• companion diagnostics
• effectiveness
• molecular diagnosis
• regulatory
• safety

• RS-2024-00331775 Ministry of Food and Drug Safety

Colorectal cancer (CRC) is the third most prevalent cancer in both men and women, and it is the second leading cause of cancer-related deaths globally. Around 60%-70% of CRC patients are diagnosed at advanced stages, with nearly 20% having liver metastases. It is noteworthy that the 5-year survival rates decline significantly from 80%-90% for localized disease to a mere 10%-15% for patients with metastasis at the time of diagnosis. Early diagnosis, appropriate therapeutic strategy, accurate assessment of treatment response, and prognostication is essential for better outcome. There has been significant technological development in the last couple of decades to improve the outcome of rectal cancer including Artificial intelligence (AI). AI is a broad term used to describe the study of machines that mimic human intelligence, such as perceiving the environment, drawing logical conclusions from observations, and performing complex tasks. At present AI has demonstrated a promising role in early diagnosis, prognosis, and treatment outcomes for patients with rectal cancer, a limited role in surgical decision making, and had a bright future.

• Rectal cancer
• Artificial intelligence
• Role in treatment
• Current status
• Future implications

• CRC
• Colorectal cancer
• Detection method
• Epigenetic profiling
• Genetic profiling

• Humans
• Biosensing Techniques
• Biomarkers
• Cell-Free Nucleic Acids
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• Epigenesis, Genetic/genetics

• CT
• Colorectal cancer
• KRAS mutation
• Radiomics
• Triphasic enhanced phase

• Humans
• Proto-Oncogene Proteins p21(ras)/genetics
• Tomography, X-Ray Computed/methods
• ROC Curve
• Mutation
• Colorectal Neoplasms/diagnostic imaging
• Colorectal Neoplasms/genetics
• Retrospective Studies

• (82260346) National Natural Science Foundation of China
• 2023-ZJ-918M Qinghai Provincial Department of science and technology of China

• X-ray computed
• diagnosis
• differential
• myocardial ischemia
• radiomics

• Colorectal Neoplasms
• KRAS
• Radiomics
• Radiomics Quality Scoring

• Humans
• Positron Emission Tomography Computed Tomography
• Proto-Oncogene Proteins p21(ras)/genetics
• Tomography, X-Ray Computed/methods
• Colorectal Neoplasms/diagnostic imaging
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Mutation
• Multicenter Studies as Topic

• Colorectal Neoplasms/diagnostic imaging
• Colorectal Neoplasms/genetics
• Humans
• Mutation
• Nomograms
• Proto-Oncogene Proteins p21(ras)/genetics
• Retrospective Studies
• Tomography, X-Ray Computed/methods

KRAS mutations, present in over 40% of metastatic colorectal cancer (mCRC), are negative predictive factors for anti-EGFR therapy. Mutations in KRAS-G12C have a cysteine residue for which drugs have been developed. Published data on this specific mutation are conflicting; thus, we studied the frequency and clinical characteristics in a real-world and population-based setting.

Patients from three Nordic population-based cohorts and the real-life RAXO-study were combined. RAS and BRAF tests were performed in routine healthcare, except for one cohort. The dataset consisted of 2,559 patients, of which 1,871 could be accurately classified as KRAS, NRAS, and BRAF-V600E. Demographics, treatments, and outcomes were compared using logistic regression. Overall survival (OS) was estimated with Kaplan–Meier, and differences were compared using Cox regression, adjusted for baseline factors.

The KRAS-G12C frequency was 2%–4% of all tested in the seven cohorts (mean 3%) and 4%–8% of KRAS mutated tumors in the cohorts (mean 7%). Metastasectomies and ablations were performed more often (38% vs. 28%, p = 0.040), and bevacizumab was added more often (any line 74% vs. 59%, p = 0.007) for patients with KRAS-G12C- vs. other KRAS-mutated tumors, whereas chemotherapy was given to similar proportions. OS did not differ according to KRAS mutation, neither overall (adjusted hazard ratio (HR) 1.03; 95% CI 0.74–1.42, reference KRAS-G12C) nor within treatment groups defined as “systemic chemotherapy, alone or with biologics”, “metastasectomy and/or ablations”, or “best supportive care”, RAS and BRAF wild-type tumors (n = 548) differed similarly to KRAS-G12C, as to other KRAS- or NRAS-mutated (n = 66) tumors.

