Association of insertion-deletions polymorphisms with colorectal cancer risk and clinical features

AIM To investigate the association between 16 insertiondeletions(INDEL) polymorphisms, colorectal cancer(CRC) risk and clinical features in an admixed population.METHODS O n e h u n d re d a n d fo r ty p a t i e n t s w i t h C R C a n d 140 cancer-free subjects were examined. Genomic DNA was extracted from peripheral blood samples. Polymorphisms and genomic ancestry distribution were assayed by Multiplex-PCR reaction, separated by capillary electrophoresis on the ABI 3130 Genetic Analyzer instrument and analyzed on Gene Mapper ID v3.2. Clinicopathological data were obtained by consulting the patients' clinical charts, intra-operative documentation, and pathology scoring.RESULTS Logistic regression analysis showed that polymorphism variations in IL4 gene was associated with increased CRC risk, while TYMS and UCP2 genes were associated with decreased risk. Reference to anatomical localization of tumor Del allele of NFKB1 and CASP8 were associated with more colon related incidents than rectosigmoid. In relation to the INDEL association with tumor node metastasis(TNM) stage risk, the Ins alleles of ACE, HLAG and TP53(6 bp INDEL) were associated with higher TNM stage. Furthermore, regarding INDEL association with relapse risk, the Ins alleles of ACE, HLAG, and UGT1A1 were associated with early relapse risk, as well as the Del allele of TYMS. Regarding INDEL association with death risk before 10 years, the Ins allele of SGSM3 and UGT1A1 were associated with death risk.CONCLUSION The INDEL variations in ACE, UCP2, TYMS, IL4, NFKB1, CASP8, TP53, HLAG, UGT1A1, and SGSM3 were associated with CRC risk and clinical features in an admixed population. These data suggest that this cancer panel might be useful as a complementary tool for better clinical management, and more studies need to be conducted to confirm these findings.

Hereditary gastric cancer:Three rules to reduce missed diagnoses

Gastric cancer remains one of the most lethal cancers.The incidence and mortality rates are quite similar.The main reason for the high mortality is diagnosis at advanced stages of disease,when treatment options are poor.One of the supposed strategies to overcome late-stage diagnosis is identifying people at high risk with the aim of establishing rigorous clinical control,including routine endoscopy and biopsies.Hereditary gastric cancer(HGC)syndromes,though representing a sizeable group to monitor for prevention or,at least,for early diagnosis,are apparently extremely rare.The low rate of HGC diagnosis might be related to the low rates of suspicion,insufficient familiarity about clinical diagnosis criteria,and the supposed conditional necessity of a molecular diagnosis.In this review,we will discuss simple measures to increase HGC diagnosis by applying three rules that might provide an opportunity for precision care to benefit the families affected by this disease.

Piwi like RNA-mediated gene silencing 1 gene as a possible major player in gastric cancer

AIM To establish a permanent piwi like RNA-mediated genesilencing 1(PIWIL1) gene knockout in AGP01 gastric cancer cell line using CRISPR-Cas9 system and analyze phenotypic modifications as well as gene expression alterations.METHODS CRISPR-Cas9 system used was purchased from Dharmacon GE Life Sciences(Lafayette, CO, United States) and permanent knockout was performed according to manufacturer's recommendations. Woundhealing assay was performed to investigate the effect of PIWIL1 knockout on migration capability of cells and Boyden chamber invasion assay was performed to investigate the effect on invasion capability. For the gene expression analysis, a one-color microarray-based gene expression analysis kit(Agilent Technologies, Santa Clara, CA, United States) was used according to the protocol provided by the manufacturer. RESULTS PIWIL1 gene knockout caused a significant decrease in AGP01 migration capacity as well as a significant decrease in cell invasiveness. Moreover, functional analysis based on grouping of all differentially expressed m RNAs identified a total of 35 genes(5 up-regulated and 30 down-regulated) encoding proteins involved in cellular invasion and migration. According to current literature, 9 of these 35 genes(DOCK2, ZNF503, PDE4 D, ABL1, ABL2, LPAR1, SMAD2, WASF3 and DACH1) are possibly related to the mechanisms used by PIWIL1 to promote carcinogenic effects related to migration and invasion, since their functions are consistent with the changes observed(being up-or down-regulated after knockout). CONCLUSION Taken together, these data reinforce the idea that PIWIL1 plays a crucial role in the signaling pathway of gastric cancer, regulating several genes involved in migration and invasion processes; therefore, its use as a therapeutic target may generate promising results in the treatment of gastric cancer.

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.