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Some Clinical Features and Molecular Alterations of Traditional Serrated Pathway in Sporadic Colorectal Carcinogenesis

Author: ZhouZhiYong
Tutor: HanYing
School: PLA Postgraduate Medical School
Course: Internal Medicine
Keywords: Colorectal cancer Serrated adenoma Traditional adenomas Serrated colorectal cancer Microsatellite instability BRAF variation
CLC: R735.3
Type: PhD thesis
Year: 2008
Downloads: 100
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[Background]Colorectal cancer(CRC) is the third highest tumor of all kinds of malignant rumors in mortality rate worldwidely. About 80% sporadic CRC comes from a kind of colorectal polyp named adenoma, especially those comprises villous-like components. However, Hyperplastic polyps have traditionally been regarded as non-neoplastic lesions. In recent years some people have noticed that there were a series of lesion which had serrated structure in colon and rectum, called serrated lesions. These lesions including aberrant crypt foci(ACF), serrated polyps[which also has four subtypes: hyperplastic polyp(HP), sessile serrated adenoma(SSA), mixrured polyp(MP), traditional serrated aenoma(TSA)], serrated carcinoma(SCa). These serrated lesions have been found close correlation with some sporadic CRC. Hawkins conjectured that there might be a new carcinogenesis pathway associated with SA, the serrated neoplasia pathway. Moreover, some scholars thought there should be two, not one, paralleled and scarcely crossed serrated pathway, one was traditional serrated pathway, the other was sessiled serrated pathway. This theory is an very important complement to the classic "adenoma-carcinoma" carcinogenesis pathway. It is of important clinical value. So it is essential to study serrated lesions and the serrated pathway. Nowadays there was little study about SA in our country, however, many overseas’ studies have been undertaken aimed at serrated adenoma’s histology, morphology, molecular biology and clinic value, et al.[Objective]1. To know some clinic features of TSA and compare it with AD. Find the difference between the two kinds of lesion.2. To verify, the traditional serrated pathway indirectly by comparing some specific molecular markers(MSI, Braf V600E mutation) among SA, AD, serrated colorectal cancer and non-serrated colorectal cancer. [Methods]1. All colorectal polyp’s slices from 2003 to 2005 stored in our hospital’s pathology department were reviewed, then TSA was rediagnosed and the patients’ clinical data was collected. The clinical data between TSA and AD was compared and the difference between them was analysised.2. Some colorectal cancer’s slices were reviewed and serrated Cancer(SCa) was rediagnosed. Fifteen SCa samples, twenty non-SCa samples, twenty AD samples and twenty TSA samples were chosen respectively. DNA was extracted from microdissected sections of these slices using specific kit. then was stored in -20℃space for use.3. Took a certain amount DNA of each sample, used specific fluorescently-labeled primers, amplified MSI fragment: BAT25 and BAT26. The production was verified through agarose gel electrophoresis, then analyzed its microsatellite status on automatic DNA sequencer with Genemarker v1.65 software. Finally compared the four group samples’ MSI difference.4. Took the second step’s DNA as template, designed primers as the documents described, amplified exon 15 fragment of BRAF gene. The production was taken to detect the T1799A mutation with RFLP as preliminary screening. The positive samples were verified by direct sequencing. At last drew conclusion about the four group samples’ BRAF mutation.[Result]1. There were 1200 colorectal polyps’ slices totally, 29 traditional serrated adenomas were found in which, about 2.42% of all polyps. The TSA patients were younger than the traditional adenoma patients(56.0vs62.7, P=0.0336); TSA was more often found in the rectosigmoid colon than the traditional adenomas(62.07% vs 35.21%, P=0.0252), however, the situation was opposite in descending colon(0 vs 25.35%, P=0.0068), in other part of the colon, there wasn’t any difference between the two polyps. They also didn’t have any difference on the patient’s gender and the polyps’ size and pedicles’ situation (P>0.05).2. The serrated carcinoma was about 15% of all sporadic CRC. 3. MSI result: There were several samples failed to get results. In the remained samples, six of eighteen TSA harbored MSI-H, twelve samples were MSI-L/MSS; Eighteen conventional adenomas all were MSI-L/MSS; Three of thirteen serrated carcinomas harbored MSI-H, ten samples were MSI-L/MSS; Only one non-SCa samples harbored MSI-H, the other eighteen samples were MSI-L/MSS. With Chi-square test, we found the MSI frequency of AD group and non-SCa group was of significantly lower than which of SA group and SCa group(P< 0.05); however, the latter two groups was of no statistical difference in MSI frequence (P>0.05).4. Braf mutation: There were several samples failed to get results. In the remained samples, four of fifteen TSA samples harbored Braf V600E mutation; none of eleven conventional adenomas and fourteen non-SCa samples harbored Braf V600E mutation; four of eleven serrated carcinomas harbored Braf V600E mutation. With Chi-square test, we found Braf V600E mutation frequence of AD group and non-SCa group was significantly lower than which of TSA group and SCa group (P<0.05); however, the latter two groups was of no statistical difference in which (P>0.05).[conclusion]1. The TSA group is different from the AD group in patients’ age and the lesion’s location, but it’s difficult to distinguish them only through these two points. It’s still necessary to give final diagnosis by pathological assay.2. MSI-H, BRAF V600E mutation frequency of AD group and non-SCa group was obviously lower than SA group and SCa group; however, the latter two groups was of no statistical difference in which (P>0.05).3. Based on the above experimental result, we can conclude that there is actually a new traditional serrated neoplasia pathway which is different from the conventional adenoma-carcinoma carcinogenesis pathway. But we still need prospective follow-up studies to verify its existence. We also need to study serrated adenoma’s subtype, prognosis and its proteomics for this lesion’s prevention and therapy.

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