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Normalized gene expression in mucinous versus non-mucinous colorectal cancer. Dashed horizontal line represents median value a Expression of genes related to 5-FU chemoresistance. b Expression of genes related to oxaliplatin chemoresistance. c Expression of genes related to Irinotecan chemoresistance.
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Previous research has identified differences in mutation frequency in genes implicated in chemotherapy resistance between mucinous and non-mucinous colorectal cancers (CRC). We hypothesized that outcomes in mucinous and non-mucinous CRC may be influenced by expression of genes responsible for chemotherapy resistance. Gene expression data from prima...
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Citations
... It suggests that certain adverse pathological features may not lead to chemotherapy indication, or even be a sign of chemo-resistance instead. For example, previous studies have shown significant differences between mucinous adenocarcinoma and non-mucinous adenocarcinoma in terms of somatic mutation rates and copy number variation (CNV) in genes associated with resistance to 5-FU, oxaliplatin and irinotecan, which may imply a lower chemotherapy benefit in mucinous adenocarcinoma rather than non-mucinous adenocarcinoma [25][26][27]. Apart from the high-risk pathological factors mentioned in the NCCN guidelines, age was another important factor to consider when determining the administration of ACT. Past studies have preferred to use 70 as the age cutoff point, and large-scale analysis have found no survival benefit from adding oxaliplatin to patients above 70 years old [28,29], which is why our study started with 70 as the age cut-off point. ...
Background:
We aimed to analyze the benefit of adjuvant chemotherapy in high-risk stage II colon cancer patients and the impact of high-risk factors on the prognostic effect of adjuvant chemotherapy.
Methods:
This study is a multi-center, retrospective study, A total of 931 patients with stage II colon cancer who underwent curative surgery in 8 tertiary hospitals in China between 2016 and 2017 were enrolled in the study. Cox proportional hazard model was used to assess the risk factors of disease-free survival (DFS) and overall survival (OS) and to test the multiplicative interaction of pathological factors and adjuvant chemotherapy (ACT). The additive interaction was presented using the relative excess risk due to interaction (RERI). The Subpopulation Treatment Effect Pattern Plot (STEPP) was utilized to assess the interaction of continuous variables on the ACT effect.
Results:
A total of 931 stage II colon cancer patients were enrolled in this study, the median age was 63 years old (interquartile range: 54-72 years) and 565 (60.7%) patients were male. Younger patients (median age, 58 years vs 65 years; P < 0.001) and patients with the following high-risk features, such as T4 tumors (30.8% vs 7.8%; P < 0.001), grade 3 lesions (36.0% vs 22.7%; P < 0.001), lymphovascular invasion (22.1% vs 6.8%; P < 0.001) and perineural invasion (19.4% vs 13.6%; P = 0.031) were more likely to receive ACT. Patients with perineural invasion showed a worse OS and marginally worse DFS (hazardous ratio [HR] 2.166, 95% confidence interval [CI] 1.282-3.660, P = 0.004; HR 1.583, 95% CI 0.985-2.545, P = 0.058, respectively). Computing the interaction on a multiplicative and additive scale revealed that there was a significant interaction between PNI and ACT in terms of DFS (HR for multiplicative interaction 0.196, p = 0.038; RERI, -1.996; 95%CI, -3.600 to -0.392) and OS (HR for multiplicative interaction 0.112, p = 0.042; RERI, -2.842; 95%CI, -4.959 to -0.725).
Conclusions:
Perineural invasion had prognostic value, and it could also influence the effect of ACT after curative surgery. However, other high-risk features showed no implication of efficacy for ACT in our study.
Trial registration:
This study is registered on ClinicalTrials.gov, NCT03794193 (04/01/2019).
... Predictive value of mucinous histology remains controversial. Several studies emphasized that mucinous and non-mucinous CRCs show differential expression of CT metabolism and resistance genes (25,26). Furthermore, Cantero-Recasens et al (27) suggested that controlling mucin secretion may reverse chemo-refraction in CRC cells. ...