In these real-life and population-based cohorts, there were no significant differences in patient characteristics and outcomes between patients with KRAS-G12C tumors and those with other KRAS mutations. This contrasts with the results of most previous studies claiming differences in many aspects, often with worse outcomes for those with a KRAS-G12C mutation, although not consistent. When specific drugs are developed, as for this mutation, differences in outcome will hopefully emerge.

• KRAS mutation
• KRAS-G12C mutation
• colorectal cancer
• metastatic
• population-based
• real-world

• Colorectal cancer
• KRAS
• Mutation
• Therapy

Accurate and rapid diagnosis is essential for correct treatment in rectal cancer. Determining the optimal treatment plan for a patient with rectal cancer is a complex process, and the oncological results and toxicity are not the same in every patient with the same treatment at the same stage. In recent years, the increasing interest in artificial intelligence in all fields of science has also led to the development of innovative tools in oncology. Artificial intelligence studies have increased in many steps from diagnosis to follow-up in rectal cancer. It is thought that artificial intelligence will provide convenience in many ways from personalized treatment to reducing the workload of the physician. Prediction algorithms can be standardized by sharing data between centers, diversifying data, and creating big data.

• Rectal cancer
• Artificial intelligence
• Deep learning
• Machine learning

• Bisulfite conversion
• CpG islands
• DNA methylation
• Digital PCR
• Epigenetics
• Locus specific analyses
• Target region

• Magnetic resonance imaging
• Mutation
• Radiomics
• Rectal neoplasms

KRAS and BRAF mutations are prognostic and predictive tools in metastatic colorectal cancer, but little is known about their prognostic value in patients scheduled for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Therefore, we analyzed the prognostic impact of KRAS and BRAF mutations in patients with peritoneal metastases scheduled for CRS and HIPEC.

In a consecutive series of 399 patients scheduled for CRS and HIPEC between 2009 and 2017, 111 subjects with peritoneal metastases from primaries of the appendix, colon, or rectum were analyzed for KRAS mutation and 92 for BRAF mutation.

Mutation in KRAS was present in 51/111 (46%), and mutated BRAF was found in 10/92 (11%). There was no difference in overall survival between KRAS mutation tumors and KRAS wild type, whereas BRAF mutation was associated with short survival. No subject with BRAF mutation survived 2 years. On multivariate analysis, completeness of cytoreduction score (CCS, p = 0.000001), presence of signet cell differentiation (p = 0.000001), and BRAF mutation (p = 0.0021) were linked with poor prognosis.

BRAF mutation is a marker of poor prognosis in patients with appendiceal and colorectal peritoneal metastases scheduled for CRS and HIPEC, whereas survival outcome in subjects with mutated KRAS does not differ from wild-type KRAS. This finding suggests that those with BRAF mutation should be considered for alternative treatment options.

• Colorectal cancer
• KRAS mutations
• overall survival
• prognosis
• progression free survival

The RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase (MAPK) signaling pathways, Mutations in any one of the upstream genes (such as the RAS gene or the BRAF gene) may be transmitted to the protein through transcription or translation, resulting in abnormal activation of the signaling pathway. This study investigated the relationship between the KRAS gene mutation and the clinicopathological features and prognosis of colorectal cancer (CRC), and the effect of KRAS mutations on its associated proteins in CRC, with an aim to clarify the cause of tumor progression and drug resistance caused by mutation of the KRAS gene.

