Exosomes in metastasis of colorectal cancers: Friends or foes?

Colorectal cancer(CRC),the third most common type of cancer worldwide,threaten human health and quality of life.With multidisciplinary,including surgery,chemotherapy and/or radiotherapy,patients with an early diagnosis of CRC can have a good prognosis.However,metastasis in CRC patients is the main risk factor causing cancer-related death.To elucidate the underlying molecular mechanisms of CRC metastasis is the difficult and research focus on the investigation of the CRC mechanism.On the other hand,the tumor microenvironment(TME)has been confirmed as having an essential role in the tumorigenesis and metastasis of malignancies,including CRCs.Among the different factors in the TME,exosomes as extracellular vesicles,function as bridges in the communication between cancer cells and different components of the TME to promote the progression and metastasis of CRC.MicroRNAs packaged in exosomes can be derived from different sources and transported into the TME to perform oncogenic or tumor-suppressor roles accordingly.This article focuses on CRC exosomes and illustrates their role in regulating the metastasis of CRC,especially through the packaging of miRNAs,to evoke exosomes as novel biomarkers for their impact on the metastasis of CRC progression.

Clinicopathological features of small T1 colorectal cancers

BACKGROUND Although small colorectal neoplasms(<10 mm)are often easily resected endoscopically and are considered to have less malignant potential compared with large neoplasms(≥10 mm),some are invasive to the submucosa.AIM To clarify the clinicopathological features of small T1 colorectal cancers.METHODS Of 32025 colorectal lesions between April 2001 and March 2018,a total of 1152 T1 colorectal cancers resected endoscopically or surgically were included in this study and were divided into two groups by tumor size:a small group(<10 mm)and a large group(≥10 mm).We compared clinicopathological factors including lymph node metastasis(LNM)between the two groups.RESULTS The incidence of small T1 cancers was 10.1%(116/1152).The percentage of initial endoscopic treatment in small group was significantly higher than in large group(<10 mm 74.1%vs≥10 mm 60.2%,P<0.01).In the surgical resection cohort(n=798),the rate of LNM did not significantly differ between the two groups(small 12.3%vs large 10.9%,P=0.70).In addition,there were also no significant differences between the two groups in pathological factors such as histological grade,vascular invasion,or lymphatic invasion.CONCLUSION Because there was no significant difference in the rate of LNM between small and large T1 colorectal cancers,the requirement for additional surgical resection should be determined according to pathological findings,regardless of tumor size.

The significance of cyclin B1 expression in colorectal cancers

Objective: To study the relationship between the expression of human cyclin B1 in colorectal carcinomas and the pathological characters. Methods: The Expression of cyclin B1 in 66 cases of colorectal carcinomas were detected by flow cytometry and immunohistochemistry. Then the relationship between the expression of cyclin B1 in colorectal carcinomas and pathological characters was analyzed with statistics. Results: The expression of cyclin B1 in colorectal carcinomas had associa- tivity with the cancer cell differentiation (P<0.05); However, the expression of cyclin B1 in colorectal carcinomas had no obvious associativity with cancer cell infiltrate depth and lymph nodes metastasis (P>0.05). Conclusion: In the colorectal cancers with high expression of cyclin B1, the cancer cells would present high differentiation; with low expression of cyclin B1 the cancer cells would present low differentiation. Along with the expression of cyclin B1 from high to low, the cancer cells differentiation has the tendency from high to low too.

Aberrant expression of krUppel-like factor 6 protein in colorectal cancers

AIM： TO investigate whether krüppel-like factor 6 （KLF6） plays an important role in the development and/or progression of colorectal cancer. METHODS： A total of 123 formalin-fixed and paraffinembedded colorectal cancer specimens were analyzed by immunohistochemistry using tissue microarray for the expression of KLF6 protein. The specimens were collected over a 3-year period in the laboratories at our large teaching hospital in Seoul, Republic of Korea. The correlation of KLF6 expression with clinicopathologic parameters was analyzed by χ^2 test and Bartholomew test. RESULTS： Normal colonic epithelium showed weak to moderate expression of KLF6, whereas reduced KLF 6 expression or loss of KLF6 expression was seen in 45 （36.6%） of the 123 colorectal carcinoma specimens. Interestingly, aberrant expression of KLF6 was detected in 25 （43.1%） of 58 cases with metastasis to regional lymph node and in 31 （47.0%） of 66 tumors more than 5 cm in size. Statistically, loss of KLF6 expression was significantly associated with tumor size （P〈0.05）. However, there was no significant correlation between KLF6 expression and Dukes＇ stage （Bartholomew test, P〉 0.05）, tumor location and lymph node metastasis （χ^2 test, P〉0.05）.CONCLUSION： Loss of KLF6 expression may be a common and early event in colorectal carcinogenesis.

