Multivariate Risk Analysis of RAS, BRAF and EGFR Mutations Allelic Frequency and Coexistence as Colorectal Cancer Predictive Biomarkers

Ionescu, Adriana; Bîlteanu, Liviu; Geicu, Ovidiu Ionuț; Iordache, Florin; Stanca, Loredana; Pisoschi, Aurelia Magdalena; Miron, Adrian; Serban, Andreea Iren; Calu, Valentin

doi:10.3390/cancers14112792

Cited by 3 publications

(2 citation statements)

References 43 publications

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“…EGFR is closely linked to the progression of tumor resistance mechanisms when using anti-cancer medication, accompanied by the marked induction of specific point mutations in EGFR and ALK rearrangements [ 51 ]. Abnormally overactivated EGFR has been found in human CRC samples, and EGFR Mutation may be as CRC predictive biomarkers [ 52 ]. These reference analyses forementioned imply that genistein may treat CRC by modulating ESR1 and EGFR expressions and activities.…”

Section: Discussionmentioning

confidence: 99%

Genistein exerts anti-colorectal cancer actions: clinical reports, computational and validated findings

Liu

Lan

Zhang

et al. 2023

Aging

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Colorectal cancer (CRC) is presently a health challenge in China. Although clinical chemotherapy is prescribed availably, the negative effects and poor prognoses still occur. Genistein has antitumor properties in our previous studies. However, the molecular mechanisms underlying the anti-CRC effects of genistein remain unclear. Increasing evidences have indicated that the induction of autophagy, one of cell death models, is closely associated with the formation and development of human cancer. In the current study, a systematic bioinformatics approach using network pharmacology and molecular docking imitation was aimed at identifying the pharmacological targets and anti-CRC mechanisms of genistein, characterized by autophagy-related processes and pathways. Moreover, experimental validation was conducted by using clinical and cell culture samples. All 48 potential targets of genistein-anti-CRC-associated autophagy were screened accordingly. Further bioinformatics analyses identified 10 core genistein-anti-CRC targets related to autophagy, and enrichment-assayed results revealed that the biological processes of these core targets might regulate multiple molecular pathways, including the estrogen signaling pathway. Additionally, molecular docking data demonstrated that genistein has a high affinity for epidermal growth factor receptor (EGFR) and estrogen receptor 1 (ESR1). Both EGFR and ESR1 proteins were highly expressed in clinical CRC samples. Preliminary in vitro data showed that genistein effectively reduced cellular proliferation, activated apoptosis, and suppressed EGFR and ESR1 protein expressions in CRC cells. Our research findings uncovered the molecular mechanisms of genistein against CRC, and the potential drug targets associated with autophagy in genistein treatment of CRC were identified and validated experimentally, including EGFR and ESR1.

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Section: Discussionmentioning

confidence: 99%

Genistein exerts anti-colorectal cancer actions: clinical reports, computational and validated findings

Liu

Lan

Zhang

et al. 2023

Aging

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“…Interestingly, we observed a significant association between high expression of SFRP1 and intermediate/immature desmoplastic reaction. Immature desmoplastic reaction was proved to be a poor prognostic feature for cancers including esophageal SCC [30][31][32][33], and might be related to the poor survival of SFRP1 high-expression bSCCs. Besides, SFRP1 high expression also had an unfavorable impact on RFS and OS in Cohort1 (supplementary material, Figure S8), although no statistical significance was observed, perhaps due to the limited sample size and variety of the tumor stages.…”

Section: Ihc Validation Of Sfrp1 In Diagnosis and Prognosis Of Esopha...mentioning

confidence: 99%

Integrated molecular characterization of esophageal basaloid squamous cell carcinoma: a subtype with distinct RNA expression pattern and immune characteristics, but no specific genetic mutations