To investigate the KRAS gene and RAS pathway signaling molecules in CRC and to analyze their relationship with clinicopathological features and prognosis

Colorectal cancer tissue specimens from 196 patients were analyzed for KRAS mutations using quantitative polymerase chain reaction and for KRAS, BRAF, MEK, and ERK protein expression levels using immunohistochemistry of tumor microarrays. To analyze differences of RAS pathway signaling molecule expression levels in different KRAS gene status, the relationships between these parameters and clinicopathological features, 4-year progression-free survival, and overall survival were analyzed by independent sample t test, Kaplan-Meier plots, and the log-rank test. Predictors of overall and disease-free survival were assessed using a Cox proportional hazards model.

Of the 196 patients, 62 (32%) carried mutations in codon 12 (53/62) or codon 13 (9/62) in exon 2 of the KRAS gene. KRAS, BRAF, ERK, and MEK protein expression was detected in 71.4%, 78.8%, 64.3%, and 50.8% of CRC tissues, respectively. There were no significant differences between KRAS mutation status and KRAS, BRAF, MEK, or ERK protein levels. Positive expression of KRAS and ERK was associated with poor tumor differentiation, and KRAS expression was also associated with age < 56 years. MEK expression was significantly associated with distant metastasis (P < 0.05). The 4-year progression-free survival rate, but not overall survival rate, was significantly higher in patients with KRAS-negative tumors than in those with KRAS-positive tumors (P < 0.05), whereas BRAF, MEK, and ERK expression was unrelated to survival. Multivariate analysis showed that only the expression of KRAS protein was a risk factor for tumor recurrence (P < 0.05). No other clinicopathological factors correlated with KRAS, BRAF, MEK, or ERK expression.

KRAS gene mutations do not affect downstream protein expression in CRC. KRAS protein is associated with poor tumor differentiation, older age, and a risk of tumor recurrence.

• Colorectal cancer
• KRAS gene
• KRAS protein
• BRAF protein
• MEK protein
• ERK protein

• Adult
• Age Factors
• Aged
• Aged, 80 and over
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/mortality
• Colorectal Neoplasms/pathology
• Disease-Free Survival
• Exons/genetics
• Extracellular Signal-Regulated MAP Kinases/metabolism
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Kaplan-Meier Estimate
• MAP Kinase Signaling System/genetics
• Male
• Middle Aged
• Mitogen-Activated Protein Kinase Kinases/metabolism
• Mutation
• Neoplasm Recurrence, Local/diagnosis
• Neoplasm Recurrence, Local/epidemiology
• Neoplasm Recurrence, Local/genetics
• Prognosis
• Progression-Free Survival
• Proto-Oncogene Proteins B-raf/metabolism
• Proto-Oncogene Proteins p21(ras)/genetics
• Proto-Oncogene Proteins p21(ras)/metabolism
• Survival Rate
• Young Adult

Ameloblastoma of the jaws remains the top difficult to treat odontogenic tumour and has a high recurrence rate. New evidence suggests that non-coding RNAs (ncRNAs) play a critical role in tumourgenesis and prognosis of cancer. However, ameloblastoma ncRNA expression data is lacking. Here we present the first report of ameloblastoma ncRNA signatures. A total of 95 ameloblastoma cases and a global array transcriptome technology covering > 285.000 full-length transcripts were used in this two-step analysis. The analysis first identified in a test cohort 31 upregulated ameloblastoma-associated ncRNAs accompanied by signalling pathways of cancer, spliceosome, mRNA surveillance and Wnt. Further validation in an independent cohort points out the long non-coding (lncRNAs) and small nucleolar RNA (snoRNAs): LINC340, SNORD116-25, SNORA11, SNORA21, SNORA47 and SNORA65 as a distinct ncRNA signature of ameloblastoma. Importantly, the presence of these ncRNAs was independent of BRAF-V600E and SMO-L412F mutations, histology type or tumour location, but was positively correlated with the tumour size. Taken together, this study shows a systematic investigation of ncRNA expression of ameloblastoma, and illuminates new diagnostic and therapeutic targets for this invasive odontogenic tumour.

