Visit our Expo - Redox and Inflammation signaling 2012

IV. Protein kinase inhibitors: insights into drug design from structure Poster IV, 4
Aberrant methylation of p15INK4B and p14ARF and deletion of p16INK4A are
frequent events in liver fluke related cholangiocarcinoma
Temduang Limpaiboon1,4, Preeda Prakrankamanant1, Inthira Tussakhon1, Patcharee
Chinnasri1, Patcharee Jearanaikoon1,4, Chawalit Pairojkul2,4, Banchob Sripa2,4,
Vajarabhongsa Bhudhisawasdi3,4
1Department of Clinical Chemistry, Centre for Research and Development of Medical
Diagnostic Laboratories, Faculty of Associated Medical Sciences, 2Department of
Pathology, 3Department of Surgery, 4Liver Fluke and Cholangiocarcinoma Research
Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
E-mail:temduang@kku.acth
Cholangiocarcinoma (CCA) is the highest incidence cancer in Northeast Thailand. CCA is
caused by liver fluke (Opisthorchis viverrrini) infection resulting in both genetic and
epigenetic alterations. The INK4 locus located on chromosome 9p21 consisting of three
genes, p14ARF, p16INK4A and p15INK4B, which are involved in cell cycle regulation and
reported to be inactivated in many human cancers through genetic and epigenetic events. To
understand mechanisms of inactivation of these three genes in CCA, we analyzed loss of
heterozygosity (LOH) at chromosomal region 9p21 using three polymorphic microsatellite
markers; D9S1752, D9S171 and D9S161 and determined promoter hypermethylation of
p14ARF, p16INK4A and p15INK4B using methylation-specific PCR in 79 CCA. LOH was
found at least one or more loci in 32 of 74 informative cases (43.2%) in which high frequency
was found in D9S1752 (34.9%) and less frequency was observed in D9S171 (27.6%).
Aberrant methylation was present predominantly in p15INK4B (50.6%) and p14ARF (41.2%)
and less frequently in p16INK4A (25.3%). Our results suggest that promoter
hypermethylation is a predominant inactivation mechanism of p15INK4B and p14ARF,
whereas, deletion is a major event for inactivation of p16INK4A during CCA development.
This finding may lead to a new approach of CCA treatment.
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