Pyogenic liver abscesses associated with nonmetastatic colorectal cancers: An increasing problem in Eastern Asia

AIM: To elaborate the clinicopathologic features of colorectal cancer-related pyogenic liver abscess (PLA). METHODS: Reported cases of colorectal cancer-related PLAs were collected from the literature published up to October 2011 and evaluated for their clinicopathologic features. Data of collected cases included demographics, clinical presentation, microbial findings and treatment. Categorical variables were compared by 2 analysis and continuous variables were evaluated using Student's t test. RESULTS: A total 96 cases of colorectal cancer-related PLA were collected from the previous literature. Most patients (60%) were male and 40% cases occurred in the age group of 61-70 years. Apart from some special types of PLA, there were significant differences in the microbiological spectrum between Eastern Asia and non-Eastern Asian countries, which implied different risk factors and courses of the disease. Gram negative bacteria especially Klebsiella pneumoniae (K. pneu- moniae ) PLA was predominant in Eastern Asia (80.0%) in contrast to non-Eastern Asian countries (P < 0.01). Meanwhile, most of the Eastern Asian patients exhibited smaller size of liver abscess and atypical presentation. Sigmoid colon and rectum (72.73%) were the main sites of tumor in Eastern Asian patients, whereas tumor sites were uneven among most of the non-Easter Asian PLA patients. CONCLUSION:K. pneumoniae PLA was strongly associated with colorectal cancer, especially those occurring in sigmoid colon and rectum, in elderly Eastern Asian male patients.

Right-and left-sided colorectal cancers respond differently to traditional Chinese medicine

AIM To explore the differences in the responses of left-sided colorectal cancer(LSCRC) and right-sided colon cancer(RSCC) to traditional Chinese medicine(TCM).METHODS Patients with postoperative stage I-III colorectal cancer(CRC) were enrolled and divided into the LSCRC with or without TCM and RSCC with or without TCM groups depending on the primary tumor side and TCM administration. Patients in the TCM group were given TCM for at least 6 mo. Our research adopted diseasefree survival(DFS) as the primary endpoint. We applied a Cox proportional hazards regression model for the multivariate factor analysis using Stata 12.0 and SPSS 22.0 software for data analysis.RESULTS Of the 817 patients included in our study, 617 had LSCRC(TCM group, n = 404; Non-TCM group, n = 213), and 200 had RSCC(TCM group, n = 132; NonTCM group, n = 68). The 6-year DFS for patients with LSCRC was 56.95% in the TCM group and 41.50% in the Non-TCM group(P = 0.000). For patients with RSCC, the 6-year DFS was 52.92% in the TCM group and 37.19% in the Non-TCM group(P = 0.003). Differences between LSCRC and RSCC were not statistically significant regardless of TCM ingestion.CONCLUSION Patients with either LSCRC or RSCC and who took TCM experienced longer DFS; furthermore, patients with RSCC benefited more from TCM in DFS.

Frequent mutations of the CA simple sequence repeat in intron 1 of EGFR in mismatch repair-deficient colorectal cancers

AIM:To investigate the polymorphic simple sequencerepeat in intron 1 of the epidermal growth factor receptorgene(EGFR)(CA-SSRⅠ),which is known to affect theefficiency of gene transcription as a putative target of themismatch repair(MMR)machinery in colorectal tumors.METHODS:The CA-SSRⅠgenotype was analyzed ina total of 86 primary colorectal tumors,selected upontheir microsatellite instability(MSI)status[42 with highfrequency MSI(MSI-H)and 44 microsatellite stable(MSS)]and their respective normal tissue.The effect of the CA-SSRⅠgenotype on the expression of the EGFR gene wasevaluated in 18 specimens using quantitative real-timereverse transcription PCR and immunohistochemistry.RESULTS:Mutations in CA-SSRⅠwere detected in 86%(36 of 42)of MSI-H colorectal tumors and 0%(0 of 44)ofMSS tumors,indicating the EGFR gene as a novel putativespecific target of the defective MMR system(P<0.001).Impaired expression of EGFR was detected in most ofthe colorectal tumors analyzed[6/12(50%)at the mRNAlevel and 15/18(83%)at the peptide level].However,noassociation was apparent between EGFR expression andCA-SSRⅠstatus in tumors or normal tissues.CONCLUSION:Our results suggest that CA-SSRⅠsequence does not contribute to the regulation of EGFRtranscription in colon,and should thus not be consideredas a promising predictive marker for response to EGFRinhibitors in patients with colorectal cancer.