• ameloblastoma
• biomarkers
• gene expression analysis
• ncRNA
• transcriptome

Ligation-based nucleic acid detection methods are primarily limited to DNA, since they exhibit poor performance on RNA. This is attributed to reduced end-joining efficiency and/or fidelity of ligases. Interestingly, chlorella virus DNA ligase (PBCV-1 DNA ligase) has recently been shown to possess high RNA-templated DNA end-joining activity; however, its fidelity has not yet been systematically evaluated. Herein, we characterized PBCV-1 ligase for its RNA-templated end-joining fidelity at single base mismatches in 3′ and 5′ DNA probe termini and found an overall limited end-joining fidelity. To improve the specificity in PBCV-1 ligase-driven RNA detection assays, we utilized structure-specific 5′ exonucleolytic activity of Thermus aquaticus DNA polymerase, used in the invader assay. In the iLock (invader padLock) probe assay, padlock probe molecules are activated prior ligation thus the base at the probe ligation junction is read twice in order to aid successful DNA ligation: first, during structure-specific invader cleavage and then during sequence-specific DNA ligation. We report two distinct iLock probe activation mechanisms and systematically evaluate the assay specificity, including single nucleotide polymorphisms on RNA, mRNA and miRNA. We show significant increase in PBCV-1 ligation fidelity in the iLock probe assay configuration for RNA detection.

• Cancer
• GeneReader
• Kras
• Mutation
• Ngs

• Humans
• American Medical Association
• Biomarkers, Tumor/genetics
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• DNA Mutational Analysis
• ErbB Receptors/genetics
• Evidence-Based Medicine
• Genetic Testing
• Mutation
• Pathology, Clinical
• Pathology, Molecular
• Prognosis
• United States
• Systematic Reviews as Topic

• molecular diagnostics
• gastrointestinal
• histology
• genetics
• oncology

• Humans
• Antibodies, Monoclonal/therapeutic use
• Biomarkers, Tumor
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/therapy
• ErbB Receptors
• Systematic Reviews as Topic

• NIH

• Humans
• Biomarkers, Tumor
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/mortality
• Disease Management
• Gene Frequency
• Genomic Instability
• Molecular Diagnostic Techniques
• Molecular Targeted Therapy
• Mutation
• Mutation Rate
• Prognosis
• Signal Transduction
• Treatment Outcome
• Systematic Reviews as Topic
• Meta-Analysis as Topic

• UL1 TR000371 NCATS NIH HHS

• Colorectal neoplasms
• Gastric neoplasms
• Molecular diagnosis
• Prognosis
• Targeted therapy

• Colorectal cancer
• biomarker
• companion diagnostic
• next generation sequencing (NGS)

Investigations of methods for detection of mutations have uncovered major weaknesses of direct sequencing and pyrosequencing, with their high costs and low sensitivity in screening for both known and unknown mutations. High resolution melting (HRM) analysis is an alternative tool for the rapid detection of mutations. Here we describe the accuracy of HRM in screening for KRAS and BRAF mutations in metastatic colorectal cancer (mCRCs) samples.

A total of 1000 mCRC patients in Mehr Hospital, Tehran, Iran, from Feb 2008 to May 2012 were examined for KRAS mutations and 242 of them were selected for further assessment of BRAF mutations by HRM analysis. In order to calculate the sensitivity and specificity, HRM results were checked by pyrosequencing as the golden standard and Dxs Therascreen as a further method.

In the total of 1,000 participants, there were 664 (66.4%) with wild type and 336 (33.6%) with mutant codons 12 and/or 13 of the KRAS gene. Among 242 samples randomly checked for the BRAF gene, all were wild type by HRM. Pyrosequencing and Dxs Therascreen results were in line with those of the HRM. In this regard, the sensitivity and specificity of HRM were evaluated as 100%.

The findings suggest that the HRM, in comparison with DNA sequencing, is a more appropriate method for precise scanning of KRAS and BRAF mutations. It is also possible to state that HRM may be an attractive technique for the detection of known or unknown somatic mutations in other genes.

