Esophageal squamous cell carcinoma (ESCC) is a common cancer in the northeast of Iran. In a series of studies we explored the genetic basis for this. First we showed the risk to age 75 of esophageal cancer in the first-degree relatives of patients with esophageal cancer was 34%, versus 14% for the first-degree relatives of the controls (hazard ratio = 2.3, 95%CI = 1.7-3.1; P = 3 x 10 – 8). Second, in a candidate-gene association approach, we showed that the ADH1B p.Arg48His mutation was associated with a significantly decreased risk of ESCC (OR = 0.41, 95%CI = 0.29-0.76; P = 4x10-4) under a recessive mode of inheritance, although our study subjects were not alcohol drinkers. Third, we showed the BRCA2 p.Lys3326X variant to be associated with increased risk of ESCC (OR = 3.38, 95%CI = 1.97-6.91; P = 2x10-4). Then, we hypothesized that the genes for Fanconi anemia may be candidate genes for ESCC and sequenced the entire coding regions of 12 Fanconi anemia genes in the germline DNA of 190 ESCC cases. We identified three heterozygous insertion/deletions in FANCD2, FANCE and FANCL. All three patients had a strong family history of ESCC. In addition, we found two homozygous patients for the deleterious FANCA p.Ser858Arg mutation. We found two more homozygotes in 556 more ESCC patients, but in none of 1373 matched controls (OR = 16.7, 95%CI = 6.2-44.2; P = 0.01). Finally, we implemented a pilot genome-wide association study in ESCC using 182 cases and 177 matched controls. None of the 1.2 M observed and imputed SNPs showed an association with ESCC at a genome-wide significance level. This showed that an ESCC susceptibility allele with OR>3 estimated from our familial risk study, is unlikely to be identified among common variants of the human genome and we should look for it among rare variants.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/29658 |
| Date | 29 August 2011 |
| Creators | Akbari, Mohammadreza Jr. |
| Contributors | Narod, Steven |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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