Droplet digital PCR for quantification of ITGA6 in a stool mRNA assay for the detection of colorectal cancers

AIM To investigate the use of droplet digital polymerase chain reaction(dd PCR) for detecting host m RNA markers in stools as a non-invasive test for colorectal cancer screening.METHODS dd PCR and quantitative PCR were compared side by side for their performance in the detection of ITGA6 and ITGA6 A transcripts in stool samples obtained from patients with various types of colorectal lesions(advanced adenomas and stage Ⅱ-Ⅳ colorectal cancers) and control(patients displaying no pathological findings) using duplex Taq Man reactions for both methods. ITGA6 and ITGA6 A were chosen for this proof-of-concept study based on their relative medium and low abundance in stool samples, respectively, as established in a previous study.RESULTS We found that the dd PCR and q PCR methods per-formed equally well in this Taq Man duplex assay for the detection of ITGA6 and ITGA6 A transcripts in stools of patients with colorectal lesions. For ITGA6, receiver operating characteristic(ROC) curve analysis showed comparable areas under the curve of 0.91(P < 0.0001) and 0.89-0.90(P < 0.0001) for the prediction of advanced adenomas and colorectal cancers, respectively. ITGA6 A, which was detected at very low levels in control patients, was found to be significantly elevated(over 40 times) in stage Ⅱ and Ⅲ colorectal cancers(P < 0.0002). Comparison of the two sets of data revealed a strong correlation of the copy numbers obtained by dd PCR and q PCR for both ITGA6 and ITGA6 A.CONCLUSION We found that ITGA6 and ITGA6 A detection in stools of patients with colorectal cancers with dd PCR is comparable to that of q PCR using Taq Man assays.

Association of p53 codon 72 polymorphism with liver metastases of colorectal cancers positive for p53 overexpression

Objective： To evaluate the association between p53 codon 72 polymorphism （R72P） and the risk ofcolorectal liver metastases. Methods： The p53 R72P genotype was identified by polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） method in 78 consecutive colorectal cancer patients with liver metastases and 214 age- and sex-matched cases with nonmetastatic colorectal cancer. Results： The R allele of the p53 R72P polymorphism was more frequently found in metastatic cases than in nonmetastatic cases （P=0.075）. Carriers of the 72R allele had a 2.25-fold （95% CI （confidence interval）=1.05-4.83） increased risk of liver metastases. On the stratification analysis, 72R-carrying genotype conferred a 3.46-fold （95% CI=1.02-11.72） and a 1.05-fold （95% CI=0.36-3.08） increased risk of liver metastases for p53 overexpression-positive and negative colorectal cancers, respectively. Conclusion： These results demonstrate for the first time that the 72R allele of the p53 polymorphism has an increased risk for liver metastases in colorectal cancers positive for p53 overexpression.

Occupational exposures and colorectal cancers:A quantitative overview of epidemiological evidence

A traditional belief widespread across the biomedical community was that dietary habits and genetic predisposition were the basic factors causing colorectal cancer.In more recent times,however,a growing evidence has shown that other determinants can be very important in increasing(or reducing) incidence of this malignancy.The hypothesis that environmental and occupational risk factors are associated with colorectal cancer is gaining ground,and high risks of colorectal cancer have been reported among workers in some industrial branches.The aim of this study was to investigate the epidemiologic relationship between colorectal cancer and occupational exposures to several industrial activities,by means of a scientific literature review and meta-analysis.This work pointed out increased risks of colorectal cancer for labourers occupied in industries with a wide use of chemical compounds,such as leather(RR = 1.70,95%CI:1.24-2.34),basic metals(RR = 1.32,95%CI:1.07-1.65),plastic and rubber manufacturing(RR = 1.30,95%CI:0.98-1.71 and RR = 1.27,95%CI:0.92-1.76,respectively),besides workers in the sector of repair and installation of machinery exposed to asbestos(RR = 1.40,95%CI:1.07-1.84).Based on our results,the estimated crude excess risk fraction attributable to occupational exposure ranged from about 11% to about 15%.However,homogeneous pattern of association between colorectal cancer and industrial branches did not emerge from this review.