• High-Resolution Melting (HRM)
• mutation analysis
• metastatic colorectal cancer (mCRC)

Epidermal growth factor receptor (EGFR) is an important mediator of tumor cell survival and proliferation. The detection of EGFR mutations can predict prognoses and indicate when treatment with EGFR tyrosine kinase inhibitors should be used. As such, the development of highly sensitive methods for detecting EGFR mutations is important. Targeted next-generation sequencing is an effective method for diagnosing mutations. We compared the abilities of enrichment PCR followed by ultra-deep pyrosequencing (UDP), UDP alone, and PNA-mediated RT-PCR clamping to detect low-frequency EGFR mutations in tumor cell lines and tissue samples. Using enrichment PCR-UDP, we were able to detect the E19del and L858R mutations at minimum frequencies of 0.01% and 0.05%, respectively, in the PC-9 and H197 tumor cell lines. We also confirmed the sensitivity of detecting the E19del mutation by performing a titration analysis in FFPE tumor samples. The lowest mutation frequency detected was 0.0692% in tissue samples. EGFR mutations with frequencies as low as 0.01% were detected using enrichment PCR-UDP, suggesting that this method is a valuable tool for detecting rare mutations, especially in scarce tissue samples or those with small quantities of DNA.

• EGFR mutation
• diagnostic technique
• enrichment ultra-deep pyrosequencing
• lung cancer

Mutations in Human Epidermal Growth Factor Receptors (HER) are associated with poor prognosis of several types of solid tumors. Although HER-mutation detection methods are currently available, such as Next-Generation Sequencing (NGS), alternative pyrosequencing allow the rapid characterization of specific mutations. We developed specific PCR-based pyrosequencing assays for identification of most prevalent HER2 and HER3 mutations, including S310F/Y, R678Q, L755M/P/S/W, V777A/L/M, 774-776 insertion, and V842I mutations in HER2, as well as M91I, V104M/L, D297N/V/Y, and E332E/K mutations in HER3. We tested 85 Formalin Fixed and Paraffin Embbeded (FFPE) samples and we detected three HER2-V842I mutations in colorectal carcinoma (CRC), ovarian carcinoma, and pancreatic carcinoma patients, respectively, and a HER2-L755M mutation in a CRC specimen. We also determined the presence of a HER3-E332K mutation in an urothelial carcinoma sample, and two HER3-D297Y mutations, in both gastric adenocarcinoma and CRC specimens. The D297Y mutation was previously detected in breast and gastric tumors, but not in CRC. Moreover, we found a not-previously-described HER3-E332E synonymous mutation in a retroperitoneal leiomyosarcoma patient. The pyrosequencing assays presented here allow the detection and characterization of specific HER2 and HER3 mutations. These pyrosequencing assays might be implemented in routine diagnosis for molecular characterization of HER2/HER3 receptors as an alternative to complex NGS approaches.

• HER2
• HER3
• cancer
• pyrosequencing

• DNA Mutational Analysis/economics
• DNA Mutational Analysis/methods
• Female
• High-Throughput Nucleotide Sequencing/economics
• High-Throughput Nucleotide Sequencing/methods
• Humans
• Leiomyosarcoma/diagnosis
• Leiomyosarcoma/genetics
• Male
• Mutation
• Point Mutation
• Receptor, ErbB-2/genetics
• Receptor, ErbB-3/genetics
• Retroperitoneal Neoplasms/diagnosis
• Retroperitoneal Neoplasms/genetics
• Retroperitoneal Space/pathology

