX2) is an intestine-specific transcription factor with potential prognostic and predictive effect, but the importance in mCRC has not been fully investigated. Methods: Immunohistochemistry analysis of CDX2 was performed in a Scandinavian population-based cohort of mCRC (n = 796). Frequency, clinical and tumor characteristics, response rate, progression-free survival, and overall survival (OS) were estimated. Results: Loss of CDX2 expression was found in 87 (19%) of 452 stained cases, in 53% if BRAF mutated (BRAFmut) and in 9% if KRAS mutated (KRASmut). CDX2 loss was associated with microsatellite instability, BRAFmut, and poor differentiation and inversely associated with KRASmut. Patients with CDX2 loss received less first-line (53 vs. 64%, p = 0.050) and second-line (23 vs. 39%, p = 0.006) chemotherapy and secondary surgery (1 vs. 9%, p = 0.019). Median progression-free survival and OS for patients given first-line combination chemotherapy was 4 and 10 months if CDX2 loss vs. 9 and 24 months if CDX2 expressed (p = 0.001, p < 0.001). Immediate progression on first-line combination chemotherapy was seen in 35% of patients with CDX2 loss vs. 10% if CDX2 expressed (p = 0.003). Median OS in patients with BRAFmut or KRASmut and CDX2 expressed in tumor (both 21 months) was comparable to wild-type patients (27 months). However, if CDX2 loss, median OS was only 8 and 11 months in BRAFmut and KRASmut cases, respectively, and 10 months in double wild-type patients. In multivariate analysis, CDX2 loss (hazard ratio: 1.50, p = 0.027) and BRAFmut (hazard ratio: 1.62, p = 0.012) were independent poor prognostic markers for OS. Conclusion: In a population-based cohort of mCRC patients, CDX2 loss is an independent poor prognostic marker. Expression of CDX2 defines a new subgroup of BRAFmut cases with a much better prognosis. Loss of CDX2 defines a small group of KRASmut cases with a worse prognosis. Patients with CDX2 loss receive less palliative chemotherapy with less benefit and rarely reach secondary surgery.

Dataset Information

Presence of Concurrent TP53 Mutations Is Necessary to Predict Poor Outcomes within the SMAD4 Mutated Subgroup of Metastatic Colorectal Cancer.

Publications

Presence of Concurrent <i>TP53</i> Mutations Is Necessary to Predict Poor Outcomes within the <i>SMAD4</i> Mutated Subgroup of Metastatic Colorectal Cancer.

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