Promoter hypermethylation and loss of CD133 gene expression in colorectal cancers

AIM: To understand CD133 promoter hypermethyl-ation and expression in 32 colorectal cancer cell lines. METHODS: Nucleic acid was isolated from 32 colorectal cancer cell lines and CD133 expression levels were measured by reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR. Promoter methylation status of the CD133 gene was analyzed with a methylation-specific PCR after sodium-bisulfi te modification and by clonal sequencing analysis. The correlation between expression and promoter methylation of CD133 gene was confirmed with treatment of 5-aza-2’-deoxycytidine. RESULTS: We measured CD133 expression levels in 32 colorectal cancer cell lines. RT-PCR analysis showed undetectable or low levels of CD133 expression in 34.4%of cell lines. To verify the relation between CD133 expression and methylation status of the CD133 gene promoter in colorectal carcinogenesis, CD133 gene promoter hypermethylation was analyzed in 32 cancer cell lines. Promoter hypermethylation was detected in 13 (40.6%) of the cell lines using methylation specificPCR and confirmed by bisulfite sequencing analysis. Treatment of 11 of the cell lines with the demethylation agent 5-aza-2’-deoxycytidine recovered CD133 expression in most of them. CONCLUSION: Transcriptional repression of CD133 is caused by promoter hypermethylation of the CD133 CpG islands in some of colorectal cancer cell lines. The study may contribute to the understanding of the role of CD133 inactivation in the progression of colorectal cancers.

What is the most cost-effective strategy to screen for second primary colorectal cancers in male cancer survivors in Korea?

AIM： To identify a cost-effective strategy of second primary colorectal cancer （CRC） screening for cancer survivors in Korea using a decision-analytic model. METHODS： A Markov model estimated the clinical and economic consequences of a simulated 50-year- old male cancer survivors＇ cohort, and we compared the results of eight screening strategies： no screening, fecal occult blood test （FOBT） annually, FOBT every 2 years, sigmoidoscopy every 5 years, double contrast barium enema every 5 years, and colonoscopy every 10 years （COL10）, every 5 years （COL5）, and every 3 years （COL3）. We included only direct medical costs, and our main outcome measures were discounted lifetime costs, life expectancy, and incremental cost- effectiveness ratio （ICER）. RESULTS： In the base-case analysis, the non-dominat- ed strategies in cancer survivors were COL5, and COL3. The ICER for COL3 in cancer survivors was $5593/life- year saved （LYS）, and did not exceed $10000/LYS in one-way sensitivity analyses. If the risk of CRC in can- cer survivors is at least two times higher than that in the general population, COL5 had an ICER of less than $10500/LYS among both good and poor prognosis of index cancer. If the age of cancer survivors starting CRC screening was decreased to 40 years, the ICER of COL5 was tess than $7400/LYS regardless of screening compliance. CONCLUSION： Our study suggests that more strict and frequent recommendations for colonoscopy such as COL5 and COL3 could be considered as economically reasonable second primary CRC screening strategies for Korean male cancer survivors.

Amplifi cations of NCOA3 gene in colorectal cancers in a Chinese population

AIM: To investigate the copy number variation of NACO3 gene in colorectal cancer (CRC) and its correlation with tumor progression. METHODS: A total of 142 samples of case-matched CRC tissues and adjacent normal tissues were obtained from patients undergoing bowel resection. Quantitative real-time polymerase chain reaction method was used to investigate the copy number variations of NCOA3 as well as gene expression in the collected tissues. RESULTS: Copy number gains of NCOA3 were detected in 39 CRC samples (27.5%) and were correlatedwith tumor progression (χ2 = 6.42, P = 0.0112). Moreover, there was a positive correlation between copy number gain and mRNA over-expression of NCOA3 in CRCs (P = 0.0023). Expression level of NCOA3 mRNA was also enhanced in the CRC samples with unaltered copy numbers (3.85 ± 1.23 vs 2.71 ± 0.64, P < 0.01). CONCLUSION: Sporadic colorectal cancers exhibit different mechanisms of NCOA3 regulation.

