Prognostic and predictive role of DNA mismatch repair status in stage II‐III colorectal cancer: A systematic review and meta‐analysis

Deng, Zifeng; Qin, Yun; Wang, Jing; Wang, Gang; Lang, Xiaoqiang; Juan, José; Ke, Xie; Zhang, Wengeng; Xu, Hong‐Xi; Shu, Yang; Zhang, Yan

doi:10.1111/cge.13628

Cited by 19 publications

(10 citation statements)

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“… 33 This finding has implications for daily clinical practice in relation to three important issues: prognosis, treatment and surveillance. In (early stage) colorectal cancer, MMR deficiency has been linked to a better prognosis, 25 34 35 an association that may also hold true for MMR-deficient small bowel cancers. Indeed, the aforementioned study by Aparicio et al reported a trend towards better prognosis for Lynch-associated small bowel adenocarcinomas versus those related to Crohn’s disease.…”

Section: Discussionmentioning

confidence: 97%

“…Of particular note, the prevalence of MMR deficiency in our study differed considerably between the resected and biopsied specimens. A higher prevalence of MMR deficiency in resected versus biopsied samples might be related to the association of MMR deficiency with a better prognosis in other cancers, 25 so resections may represent patients with cancer with a relatively good prognosis, whereas biopsies may represent patients with a poor prognosis who are less likely to undergo resection. Interestingly, the prevalence of MMR deficiency identified in biopsied samples, 4.4%, is close to the 5.0% prevalence identified in a metastatic colorectal cancer cohort.…”

Section: Discussionmentioning

confidence: 99%

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Prevalence of mismatch repair deficiency and Lynch syndrome in a cohort of unselected small bowel adenocarcinomas

et al. 2020

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AimsPrevious estimates of the prevalence of mismatch repair (MMR) deficiency and Lynch syndrome in small bowel cancer have varied widely. The aim of this study was to establish the prevalence of MMR deficiency and Lynch syndrome in a large group of small bowel adenocarcinomas.MethodsTo this end, a total of 400 small bowel adenocarcinomas (332 resections, 68 biopsies) were collected through the Dutch nationwide registry of histopathology and cytopathology (Pathologisch-Anatomisch Landelijk Geautomatiseerd Archief (PALGA)). No preselection criteria, such as family history, were applied, thus avoiding (ascertainment) bias. MMR deficiency status was determined by immunohistochemical staining of MMR proteins, supplemented by MLH1 promoter hypermethylation analysis and next generation sequencing of the MMR genes.ResultsMMR deficiency was observed in 22.3% of resected and 4.4% of biopsied small bowel carcinomas. Prevalence of Lynch syndrome was 6.2% in resections and 0.0% in biopsy samples. Patients with Lynch syndrome-associated small bowel cancer were significantly younger at the time of diagnosis than patients with MMR-proficient and sporadic MMR-deficient cancers (mean age of 54.6 years vs 66.6 years and 68.8 years, respectively, p<0.000).ConclusionsThe prevalence of MMR deficiency and Lynch syndrome in resected small bowel adenocarcinomas is at least comparable to prevalence in colorectal cancers, a finding relevant both for treatment (immunotherapy) and family management. We recommend that all small bowel adenocarcinomas should be screened for MMR deficiency.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Prevalence of mismatch repair deficiency and Lynch syndrome in a cohort of unselected small bowel adenocarcinomas

et al. 2020

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“…Higher MRS was found in patients in cluster-B, and in those with advanced TNM stages, the C4C6 subtype, proximal colon cancer, and pMMR status (all P values < 0.05, Fig. 5 b–i), which have been previously confirmed to have a poor prognosis [ 18 , 31 , 32 ]. No significant difference in MRS were found for BRAF status, KRAS status, TP53 status, sex, CIN status, or CIMP status (Additional file 12 : Figure S5a–f).…”

Section: Resultsmentioning

confidence: 67%

Molecular subtype identification and prognosis stratification by a metabolism-related gene expression signature in colorectal cancer

