APC and AXIN2 Are Promising Biomarker Candidates for the Early Detection of Adenomas and Hyperplastic Polyps.

Aberrant activation of the WNT/CTNNB1 pathway is notorious in colorectal cancer (CRC). Here, we demonstrate that the expression of specific and crucial WNT signaling pathway genes is linked to disease progression in colonic adenomatous (AP) and hyperplastic (HP) polyps in an Iranian patient population. Thus, we highlight potential gene expression profiles as candidate novel biomarkers for the early detection of CRC. From a 12-month study (2016-2017), 44 biopsy samples were collected during colonoscopy from the patients with colorectal polyps and 10 healthy subjects for normalization. Clinical and demographic data were collected in all cases, and mRNA expression of APC, CTNNB1, CDH1, AXIN1, and AXIN2 genes was investigated using real-time polymerase chain reaction (PCR). CTNNB1 and CDH1 expression levels were unaltered in AP and HP subjects, whereas mRNA expression of APC was decreased in AP contrasted with HP subjects, with a significant association between APC downregulation and polyp size. Although AXIN1 showed no changes between AP and HP groups, a significant association between AXIN1 and dysplasia grade was found. Also, significant upregulation of AXIN2 in both AP and HP subjects was detected. In summary, we have shown increased expression of AXIN2 and decreased expression of APC correlating with grade of dysplasia and polyp size. Hence, AXIN2 and APC should be explored as biomarker candidates for early detection of AP and HP polyps in CRC.

Prognostic Value of BRAF and KRAS Mutation in Relation to Colorectal Cancer Survival in Iranian Patients: Correlated to Microsatellite Instability.

PURPOSE: To evaluate the prognostic role of BRAF and KRAS mutations after adjustment for microsatellite instability (MSI) in Iranian colorectal cancer (CRC) patients. METHODS: BRAF and KRAS mutations and MSI status were assessed in 258 Iranian subjects with CRC. Two hundred fifty-eight consecutive stages I-IV CRC patients, who underwent surgical resection of adenocarcinoma from 2012 to 2016, were enrolled in the research. Pyrosequencing and Cast-PCR methods were used to the detection of KRAS and BRAF mutations. Kaplan-Meier and Cox regression were employed to estimate hazard ratios (HR) for the association between BRAF and KRAS mutation and overall survival (OS). RESULTS: KRAS and BRAF mutations were detected in 36 (14%) and 15 (5.8%) cases of 258 patients with CRC, respectively. BRAF mutations that all comprised V600E and KRAS mutations was found in codon 12 and 13 (80.6% and 19.4%), respectively. KRAS mutations were detected in 19 (15.4%) patients of 123 microsatellite stable (MSS) CRC and it is significantly associated with tumor location and metastasis. BRAF and KRAS mutant vs. wild type of BRAF and KRAS, 5-year OS was 73.3% vs. 82.3% and 83.3% vs. 81.5% (long-rank P > 0.05), respectively. KRAS mutant vs. KRAS-wild-type tumors in MSS/MSI-L status CRC patients, 5-year OS was 78.9% vs. 90.4% (long-rank p = 0.046). CONCLUSION: The present study revealed that BRAF and KRAS mutations were not related to the worse overall survival, while KRAS mutation can be a prognostic factor for overall survival in sporadic microsatellite-stable (MSS) status in Iranian CRC patients.

Novel Missense Mutation at Codon 2774 (C.8321 G>A) p.S2774N of APC Gene in a Denovo Case of Familial Adenomatous Polyposis.

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease caused by germline mutation in Adenomatous Polyposis Coli (APC) gene. FAP accounts less than 1% of all colorectal cancers incidence. Patients generally present hundreds to thousands of adenomas in colon and rectum and develop colorectal cancer by age 35 - 40 if left untreated. A milder form of FAP with fewer numbers of polyps (< 100) is Attenuated FAP (AFAP) and in comparison with classical FAP, it usually diagnosed at an older age. Approximately 15% - 20% of FAP patients are ''de novo'' cases without any family history of the disease and novel APC mutations account for approximately 25% of FAP cases. In our study, we reported a novel missense mutation at the APC gene in a denovo patient with AFAP like phenotype.

Frameshift Mutations (Deletion at Codon 1309 and Codon 849) in the APC Gene in Iranian FAP Patients: a Case Series and Review of the Literature.

Familial adenomatous polyposis (FAP) is responsible for <1% of colorectal cancer (CRC) cases and is inherited an autosomal dominant trait. Patients generally present hundreds to thousands of adenomas and develop colorectal cancer by age 35- 40 if left untreated. Here we report four patients with germline frameshift mutation (small deletion) at exon 15 of adenomatous polyposis coli (APC) tumor suppressor gene. Peripheral blood samples were collected from patients and Exon 15 of the APC gene was studied by direct sequencing after genomic DNA extraction. Four frameshift mutations were detected. Two patients had 5 bp deletion, c.3927_3931delAAAGA and two siblings presented deletion at codon 849 (c.2547_2548delTA p.Asp849fsX62). This study was the first report of genetic screening in Iranian FAP patients. In contrast to other studies we revealed that one patient with mutation at codon 1309 had an attenuated phenotype.

MUTYH the base excision repair gene family member associated with colorectal cancer polyposis.

COLORECTAL CANCER IS CLASSIFIED IN TO THREE FORMS: sporadic (70-75%), familial (20-25%) and hereditary (5-10%). hereditary colorectal cancer syndromes classified into two different subtypes: polyposis and non polyposis. Familial Adenomatous polyposis (FAP; OMIM #175100) is the most common polyposis syndrome, account for <1% of colorectal cancer incidence and characterized by germline mutations in the Adenomatous polyposis coli (APC, 5q21- q22; OMIM #175100). FAP is a dominant cancer predisposing syndrome which 20-25% cases are de novo. There is also another polyposis syndrome; MUTYH associated polyposis (MAP, OMIM 608456) which it is caused by mutation in human Mut Y homologue MUTYH (MUTYH; OMIM 604933) and it is associated with multiple (15-100) colonic adenomas. In this paper we discuss MUTYH mechanism as an important member of Base Excision Repair (BER) family and its important role in polyposis condition.