Mucinous colorectal adenocarcinoma (MCAC) is a distinct subtype of colorectal carcinoma (CRC). The prognostic and predictive significance of mucinous histology remains controversial. It was aimed to investigate the prognostic and/or predictive role of mucinous histology in left-sided metastatic CRC (mCRC) with wild-type RAS. This is a retrospective multicenter study of mCRC treated with first line anti-EGFR combined 5-fluorouracil based chemotherapy (CT). Patients were stratified according to presence (>50% extracellular mucin) or absence of mucinous histology. Survival analyses were performed firstly regardless of treatment options and then performed as separating according to CT regimens. Additional analyses were performed for MCAC patients considering backbone CT regimens. A total of 125 patients were included, consisting of 40 (32.0%) patients with MCAC and 85 (68.0%) patients with non-MCAC. Median follow-up time was 19.7 months. Median progression-free survival (PFS) was 10.7 months in all patients, and PFS was lower in MCAC than non-MCAC (9.9 vs. 12.0 months, respectively, P=0.005). Median overall survival (OS) was 25.7 months in all patients. OS was lower in MCAC than non-MCAC (22.8 vs. 29.7 months, respectively, P=0.005). When considering backbone CT regimens, in multivariate analyses, mucinous histology was an independent prognostic factor for OS in both for mFOLFOX6 (HR: 1.92, P=0.04) and FOLFIRI (HR: 2.04, P=0.04) groups and was associated with poor PFS in only mFOLFOX6 (HR: 3.86, P<0.001) group. When outcomes were analyzed for the MCAC group, median OS of MCAC patients receiving mFOLFOX6 and FOLFIRI was 22.47 and 14.22 months, respectively (P=0.41). Median PFS of MCAC patients receiving mFOLFOX6 and FOLFIRI was 10.15 and 8.11 months, respectively (P=0.73). The study revealed poor prognosis of mucinous histology, both in whole study population and in backbone CT groups. Moreover, lower PFS of MCAC patients was revealed in only mFOLFOX6 group and this finding may be a valuable issue for the future research. However, considering all analyses, the present results did not indicate a special benefit of any backbone CT regimen for MCAC patients.
... For CRC, it has been proposed that differences in gene expression and metabolism between colorectal adenocarcinoma with and without extracellular mucin may explain the chemotherapy resistance in adenocarcinoma with extracellular mucin [22,23]. Another study suggested that specific mucins may play a role in the ability of tumour cells to escape the effect of systemic therapy [2]. ...
Background
Adenocarcinoma with more than 50% extracellular mucin is a relatively rare histological subtype of gastrointestinal adenocarcinomas. The clinical impact of extracellular mucin in oesophageal adenocarcinoma (OeAC) has not been investigated in detail. We hypothesised that patients with mucinous OeAC (OeACmucin) do not benefit from neoadjuvant chemotherapy.
Methods
OeAC patients either treated by surgery alone in the OE02 trial (S-patients) or by neoadjuvant chemotherapy followed by surgery (CS-patients) in OE02 or OE05 trials were included. Cancers from 1055 resection specimens (OE02 [test cohort]: 187 CS, 185 S; OE05 [validation cohort]: 683 CS) were classified as either mucinous (more than 50% of the tumour area consists of extracellular mucin, OeACmucin) or non-mucinous adenocarcinoma (OeACnon-mucin). The relationship between histological phenotype, clinicopathological characteristics, survival and treatment was analysed.
Results
Overall, 7.3% and 9.6% OeAC were classified as OeACmucin in OE02 and OE05, respectively. In OE02, the frequency of OeACmucin was similar in S and CS-patients. Patients with OeACmucin treated with surgery alone had a poorer overall survival compared with OeACnon-mucin patients (hazard ratio: 2.222, 95% confidence interval: 1.08–4.56, P = 0.025). Patients with OeACmucin treated with neoadjuvant chemotherapy and surgery had similar survival as OeACnon-mucin patients in test and validation cohort.
Conclusions
This is the first study to suggest in a post-hoc analysis of material from two independent phase III clinical trials that the poor survival of patients with mucinous OeAC can be improved by neoadjuvant chemotherapy. Future studies are warranted to identify potential underlying biological, biochemical or pharmacokinetic interactions between extracellular mucin and chemotherapy.
... Oncogenesis is driven by a host of deregulated signalling pathways that allow cells move through various processes to acquire additional oncogenic properties [2]. Though all cancers may display similar characteristics, molecular differences within specific cancer subtypes are frequently observed, and can have a profound impact on disease progression, treatment response and survival [3,4]. Apart from molecular differences, differences in tumour structure and environment are also important. ...
... Thirteen studies explored the role of SRPK1 in colorectal cancer [3,25,[27][28][29][30][55][56][57][58][59][60][61]. SRPK1 expression was generally found to be elevated in colorectal cancer, with the exception of the mucinous subtype [3, 25, 27-30, 60, 61] ( Table 1). ...
... Plascencia et al., also previously provided evidence linking SRPK1 expression to oxaliplatin resistance in colorectal cancer [59]. Interestingly, interrogation of the cancer genome atlas (TCGA), found SRPK1 expression to be significantly lower in mucinous colon tumours compared to non-mucinous, with reduced expression correlating with reduced survival [3,60]. This is potentially pertinent given the poor response of this distinct molecular subtype to standard adjuvant treatment regimens [66] Endometrial cancer Using multiplexed inhibitory beads and mass spectrometry, the kinome profile of primary endometrial tumours was analysed in detail. ...
