Naturally occurring mutations and functional polymorphisms in multidrug resistance 1 gene: correlation with microsatellite instability and lymphoid infiltration in colorectal cancers

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Abstract
Pglycoprotein (Pgp), encoded by the MDR1 gene, is a transmembrane transporter that acts as an efflux pump in an ATP dependent fashion.1 Multidrug resistance, the main problem in efficient cancer chemotherapy, is mainly caused by increased expression and acquired mutations in the MDR1 gene.2 Pgp is expressed physiologically in epithelial cells of the kidney, liver, pancreas, and colon, suggesting its role in secretion of toxic compounds.3 Pgp is also expressed in the blood-brain barrier, adrenal glands, and lymphocytes where its role is still uncertain. Recently, additional functions for Pgp, including immune response4 and regulation of apoptosis,5 have been suggested in normal tissues and in cancers. High expression of Pgp at the apical surface of differentiated tubular structures was identified in previously untreated colorectal cancers (CRC)6 and its high expression at the leading edge of a colorectal carcinoma was associated with tumour progression.7 In contrast to the majority of CRC, which develop as a result of chromosomal instability (CIN), a proportion of sporadic CRC and 90% of cancers in patients with hereditary non-polyposis colorectal cancer (HNPCC) exhibit microsatellite instability (MSI).8 In MSI CRC, chromosomal aberrations such as large deletions, translocations, and gene amplifications are rare; the great majority of MSI tumours are usually diploid or near diploid. In MSI CRC, inactivation of the mismatch repair (MMR) system owing to mutations or methylation of MMR genes results in a 1000-fold accumulation of point mutations in oncogenes and tumour suppressor genes which trigger tumour progression. Therefore, in addition to genes mutated in microsatellite stable (MSS) CRC, such as APC , p53 , and K-ras , there are other genes important in the development of MSI cancers. Interestingly, MSI CRCs are also more often resistant to several chemotherapy drugs; the selection of cells for resistance to …