| dc.description.abstract | Background: In Western countries most of colorectal cancer (CRC) cases are
found in the colon (proximal and distal) rather than in the rectum. Each location
can result in defferent clinical, pathological and molecular characteristics of the
cancer, and most of studies have only compared between proximal and distal
colon. In Indonesia the majority of this cancer is located in the rectum rather
than in the colon, and a research on the adenomatous polyposis coli (APC),
mismatch repair (MMR) and microsatellite instability (MSI) of CRC based on the
three different locations (proximal, distal colon and rectal cancer) had never
been conducted.
Objectives: To investigate and study the APC protein expression (PE), MMR
PE and MSI in CRC based on the three different locations, among Indonesian
patients in Adam Malik Hospital, Pirngadi Hospital and other hospitals within the
network of the Faculty of Medicine University of Sumatera Utara, Medan
Indonesia.
Methods: This prospective study was conducted from April to December 2012.
The minimum number of sample size patients had been statistically calculated
and decided to be 24 patients for each location, as this was a comparative
study. The Fresh tissues were obtained either by colonoscopic biopsy or
surgery. Inclusion criteria were adenocarcinoma confirmed histologically, and
no family history of tumor or CRC. The PE of APC and MMR (MLH1, MSH2,
PMS2 and MSH6) were assessed by immunohistochemistry (IHC), while MSI
was determined by polymerase chain reaction (PCR) using five microsatellite
markers, BAT-25, BAT-26, O2S123, O5S346 and O17S250. The primary
antibodies used for IHC examination were: MLH1: Flex monoclonal mouse
antibody (Clone: ES05, DAKO); MSH2: (3A2B8C); MSH6: Abeam Inc:
Cambridge MA (ab92471); PMS2: (H-300), sc-11440.lnc, and APC: (F-3): sc-
9998. Biotechnology. Dako Real Envision Rabbit/Mouse was used as Universal
Secondary Antibody. Primers and Characteristics of Microsatellite Loci
Analyzed: BAT-25 (Hex), Genbank no. 9834508, U63834; BAT-26 (Tet),
Genbank no. 9834505, L47575; O2S123 (Tet), Genbank no. 187953; O5S346
(Fam), Genbank no. 181171, M73547; and O17S250 (Fam), Genbank no.
177030, X54562.
Results: Among the 77 CRC, 24 were located in the proximal colon, 24 in distal
colon and 29 in rectum. Loss of MMR protein expression (MMR PE negative)
was found in 54 out of 77 (70.1 %) CRC patients. Bivariate analysis showed
that there were significant differences of MLH 1 protein expression (PE) negative
between distal colon and rectal cancer (p=0.008), and MSH6 protein expression
negative between proximal colon and rectal cancer (p=0.020). Multivariate analysis showed that MLH 1 protein expression negative was
significantly related to the location of the cancer (p=0.006) with Odds Ratio:
0.12 (95% Cl OR: 0.026-0.547). It had 0.12 times probability to be found in
distal than rectum. MLH 1 protein expression negative had 1 0 times higher
probability to be found in proximal than distal colon (p=0.037). MSH6 protein
expression negative was related to the locations (p=0. 026) with Odds Ratio
0.165 (95% Cl OR 0.034-0.803). It had 0.165 times probability to be found in
proximal than rectal cancer, or 6.06 times higher probability to be found in rectal
cancer than proximal colon cancer, and had 11 times higher probability in distal
colon than proximal (p=0.043). APC protein expression negative was also
significantly related to the locations (p=0.020), with Odds Ratio: 6.897 (95%CI
OR: 1.359-34.995), and had 6.89 times higher probability to be found in distal
than rectal cancer, with other variables controlled.
MSI-High (MSI-H) was found in 29 out of 77 (37.7%), MSI-Low (MSI-L)
and Microsatellite Stable (MSS) in 48 (62.3%). The proportion of MSI-H
displayed a tendency to occur in proximal rather than in distal or rectal cancer,
but the difference was not significant.
Conclusions: This research showed that there were significant differences in
the marker of MMR PE negative between proximal, distal colon and rectal
cancer. MLH 1 PE negative was prominent in proximal colon cancer, MSH6 PE
negative in distal colon and rectal cancer, and APC PE negative in distal colon
cancer respectively. Those PE negative were significantly related to the
location of the cancer. These findings suggest that the underlying carcinogenic
pathway or molecular background differs according to the cancer locations,
among CRC patients in this region. The cancer in each colorectal location has
its specific molecular characteristics | en_US |
