Prognostic Value of KRAS Mutations in Colorectal Cancer Patients

Koulouridi, Asimina; Karagianni, Michaela; Messaritakis, Ippokratis; Sfakianaki, Maria; Voutsina, Alexandra; Trypaki, Maria; Bachlitzanaki, Maria; Koustas, Evangelos; Karamouzis, Michalis V.; Ntavatzikos, Anastasios; Koumarianou, Anna; Androulakis, Nikolaos; Mavroudis, Dimitriοs; Tzardi, Maria; Souglakos, John

doi:10.3390/cancers14143320

Cited by 27 publications

(22 citation statements)

References 32 publications

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“…However, the prognostic value of KRAS remains controversial. While some studies showed no prognostic role of KRAS mutations, others demonstrated an association with shorter disease-free survival (DSF) and overall survival (OS) and with liver metastases [ 12 ]. The rate of NRAS mutations , which are also well-established drivers of resistance to anti-EGFR therapy, was comparable between ASCs and conventional CRCs.…”

Section: Discussionmentioning

confidence: 99%

Colorectal adenosquamous carcinoma: genomic profiling of a rare histotype of colorectal cancer

et al. 2023

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Colorectal adenosquamous carcinoma (ASC) is exceedingly rare, comprising less than 0.1% of all colorectal malignancies, and is characterized by an aggressive disease course, with a higher metastatic rate and worse outcome than conventional colorectal adenocarcinoma. A comprehensive molecular profile of this group of neoplasms is still lacking. A total of 22 cases of colorectal ASCs (with 22 primary lesions and 7 metastases matched with 4 primaries) were subject to NGS targeting 67 cancer-related genes (VariantPlex solid tumor; Archer). Mismatch repair (MMR), p53, and V600EBRAF status were also investigated by immunohistochemistry. In 28 of 29 (96.6%) ASC samples, at least one single-nucleotide variant (SNV) or copy number variation (CNV) was detected. Among the 22 primary tumors, the most frequently mutated genes were TP53 (59.1%), APC (40.9%), KRAS (27.3%), BRAF (13.6%), and GNAS (9.1%). Only 1/22 (4.5%) primary ASC was MMR-deficient (MMRd) and harbored a BRAF mutation. Limited differences in SNVs were observed between primary and metastatic diseases. This study sheds light on the molecular landscape of colorectal ASCs. According to our data, the genomic profile of colorectal ASC is similar to that of conventional colorectal carcinoma, with significant druggable genetic alterations. Further studies are required to understand the more aggressive clinical behavior of this neoplasm.

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Section: Discussionmentioning

confidence: 99%

Colorectal adenosquamous carcinoma: genomic profiling of a rare histotype of colorectal cancer

et al. 2023

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“…Moreover, microsatellite instability (MSI) status was also evaluated. All materials and conditions for each gene target involved in the current study have already been described previously by our group [ 25 , 26 , 27 , 28 ].…”

Section: Methodsmentioning

confidence: 99%

Investigation of Microbial Translocation, TLR and VDR Gene Polymorphisms, and Recurrence Risk in Stage III Colorectal Cancer Patients

Messaritakis

Koulouridi

Boukla

et al. 2022

Cancers

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Gut microbial dysbiosis and microbial passage into the peripheral blood leads to colorectal cancer (CRC) and disease progression. Toll-like (TLR) and vitamin D (VDR) receptors play important role in the immune modulation and polymorphisms that may increase CRC risk and death rates. The aim of the current study was to demonstrate the prognostic value of microbial DNA fragments in the blood of stage III CRC patients and correlate such microbial detection to TLR/VDR polymorphisms. Peripheral blood was collected from 132 patients for the detection of microbial DNA fragments, and TLR/VDR gene polymorphisms. In the detection of various microbial DNA fragments, TLR and VDR polymorphisms was significantly higher compared to healthy group. Homozygous individuals of either TLR or VDR polymorphisms had significantly higher detection rates of microbial DNA fragments. Mutational and MSI status were significantly correlated with TLR9 and VDR polymorphisms. Significantly shorter disease-free survival was associated with patients with BRAF mutated tumors and ApaI polymorphisms, whereas shorter overall survival was associated with the detection of C. albicans. The detection of B. fragilis, as demonstrated by the multivariate analysis, is an independent poor prognostic factor for shorter disease-free survival. TLR/VDR genetic variants were significantly correlated with the detection of microbial fragments in the blood, and this in turn is significantly associated with tumorigenesis and disease progression.

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“…However, the oncogenic role of KLK10 in CRC remains largely unknown, especially in CRC with KRAS mutation. Therefore, we investigated KLK10 in CRC cell line SNU1033, which harbors G12D mutation, the most common KRAS mutation in CRC (Koulouridi et al, 2022). To understand the functional impact of KLK10, we respectively established stable SNU1033 cell lines with KLK10 overexpression (Lv-KLK10) and knockdown (sh-KLK10) (Figure 2a,b).…”

Section: Kras Mutation Is Associated With Klk10 Overexpressionmentioning

confidence: 99%

“…KRAS targeted therapy could be an alternative for KRAS mutant CRC. However, up to now, the only Food and Drug Administration‐approved KRAS inhibitor, sotorasib, is used for treating lung cancers with KRAS‐G12C mutation, while the dominant KRAS mutations in CRC are G12D, G12V, and G13D (Koulouridi et al, 2022). Moreover, the benefits of KRAS inhibitors are often short‐lived due to rapidly acquired resistance (Akhave et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

KLK10 promotes the progression of KRAS mutant colorectal cancer via PAR1‐PDK1‐AKT signaling pathway

Wu,

Yan

et al. 2023

Cell Biology International

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Kirsten rat sarcoma virus (KRAS) gene mutation is common in colorectal cancer (CRC) and is often predictive of treatment failure and poor prognosis. To understand the mechanism, we compared the transcriptome of CRC patients with wild‐type and mutant KRAS and found that KRAS mutation is associated with the overexpression of a secreted serine protease, kallikrein‐related peptidase 10 (KLK10). Moreover, using in vitro and in vivo models, we found that KLK10 overexpression favors the rapid growth and liver metastasis of KRAS mutant CRC and can also impair the efficacy of KRAS inhibitors, leading to drug resistance and poor survival. Further functional assays revealed that the oncogenic role of KLK10 is mediated by protease‐activated receptor 1 (PAR1). KLK10 cleaves and activates PAR1, which further activates 3‐phosphoinositide‐dependent kinase 1 (PDK1)‐AKT oncogenic pathway. Notably, suppressing PAR1‐PDK1‐AKT cascade via KLK10 knockdown can effectively inhibit CRC progression and improve the sensitivity to KRAS inhibitor, providing a promising therapeutic strategy. Taken together, our study showed that KLK10 promotes the progression of KRAS mutant CRC via activating PAR1‐PDK1‐AKT signaling pathway. These findings expanded our knowledge of CRC development, especially in the setting of KRAS mutation, and also provided novel targets for clinical intervention.

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Prognostic Value of KRAS Mutations in Colorectal Cancer Patients

Cited by 27 publications

References 32 publications

Colorectal adenosquamous carcinoma: genomic profiling of a rare histotype of colorectal cancer

Colorectal adenosquamous carcinoma: genomic profiling of a rare histotype of colorectal cancer

Investigation of Microbial Translocation, TLR and VDR Gene Polymorphisms, and Recurrence Risk in Stage III Colorectal Cancer Patients

KLK10 promotes the progression of KRAS mutant colorectal cancer via PAR1‐PDK1‐AKT signaling pathway

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