Genetic alterations and growth pattern in biliary duct carcinomas: loss of heterozygosity at chromosome 5q bears a close relation with polypoid growth

Abstract

Biliary duct carcinomas (BDCs) are relatively rare and the carcinogenic mechanisms underlying their induction are poorly understood. There are two growth patterns, polypoid and non-polypoid infiltrative type, but little information is available concerning the relation between growth pattern and genetic alterations. A comparative study was therefore conducted to clarify if differences in genetic changes, including loss of heterozygosity (LOH) at 5q, 9p, 17p, and 18q, and K-ras mutations exist between polypoid and non-polypoid infiltrative type BDCs. LOH analysis was performed using microsatellite markers and K-ras point mutations were analysed by dot blot hybridisation. The incidences of changes for polypoid and non-polypoid infiltrative types were 73% and 26% on 5q, 63% and 59% on 9p, 55% and 50% on 17p, and 20% and 18% on 18q, and 25% and 27% for K-ras mutations. Most importantly, we found the frequency of 5qLOH to be significantly higher with polypoid growth than in the non-polypoid infiltrative type (p<0.05), especially in extrahepatic duct carcinomas (p<0.05). The incidences of other genetic alterations (LOH at 9p, 17p, and 18q, and K-ras mutations) showed similar rates with both tumour types. The present data suggest that 5qLOH may have a close relation with polypoid growth in BDCs.

Figure 1

Examples of the two growth patterns. (A) Polypoid growth type (haematoxylin-eosin, ×12.5). (B) Invasive portion (haematoxylin-eosin, ×100) with cholangiography of the same case (C). (D) Non-polypoid infiltrative type (haematoxylin-eosin, ×12.5). (E) Invasive portion (haematoxylin-eosin, ×100) with cholangiography of the same case (F).

Figure 2

Illustration of examples of loss of heterozygosity (LOH). Polymerase chain reaction products for normal tissue (N) and tumour (T) DNA are shown. Microsatellite alleles are represented by two signals in the case of heterozygosity. LOH at one allele corresponds to almost complete loss of one of two signals (arrowheads).