The quantitative expressions of lymphangiogenic factors and metastasis in human colorectal cancers

Objective： The purpose of this paper was to study the expression levels of newly described lymphatic endothelial markers – LYVE-1, Prox-1, podoplanin and 5’-nucleotidase, and their correlation with metastasis of human colorectal cancers. Methods： Tumor and corresponding tumor-side normal tissue samples were obtained from resected specimens immediately after operation. Expression level of each factor was determined by quantitative real-time PCR （RT-PCR） and Western blot technique. Results： Expression levels of lymphatic endothelial markers LYVE-1, Prox-1, podoplanin and 5’-nucleotidase were significantly different in tumor and tumor-side normal groups. Expression levels of Prox-1 and podoplanin were higher in patients with positive lymph node metastasis than those without metastasis. LYVE-1, but not 5’-nucleotidase expression level was higher in both cancer and normal groups. Conclusion： These results indicate that combined quantitative analysis of lymphangiogenic markers LYVE-1, Prox-1 and podoplanin in colorectal cancer specimens may be useful in predicting metastasis of colorectal cancer to regional lymph nodes. However, the role of 5’-nucleotidase in predicting metastasis of colorectal cancer still remains to be further analyzed.

Deletion and down-regulation of SMAD4 gene in colorectal cancers in a Chinese population

Objective： Colorectal cancer（CRC） is one of the most common types of human cancers. As a tumor suppressor, SMAD4 plays a key role in colorectal carcinogenesis and invasiveness. Copy number variations（CNVs） of the SMAD4 gene have been reported to be associated with cancer pathogenesis in array-based studies in different populations. Here we aimed to investigate the CNVs of the SMAD4 gene in a relatively large number of CRC patients from China. Methods： In the present study, we collected 147 Chinese CRC tumors as well as self-paired normal control tissues. Quantitative PCR was carried out to examine the copy number as well as the m RNA expression of the SMAD4 gene. Results： Our results showed that the copy number deletions of SMAD4 were frequent in a relatively high percentage of CRC samples（34.7%, 51 out of 147）. There was a positive correlation between the copy number decrease of SMAD4 and tumor progression in CRCs. Furthermore, copy number loss of SMAD4 was correlated with decreased m RNA expression.Conclusions： These findings suggested that the copy number deletions of SMAD4 were frequent in CRC patients from China and had the potential to serve as a diagnostic indicator, alone or in combination with other markers, for CRC.

The more the messier：centrosome amplification as a novel biomarker for personalized treatment of colorectal cancers

Colon cancer is currently the third most common cancer and second most fatal cancer in the United States,resulting in approximately 600,000 deaths annually.Though colorectal cancer death rates are decreasing by about 3%every year,disease outcomes could be substantially improved with more research into the drivers of colon carcinogenesis,the determinants of aggressiveness in colorectal cancer and the identification of biomarkers that could enable choice of more optimal treatments.Colon carcinogenesis is notably a slow process that can take decades.Known factors that contribute to the development of colon cancer are mutational,epigenetic and environmental,and risk factors include age,history of polyps and family history of colon cancer.Colorectal cancers exhibit heterogeneity in their features and are often characterized by the presence of chromosomal instability,microscopic satellite instability,or CpG island methylator phenotype.In this review,we propose that centrosome amplification may be a widespread occurrence in colorectal cancers and could potently influence tumor biology.Moreover,the quantitation of this cancer-specific anomaly could offer valuable prognostic information and pave the way for further customization of treatment based on the organellar profile of patients.Patient stratification models that take into account centrosomal status could thus potentially reduce adverse side effects and result in improved outcomes for colorectal cancer patients.

Relationships of tumor inflammatory infiltration and necrosis with microsatellite instability in colorectal cancers

AIM:The relationships between microsatellite instability (MSI) and survival in colorectal cancer patients are not consistent. The favorable survival of patient with MSI has been suggested to be related to pronounced inflammatory infiltration; however,the reason for non-association of MSI with survival is unclear. Our aims were to investigate the associations of inflammatory infiltration and tumor necrosis (TIM) with microsatellite status and clinicopathological factors in colorectal cancer patients in whom MSI was not related to survival. METHODS: Three hundred and one colorectal adenocar-cinomas were evaluated for inflammatory infiltration and 300 for TN under light microscope. RESULTS: Low infiltration at invasive margin (X2=3.94, P= 0.047) and in whole tumor stroma (X2=3.89, P= 0.049) was associated with MSI, but TN was not (X2=0.10, P = 0.75). Low infiltration was related to advanced stage (X2 = 8.67, P= 0.03), poorer differentiation (X2=8.84, P= 0.03), DNA non-diploid (X2=10.04, P= 0.002), higher S-phase fraction (X2=11.30,P=0.004),positive p53 expression (X2=7.94,P=0.01),and worse survival (P = 0.03 for both univariate and multivariate analyses). Abundant TN was related to advanced stage (X2=17.74, P= 0.001) and worse survival (P= 0.02 for univariate, and P= 0.05 for multivariate analysis). CONCLUSION: The result that high inflammatory infiltration was not related to MSI might help explain the non-association of MSI with survival in colorectal cancer patients.

