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High resolution analysis of chromosome 18 alterations in ulcerative colitis-related colorectal cancer
Jonathan P Terdiman1, Daniela E Aust, Cornell G Chang
1Cancer Center, University of California-San Francisco, San Francisco, CA, USA. jterd@itsa.ucsf.edu
Abstract:
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.
Insights
Loss of tumor suppressor genes SMAD4 and DCC on chromosome 18 is common in ulcerative colitis-related colorectal cancers. This study analyzed chromosome 18 alterations, finding frequent allelic imbalance and copy number loss of these key genes.
Area of Science:
- Genetics
- Oncology
- Gastroenterology
Background:
- Ulcerative colitis (UC) is associated with an increased risk of colorectal cancer (CRC).
- Comparative genomic hybridization previously showed loss of chromosome 18 in 80% of UC-related CRC.
- Chromosome 18 harbors candidate tumor suppressor genes: DCC, SMAD2, and SMAD4.
Purpose of the Study:
- To investigate the specific alterations of chromosome 18 and candidate tumor suppressor genes in colitis-related CRC.
- To determine if DCC, SMAD2, and SMAD4 are targeted during colitis-related carcinogenesis.
Main Methods:
- High-resolution analysis of chromosome 18 alterations in 32 colitis-related CRC.
- Assessed allelic imbalance using 11 microsatellite markers.
- Quantified gene copy number using quantitative polymerase chain reaction (PCR) with TaqMan assays for PACAP, DCC, SMAD2, SMAD4, and GALNR.
Main Results:
- Allelic imbalance on chromosome 18 was found in 86% of tumors (25/29).
- Loss of heterozygosity was common, with 14 tumors showing complete 18q imbalance.
- Quantitative PCR revealed copy number loss for SMAD2 (40%), SMAD4 (57%), and DCC (53%) in colitis-related cancers.
Conclusions:
- The study confirms frequent alterations on chromosome 18 in UC-related CRC.
- Loss of the tumor suppressor genes SMAD4 and DCC is a prevalent event in the majority of these cancers.
- These findings highlight the importance of SMAD4 and DCC in colitis-associated colorectal carcinogenesis.