et al. 2021

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Background Metabolic reprograming have been associated with cancer occurrence and progression within the tumor immune microenvironment. However, the prognostic potential of metabolism-related genes in colorectal cancer (CRC) has not been comprehensively studied. Here, we investigated metabolic transcript-related CRC subtypes and relevant immune landscapes, and developed a metabolic risk score (MRS) for survival prediction. Methods Metabolism-related genes were collected from the Molecular Signatures Database and metabolic subtypes were identified using an unsupervised clustering algorithm based on the expression profiles of survival-related metabolic genes in GSE39582. The ssGSEA and ESTIMATE methods were applied to estimate the immune infiltration among subtypes. The MRS model was developed using LASSO Cox regression in the GSE39582 dataset and independently validated in the TCGA CRC and GSE17537 datasets. Results We identified two metabolism-related subtypes (cluster-A and cluster-B) of CRC based on the expression profiles of 539 survival-related metabolic genes with distinct immune profiles and notably different prognoses. The cluster-B subtype had a shorter OS and RFS than the cluster-A subtype. Eighteen metabolism-related genes that were mostly involved in lipid metabolism pathways were used to build the MRS in GSE39582. Patients with higher MRS had worse prognosis than those with lower MRS (HR 3.45, P < 0.001). The prognostic role of MRS was validated in the TCGA CRC (HR 2.12, P = 0.00017) and GSE17537 datasets (HR 2.67, P = 0.039). Time-dependent receiver operating characteristic curve and stratified analyses revealed the robust predictive ability of the MRS in each dataset. Multivariate Cox regression analysis indicted that the MRS could predict OS independent of TNM stage and age. Conclusions Our study provides novel insight into metabolic heterogeneity and its relationship with immune landscape in CRC. The MRS was identified as a robust prognostic marker and may facilitate individualized therapy for CRC patients.

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“…Overall, 153 patients received adjuvant chemotherapy with mFOLOFX6 after surgery, which consisted of 6-month therapy (27.3%, n = 66; median cycles [range] = 12 [9][10][11][12]) or 3-month therapy (36.0%, n = 87; median cycles [range] = 6 [4][5][6][7]), and 89 patients (36.7%) were treated with surgery alone. Baseline patients and tumor characteristics between treatment durations were presented in Table 1.…”

Section: Patient Characteristicsmentioning

confidence: 99%

“…MSI is a consequence of a deficient mismatch repair (dMMR) system that results in error accumulation within microsatellite region, and it occurs in approximately 15% of all colorectal cancers (10). Several studies have shown that dMMR non-metastatic CC patients were associated with a more favorable stage-adjusted prognosis compared to patients with proficient mismatch repair (pMMR) (11)(12)(13)(14). Whether a shorter duration of adjuvant therapy for patients with dMMR would lead to any decrease in efficacy is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Duration of FOLFOX Adjuvant Chemotherapy in High-Risk Stage II and Stage III Colon Cancer With Deficient Mismatch Repair

Wang

et al. 2020

Front. Oncol.

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BackgroundWe evaluated the impact of 3 months of mFOLFOX6 adjuvant chemotherapy or surgery alone in comparison with 6 months of mFOLFOX6 on disease-free survival (DFS) in deficient mismatch repair (dMMR) colon cancer (CC) patients.MethodsThis retrospective study identified a cohort of patients with high-risk stage II and III dMMR CC who underwent curative surgery between May 2011 and July 2019. DFS was compared using the Kaplan-Meier survival methods and Cox proportional hazards models. Propensity-score matching was performed to reduce imbalance in baseline characteristics.ResultsA total of 242 dMMR CC patients were identified; 66 patients received 6 months of mFOLFOX6, 87 patients received 3 months of mFOLFOX6, and 89 patients were treated with surgery alone. The 3-year DFS rate was 72.8% in 3-month therapy group and 86.1% in 6-month therapy group, with a hazard ratio (HR) of 2.78 (95CI%, 1.18 to 6.47; P= 0.019). The difference in DFS between surgery alone group and 6-month therapy group was also observed but was nonsignificant (HR= 2.30, 95%CI, 0.99 to 5.38; P=0.054). The benefit of 6-month therapy in DFS compared with 3-month therapy group was pronounced for patients with stage III (HR=2.81, 95%CI, 1.03 to 7.67; P=0.044) but not for high-risk stage II patients. Propensity score matched analysis confirmed a DFS benefit in the 6-month therapy group.ConclusionThis study suggested that a 6-month duration of mFOLFOX6 adjuvant chemotherapy in dMMR CC patients may be associated with improved DFS compared with 3-month therapy, particularly in patients with stage III. The observational nature of the study implies caution should be taken in the interpretation of these results.

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Prognostic and predictive role of DNA mismatch repair status in stage II‐III colorectal cancer: A systematic review and meta‐analysis

Cited by 19 publications

References 83 publications

Prevalence of mismatch repair deficiency and Lynch syndrome in a cohort of unselected small bowel adenocarcinomas

Prevalence of mismatch repair deficiency and Lynch syndrome in a cohort of unselected small bowel adenocarcinomas

Molecular subtype identification and prognosis stratification by a metabolism-related gene expression signature in colorectal cancer

Duration of FOLFOX Adjuvant Chemotherapy in High-Risk Stage II and Stage III Colon Cancer With Deficient Mismatch Repair

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