Analysis of 12 variants in the development of gastric and colorectal cancers

AIM To evaluate the relation between 12 polymorphisms and the development of gastric cancer(GC) and colorectal cancer(CRC).METHODS In this study,we included 125 individuals with GC diagnosis,66 individuals with CRC diagnosis and 475 cancer-free individuals. All participants resided in the North region of Brazil and authorized the use of their samples. The 12 polymorphisms(in CASP8,CYP2 E1,CYP19 A1,IL1 A,IL4,MDM2,NFKB1,PAR1,TP53,TYMS,UGT1 A1 and XRCC1 genes) were genotyped in a single PCR for each individual,followed by fragment analysis. To avoid misinterpretation due to population substructure,we applied a previously developed set of 61 ancestryinformative markers that can also be genotyped by multiplex PCR. The statistical analyses were performed in Structure v.2.3.4,R environment and SPSS v.20.RESULTS After statistical analyses with the control of confounding factors,such as genetic ancestry,three markers(rs79071878 in IL4,rs3730485 in MDM2 and rs28362491 in NFKB1) were positively associated with the development of GC. One of these markers(rs28362491) and the marker in the UGT1 A1 gene(rs8175347) were positively associated with the development of CRC. Therefore,we investigated whether the joint presence of the deleterious alleles of each marker could affect the development of cancer and we obtained positive results in all analyses. Carriers of the combination of alleles RP1 + DEL(rs79071878 and rs28361491,respectively) are at 10-times greater risk of developing GC than carriers of other combinations. Similarly,carriers of the combination of DEL + RARE(rs283628 and rs8175347) are at about 12-times greater risk of developing CRC than carriers of other combinations.CONCLUSION These findings are important for the comprehension of gastric and CRC development,particularly in highly admixed populations,such as the Brazilian population.

Missed colorectal cancers in a fecal immunochemical test-based screening program: Molecular profiling of interval carcinomas

BACKGROUND For optimizing fecal immunochemical test(FIT)-based screening programs,reducing the rate of missed colorectal cancers(CRCs)by FIT(FIT-interval CRCs)is an important aspect.Knowledge of the molecular make-up of these missed lesions could facilitate more accurate detection of all(precursor)lesions.AIM To compare the molecular make-up of FIT-interval CRCs to lesions that are detected by FIT[screen-detected CRCs(SD-CRCs)].METHODS FIT-interval CRCs observed in a Dutch pilot-program of FIT-based screening were compared to a control group of SD-CRCs in a 1:2 ratio,resulting in 27 FIT-interval CRC and 54 SD-CRCs.Molecular analyses included microsatellite instability(MSI),CpG island methylator phenotype(CIMP),DNA sequence mutations and copy number alterations(CNAs).RESULTS Although no significant differences were reached,FIT-interval CRCs were more often CIMP positive and MSI positive(33%CIMP in FIT-interval CRCs vs 21%in SD-CRCs(P=0.274);19%MSI in FIT-interval CRCs vs 12%in SD-CRCs(P=0.469)),and showed more often serrated pathway associated features such as BRAF(30%vs 12%,P=0.090)and PTEN(15%vs 2.4%,P=0.063)mutations.APC mutations,a classic feature of the adenoma-carcinoma-sequence,were more abundant in SD-CRCs(68%vs 40%in FIT-interval CRCs P=0.035).Regarding CNAs differences between the two groups;FIT-interval CRCs less often showed gains at the regions 8p11.22-q24.3(P=0.009),and more often gains at 20p13-p12.1(P=0.039).CONCLUSION Serrated pathway associated molecular features seem to be more common in FIT-interval CRCs,while classic adenoma carcinoma pathway associated molecular features seem to be more common in SD-CRCs.This indicates that proximal serrated lesions may be overrepresented among FITinterval CRCs.

Current guidelines in the surgical management of hereditary colorectal cancers

Incidence of colorectal cancer(CRC)is on rise.While approximately 70%of all CRC cases are sporadic in nature,20%-25%have familial aggregation and only<5%is hereditary in origin.Identification of individuals with hereditary predilection for CRC is critical,as it has an impact on their overall surgical management including surgical timing,approach&technique and determines the role of prophylactic surgery and outcome.This review highlights the concept of hereditary CRC,provides insight into its molecular basis,possibility of its application into clinical practice and emphasizes the current treatment strategies with surgical management,based on the available international guidelines.