RAS and BRAF mutations impact treatment and prognosis of metastatic colorectal cancer patients (mCRC), but the knowledge is based on trial patients usually not representative for the general cancer population. Patient characteristics, treatment and efficacy according to KRAS, BRAF and MSI status were analyzed in a prospectively collected unselected population-based cohort of 798 non-resectable mCRC patients. The cohort contained many patients with poor performance status (39% PS 2-4) and elderly (37% age>75), groups usually not included in clinical trials. Patients without available tissue micro array (TMA) (42%) had worse prognostic factors and inferior survival (all patients; 7m vs 11m, chemotherapy-treated;12m vs 17m). The 92 patients (21%) with BRAF mutation had a poor prognosis regardless of microsatellite instability, but receipt of 1-2^nd chemotherapy was similar to wildtype BRAF patients. Median survival in this cohort varied from 1 month in BRAF mutated patients not given chemotherapy to 26 months in wildtype KRAS/BRAF patients <75 years in good PS. TMA availability, BRAF mutation and KRAS mutation were all independent prognostic factors for survival. The observed 21% BRAF mutation incidence is higher than the previously and repeatedly reported incidence of 5-12% in mCRC. Screening for BRAF mutations before selection of treatment is relevant for many patients, especially outside clinical trials. A BRAF mutation only partly explained the very poor prognosis of many mCRC patients. Survival in unselected metastatic colorectal cancer patients is extremely variable and subgroups have an extremely short survival compared to trial patients. Patients without available TMA had worse prognostic factors and shorter survival, which questions the total generalizability of present TMA studies and implies that we lack information on the biologically worst mCRC cases. Lack of available tissue is an important underexposed issue which introduces sample bias, and this should be recognized more clearly when conclusions are made from translational mCRC studies.

• Aged
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Female
• Humans
• Male
• Microsatellite Instability
• Middle Aged
• Multivariate Analysis
• Mutation/genetics
• Mutation Rate
• Neoplasm Metastasis
• Prospective Studies
• Proto-Oncogene Proteins B-raf/genetics
• Proto-Oncogene Proteins p21(ras)/genetics
• Survival Analysis
• Tissue Array Analysis

KRAS mutation assays are important companion diagnostic tests to guide anti-EGFR antibody treatment of metastatic colorectal cancer. Direct comparison of newer diagnostic methods with existing methods is an important part of validation of any new technique. In this this study, we have compared the Therascreen (Qiagen) ARMS assay with Competitive Allele-Specific TaqMan PCR (castPCR, Life Technologies) to determine equivalence for KRAS mutation analysis.

DNA was extracted by Maxwell (Promega) from 99 colorectal cancers. The ARMS-based Therascreen and a customized castPCR assay were performed according to the manufacturer’s instructions. All assays were performed on either an Applied Biosystems 7500 Fast Dx or a ViiA7 real-time PCR machine (both from Life Technologies). The data were collected and discrepant results re-tested with newly extracted DNA from the same blocks in both assay types.

Of the 99 tumors included, Therascreen showed 62 tumors to be wild-type (WT) for KRAS, while 37 had KRAS mutations on initial testing. CastPCR showed 61 tumors to be wild-type (WT) for KRAS, while 38 had KRAS mutations. Thirteen tumors showed BRAF mutation in castPCR and in one of these there was also a KRAS mutation. The custom castPCR plate included several other KRAS mutations and BRAF V600E, not included in Therascreen, explaining the higher number of mutations detected by castPCR. Re-testing of discrepant results was required in three tumors, all of which then achieved concordance for KRAS. CastPCR assay Ct values were on average 2 cycles lower than Therascreen.

There was excellent correlation between the two methods. Although castPCR assay shows lower Ct values than Therascreen, this is unlikely to be clinically significant.

• Alleles
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• DNA/analysis
• DNA Mutational Analysis/methods
• Humans
• Mutation
• Proto-Oncogene Proteins B-raf/genetics
• Reagent Kits, Diagnostic
• Real-Time Polymerase Chain Reaction
• ras Proteins/genetics

KRAS mutations in codons 12 and 13 are established predictive biomarkers for anti-EGFR therapy in colorectal cancer. Previous studies suggest that KRAS codon 61 and 146 mutations may also predict resistance to anti-EGFR therapy in colorectal cancer. However, clinicopathological, molecular, and prognostic features of colorectal carcinoma with KRAS codon 61 or 146 mutation remain unclear.

