Although the APC/β‐catenin pathway is known to play a crucial role in sporadic colorectal carcinogenesis, its influence on ulcerative colitis (UC)–related neoplastic progression is unknown. To elucidate the role of the APC‐/β‐catenin pathway in UC‐related carcinogenesis, the authors identified APC and β‐catenin mutations in a set of UC‐related and sporadic colorectal carcinomas.

We previously have demonstrated by comparative genomic hybridization that 80% of ulcerative colitis-related cancers show loss of all or part of chromosome 18, the site of at least three candidate tumor suppressor genes: DCC, SMAD2, and SMAD4. To determine whether these genes are targeted in colitis-related carcinogenesis, we performed a high-resolution analysis of chromosome 18 alteractions in 32 colitis-related colorectal cancers by assessing allelic imbalance at 11 microsatellite markers distributed along the chromosome, and by the quantitative polymerase chain reaction (PCR) method (TaqMan). TaqMan analysis was used to determine the relative copy number of five test genes on chromosome 18 (PACAP on 18p and DCC, SMAD2, SMAD4, and GALNR on 18q). We found allelic imbalance, as assessed by loss of heterozygosity, in at least one marker on chromosome 18 in 25 of the 29 tumors (86%) successfully tested. In 14 tumors, allelic imbalance was detected at all informative markers on 18q, while the other 11 tumors showed only partial loss. Allelic imbalance was most commonly detected at D18S363 (78% of informative cases). This marker is in closest proximity to SMAD4. By quantitative PCR analysis, a relative loss of copy number of SMAD2, SMAD4, and DCC were detected in 40%, 57%, and 53%, respectively, of the colitis-related cancers. SMAD2 was retained in four tumors having loss of SMAD4 and DCC. Loss of SMAD4 alone was seen in one tumor. The present data indicate that the loss of SMAD4 and DCC occurs in the majority of colitis-related cancers.

We previously have demonstrated that most ulcerative colitis-related cancers show loss of all or part of cbromosome 18 by comparative genomic hybridization (CGH).Chromosome 18q is the site of at least three candidate tumor suppressor genes: DCC, SMAD2 and SMAD4.One or more of these genes may be involved in the development of sporadic colorectal cancer.The goal of this study was to determine whether these genes are targeted in colitis-related carcinogenesis.We performed a high-resolution analysis of chromosome 18 alterations in thirty-two colitis-related colorectal cancers by assessing allelic imbalance at 11 microsatellite markers and determining the relative copy number of five genes on chromosome 18 (PACAP, DCC, SMAD2, SMAD4, GALNR) using the TaqMan method.The results were compared with our previous CGH data.Allelic imbalance was assessed successfully in 29 of 31 tumors.Allelic imbalance was detected in at least one marker on chromosome 18 in 25 tumors (86%).Allelic imbalance was most commonly detected at D18S363 (78% of informative cases).This marker is in closest proximity to SMAD4.By TaqMan analysis, a relative loss of copy number of SMAD2, SMAD4, and DCC were detected in 40%, 57% and 53% respectively.Loss of all or part of the long arm of chromosome 18 was detected by LOH or CGH in approximately 80% of colitis-related cancers.Allelic imbalance and gene copy number analysis indicated that loss of one or more of the candidate tumor suppressor genes on 18q (SMAD2, SMAD4, and DCC) occurred in most of the tumors with 18q losses.SMAD4 appears to be the most frequent target of loss on 18q in colitis-related cancer.

Organ transplant recipients have an increased tumor incidence owing to their immunocompromised state. The origin of such tumors, whether donor or recipient, will have a clinical impact on decision-making concerning immunosuppressive therapy, retransplantation, and for recipients of other organs from the same donors. We report molecular cytogenetic determination of donor origin in 2 cases of small-cell neuroendocrine carcinoma developing in sex-mismatched transplant recipients (kidney and liver). Fluorescence in situ hybridization (FISH) analysis was performed on liver core needle biopsy material from the liver transplant patient and on liver fine needle aspiration cytopreparations from the kidney transplant patient. The results for the liver transplant patient were confirmed with microsatellite allelic analysis and with comparative genomic hybridization. In both cases, FISH showed the presence of only X chromosomes within the tumor cells, indicating the donor origin of the neoplasms. FISH is an excellent method to determine neoplastic origin in sex-mismatched transplant patients. HUM PATHOL 31:1425-1429.