Liu

Pan

et al. 2022

The Journal of Pathology

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Esophageal basaloid squamous cell carcinoma (bSCC) is a subtype of squamous cell carcinoma (SCC) with a different behavior and poor prognosis. Exploring bSCC's molecular characteristics and treatment strategies are of great clinical significance. We performed multi-omics analysis of paired bSCC and common SCC (cSCC) using whole exome sequencing and a NanoString nCounter gene expression panel. Immunohistochemistry was used for verification of candidate biomarkers. Different treatment response was analyzed on both patients receiving neoadjuvant treatment and late-stage patients. The common genetically-clonal origin of bSCC and cSCC was confirmed. No significant differences between their genetic alterations or mutation spectra were observed. Mutation signature 15 (associated with defective DNA damage repair) was less prominent, and tumor mutational burden (TMB) was lower in bSCC. bSCC with an RNA expression pattern resembling cSCC had a better survival than other bSCCs. Moreover, bSCC showed significant upregulation of expression of genes associated with angiogenesis response, basement membranes, and epithelial-mesenchymal transition, and downregulation of KRT14 (squamous differentiation) and CCL21 (associated with immune response). Immunohistochemistry for SFRP1 was shown to be highly sensitive and specific for bSCC diagnosis (p < 0.001). In addition, bSCC receiving neoadjuvant immuno-chemotherapy had a worse pathological response than bSCC receiving neoadjuvant chemotherapy (but without statistical significance), even in bSCC positive for PD-L1. Our results demonstrated the molecular characteristics of esophageal bSCC as a subtype with a distinct RNA expression pattern and immune characteristics, but no specific genetic mutations. We provided a useful biomarker, SFRP1, for diagnosis. After outcome analysis for six bSCCs with neoadjuvant immunotherapy treatment and four late-stage bSCCs with immunotherapy, we found that immunotherapy may not be an effective treatment option for most bSCCs. This may also provide a clue for the same subtypes of lung and head and neck cancer. Our study highlighted the heterogeneity among bSCC patients, and might explain the conflicting results of bSCC outcomes in existing studies.

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Association of various RAS codon mutations and prognostic outcomes of patients with colorectal liver metastases after hepatectomy

Wu,

Liu,

Wang

et al. 2024

Cancer Medicine

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PurposeThe prognostic and predictive value of RAS mutations in patients with colorectal liver metastases (CRLM) who have undergone hepatectomy holds substantial importance. The present study aimed to investigate the impact of different RAS codon mutations on long‐term survival in CRLM patients.MethodsA retrospective analysis was conducted on clinicopathological data from 399 CRLM patients with RAS mutations who underwent hepatectomy between January 2000 and December 2020. The RAS mutation gene status was assessed in KRAS codons (G12, G13, Q61, and A146) and NRAS codons (G12, G13, and Q61). Survival curves were generated using the Kaplan–Meier plotter and compared using the log‐rank test. Univariate and multivariate analyses were performed to analyze the clinicopathological data.ResultsIn the entire cohort, patients with KRAS G12 mutations exhibited the most favorable prognosis (p = 0.018). Comparatively, patients harboring KRAS Q61 mutations experienced poorer overall survival (OS) with a median of 15 months versus 33 months (p = 0.011) when compared to those with KRAS G12 mutations. Moreover, patients with NRAS Q61 mutations also showed decreased OS with a median of 26 months versus 33 months (p = 0.020) in comparison to KRAS G12 mutation patients. The results of multivariate analysis showed that both KRAS Q61 mutation (HR 2.130; 95% CI 1.088–4.168; p = 0.027) and NRAS Q61 mutation (HR 2.877; 95% CI 1.398–5.922; p = 0.004) were independent influencing factors of OS. Based on all identified risk factors, patients with RAS mutation were divided into high‐risk and low‐risk groups. Notably, in the high‐risk group, the incorporation of postoperative chemotherapy was associated with longer OS, while it did not improve the survival of patients in the low‐risk group.ConclusionsKRAS Q61 and NRAS Q61 mutations are promising predictors for OS in CRLM patients after hepatectomy. Postoperative chemotherapy may significantly benefit CRLM patients with RAS mutations, particularly those identified as high‐risk.

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Multivariate Risk Analysis of RAS, BRAF and EGFR Mutations Allelic Frequency and Coexistence as Colorectal Cancer Predictive Biomarkers

Cited by 3 publications

References 43 publications

Genistein exerts anti-colorectal cancer actions: clinical reports, computational and validated findings

Genistein exerts anti-colorectal cancer actions: clinical reports, computational and validated findings

Integrated molecular characterization of esophageal basaloid squamous cell carcinoma: a subtype with distinct RNA expression pattern and immune characteristics, but no specific genetic mutations

Association of various RAS codon mutations and prognostic outcomes of patients with colorectal liver metastases after hepatectomy

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