Alternative splicing is implicated in each of the hallmarks of cancer, and is mechanised by various splicing factors. Serine-Arginine Protein Kinase 1 (SRPK1) is an enzyme which moderates the activity of splicing factors rich in serine/arginine domains. Here we review SRPK1’s relationship with various cancers by performing a systematic review of all relevant published data. Elevated SRPK1 expression correlates with advanced disease stage and poor survival in many epithelial derived cancers. Numerous pre-clinical studies investigating a host of different tumour types; have found increased SRPK1 expression to be associated with proliferation, invasion, migration and apoptosis in vitro as well as tumour growth, tumourigenicity and metastasis in vivo. Aberrant SRPK1 expression is implicated in various signalling pathways associated with oncogenesis, a number of which, such as the PI3K/AKT, NF-КB and TGF-Beta pathway, are implicated in multiple different cancers. SRPK1-targeting micro RNAs have been identified in a number of studies and shown to have an important role in regulating SRPK1 activity. SRPK1 expression is also closely related to the response of various tumours to platinum-based chemotherapeutic agents. Future clinical applications will likely focus on the role of SRPK1 as a biomarker of treatment resistance and the potential role of its inhibition.
... For CRC, it has been proposed that differences in gene expression and metabolism between colorectal adenocarcinoma with and without extracellular mucin may explain the chemotherapy resistance in adenocarcinoma with extracellular mucin [22,23]. Another study suggested that specific mucins may play a role in the ability of tumour cells to escape the effect of systemic therapy [2]. ...
Although rectal mucinous adenocarcinoma (RMC) is less sensitive to radiotherapy, adjuvant radiotherapy is still recommended for RMC patients. This study aimed to explore whether adjuvant radiotherapy is necessary for stage III RMC.
Data of patients with stage III RMC were obtained from the National Cancer Institute’s SEER database (2004–2015). The survival rates were calculated by Kaplan–Meier method and compared by log-rank test. Univariate and multivariate Cox regression analyses were used to assess the impact of clinicopathological parameters on overall survival (OS) and cancer-specific survival (CSS).
RMC has a worse T and N stage at diagnosis than rectal adenomatous carcinoma (RAC) (all p < 0.001). Multivariate Cox regression analyses revealed that histopathological type MC was an independent poor prognostic factor for OS (HR 1.27; 95%CI 1.14–1.41; p < 0.001) and CSS (HR 1.34; 95%CI 1.18–1.51; p < 0.001). Subgroup analysis based on different treatment regimens showed no significant difference between chemotherapy group and chemotherapy plus radiotherapy group. After the propensity score matching, no significant difference was also found in OS and CSS between chemotherapy group and chemotherapy plus radiotherapy group.
RMC is an independent poor prognostic factor for OS and CSS. Adjuvant radiotherapy for RMC was not beneficial in improving survival outcomes.
Purpose:
Postoperative adjuvant chemotherapy followed surgery is the standard management for localized advanced colorectal carcinoma (CRC). Mucinous adenocarcinoma (MAC) is a peculiar histological subtype of CRC, but the prognosis of MAC patients is controversial. The objective of this study is to assess the implication of MAC in survival of patients treated with surgery and firs-line adjuvant chemotherapy.
Methods:
Studies describing outcomes for advanced MAC and non-specific adenocarcinoma (AC) of CRC patients treated with first-line postoperative adjuvant chemotherapy followed surgery were searched in PubMed, Embase, Medline, EBSCO, Wiley, and Cochrane Library (January 1963-August 2021). Hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS) and cancer-specific survival (CSS) for MAC to AC were extracted. Random-effects model was used for calculating the pooled HRs and 95% confidence interval (CI).
Results:
This meta-analysis is comprised of 8 studies involving a total of 124,303 CRC patients treated with first-line adjuvant chemotherapy followed surgery. The pooled HR for MAC was 1.23 (95% CI, 1.07-1.41, p < 0.01, I2 = 80%), and the DFS (HR, 2.95, 95% CI, 1.22-7.14) of MAC patients were significantly poorer than AC patients. Similar results were also observed in stage III and FOLFOX regimen subgroups.
Conclusion:
MAC was a risk factor for prognosis of localized advanced CRC patients treated with postoperative first-line adjuvant chemotherapy. Thus, the role of first-line adjuvant chemotherapy regimens should be further studied in these MAC patients.