We utilized a molecular pathological epidemiology database of 1267 colon and rectal cancers in the Nurse’s Health Study and the Health Professionals Follow-up Study. We examined KRAS mutations in codons 12, 13, 61 and 146 (assessed by pyrosequencing), in relation to clinicopathological features, and tumor molecular markers, including BRAF and PIK3CA mutations, CpG island methylator phenotype (CIMP), LINE-1 methylation, and microsatellite instability (MSI). Survival analyses were performed in 1067 BRAF-wild-type cancers to avoid confounding by BRAF mutation. Cox proportional hazards models were used to compute mortality hazard ratio, adjusting for potential confounders, including disease stage, PIK3CA mutation, CIMP, LINE-1 hypomethylation, and MSI.

KRAS codon 61 mutations were detected in 19 cases (1.5%), and codon 146 mutations in 40 cases (3.2%). Overall KRAS mutation prevalence in colorectal cancers was 40% (=505/1267). Of interest, compared to KRAS-wild-type, overall, KRAS-mutated cancers more frequently exhibited cecal location (24% vs. 12% in KRAS-wild-type; P < 0.0001), CIMP-low (49% vs. 32% in KRAS-wild-type; P < 0.0001), and PIK3CA mutations (24% vs. 11% in KRAS-wild-type; P < 0.0001). These trends were evident irrespective of mutated codon, though statistical power was limited for codon 61 mutants. Neither KRAS codon 61 nor codon 146 mutation was significantly associated with clinical outcome or prognosis in univariate or multivariate analysis [colorectal cancer-specific mortality hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.29-2.26 for codon 61 mutation; colorectal cancer-specific mortality HR = 0.86, 95% CI = 0.42-1.78 for codon 146 mutation].

Tumors with KRAS mutations in codons 61 and 146 account for an appreciable proportion (approximately 5%) of colorectal cancers, and their clinicopathological and molecular features appear generally similar to KRAS codon 12 or 13 mutated cancers. To further assess clinical utility of KRAS codon 61 and 146 testing, large-scale trials are warranted.

Colorectal cancer (CRC) is one of the most prevalent cancers in developed countries. On the other hand, CRC is also one of the most curable cancers if it is detected in early stages through regular colonoscopy or sigmoidoscopy. Since CRC develops slowly from precancerous lesions, early detection can reduce both the incidence and mortality of the disease. Fecal occult blood test is a widely used non-invasive screening tool for CRC. Although fecal occult blood test is simple and cost-effective in screening CRC, there is room for improvement in terms of the accuracy of the test. Genetic dysregulations have been found to play an important role in CRC development. With better understanding of the molecular basis of CRC, there is a growing expectation on the development of diagnostic tests based on more sensitive and specific molecular markers and those tests may provide a breakthrough to the limitations of current screening tests for CRC. In this review, the molecular basis of CRC development, the characteristics and applications of different non-invasive molecular biomarkers, as well as the technologies available for the detection were discussed. This review intended to provide a summary on the current and future molecular diagnostics in CRC and its pre-malignant state, colorectal adenoma.

• Colorectal cancer
• Colorectal adenoma
• Molecular diagnostics
• Fecal occult blood test
• Non-invasive

• Adenoma/diagnosis
• Adenoma/genetics
• Biomarkers, Tumor/metabolism
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/epidemiology
• Colorectal Neoplasms/genetics
• Cost-Benefit Analysis
• DNA, Neoplasm/metabolism
• Epigenesis, Genetic
• Feces
• Gene Silencing
• Humans
• MicroRNAs/metabolism
• Microsatellite Instability
• Occult Blood
• Pathology, Molecular/methods
• Pathology, Molecular/trends
• Reproducibility of Results

• Colorectal cancer
• KRAS gene
• Method and mutation analysis
• Mutation

• KRAS protein
• colonic neoplasms
• comparative study
• diagnostic imaging
• human