Premium
A search for germline APC mutations in early onset colorectal cancer or familial colorectal cancer with normal DNA mismatch repair
Author(s) -
Boardman Lisa A.,
Schmidt Shauna,
Lindor Noralene M.,
Burgart Larry J.,
Cunningham Julie M.,
PriceTroska Tammy,
Snow Karen,
Ahlquist David A.,
Thibodeau Stephen N.
Publication year - 2001
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/1098-2264(2000)9999:9999<::aid-gcc1074>3.0.co;2-k
Subject(s) - familial adenomatous polyposis , germline mutation , colorectal cancer , microsatellite instability , dna mismatch repair , germline , genetics , adenomatous polyposis coli , population , medicine , cancer , cancer research , mutyh , biology , mutation , gene , microsatellite , allele , environmental health
Twenty percent of colorectal cancers (CRCs) arise in people who have a family history of CRC in at least one other relative. Although a fraction of these CRCs are explained by two well‐described autosomal dominant syndromes—5% by hereditary nonpolyposis colorectal cancer (HNPCC) and 1% by familial adenomatous polyposis (FAP)—the cause of the remaining 14% of familial aggregates of CRC is unknown. Many cases of HNPCC are due to germline mutations in DNA mismatch repair genes, leading to the tumor phenotype of microsatellite instability (MSI), and most cases of FAP are caused by germline APC mutations. To date, non‐FAP familial CRC aggregates have not been evaluated for germline APC mutations. In this study, we examined the involvement of germline APC mutations in 79 individuals with CRC who had early‐age onset of their cancer (age < 50 years) and/or a family history of CRC. Cases with FAP or HNPCC due to defective mismatch repair were excluded from the study. Using conformation‐sensitive gel electrophoresis and the protein truncation test as the screening methods, no functionally significant germline mutations were detected for any of the cases. An apparently silent polymorphism resulting in a 1‐bp alteration of A → G (proline → proline) in exon 4 was observed. Additionally, four intervening sequence (IVS) alterations were detected: IVS2‐53t→c in 3 cases; IVS4‐17ins T in 3 cases; IVS5+32t→c in 16 cases; and IVS5+33g→a in 1 case. All appeared to be polymorphisms present in similar proportions in an average‐risk population. We conclude that germline APC mutations do not account for familial MSS (stable microsatellite) CRC associated with few synchronous polyps. ©2000 Wiley‐Liss, Inc.