American Association for Clinical Chemistry
Better health through laboratory medicine
March 2009 Clinical Laboratory News: Diagnostic Profiles

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March 2009: Volume 35, Number 3

DNA Repair Gene Polymorphisms Associated with Pancreatic Cancer Risk

New research indicates that abnormalities in DNA repair genes alone or in joint action with diabetes significantly modified the risk of pancreatic cancer (Clin Cancer Res 2009;15:740–746). The study builds on previous research by the authors that showed that single nucleotide polymorphisms of repair genes were significantly associated with clinical outcome and overall survival of patients with pancreatic cancer who received chemoradiation. If confirmed in other studies, the findings of their latest study could lead to a means of identifying high-risk individuals for early detection and intervention in this highly fatal disease.

The researchers analyzed nine SNPs of seven DNA repair genes in 734 patients with pancreatic cancer and 780 healthy control subjects, and collected via personal interviews information about cigarette smoking, alcohol intake, medical history, and other risk factors. The genotypes analyzed included LIG3 G-39A, LIG4 C54T, OGG1 T2657C, OGG1 C-315G, ATM C-77T, ATM D1853N, POLB T-2133C, RECQL A159C, and RAD54L C154T. Of these, the variant forms of LIG3 G-39A and ATM D1853N were significantly associated with altered risk for pancreatic cancer. Individuals with the variant form of the LIG3 gene (LIG3 G-39A AA) had a 77% lower risk of developing the disease after adjusting for age, sex, smoking, alcohol, diabetes, and family cancer history status, while those with the variant form of ATM D1853N had a 2.5 times greater risk. For the remaining seven SNPs there were no statistically significant differences in genotype distributions between cases and controls.

There also was a statistically significant interaction between the ATM D1853N genotype and diabetes and the risk of diabetes. The odds ratio of pancreatic cancer was 4.17 for diabetics carrying the A allele versus 2.08 for diabetics carrying the G allele compared with non-diabetics. The researchers speculate that diabetes increases oxidative stress and any deficiency in DNA repair genes could lead to a greater chance for tumor development.

RaArray Comparative Genomic Hybridization Effective in Prenatal Diagnosis

A study evaluating array comparative genomic hybridization (aCGH) in prenatal diagnosis found that the method reliably detected clinically significant copy number changes in 5% of samples, while identifying an acceptably low 1% rate of copy number variants of uncertain clinical significance (Prenat Diagn 2009;29:29–39). According to the authors, the results suggest that the method is a promising diagnostic tool for prenatal detection of chromosomal abnormalities, and if confirmed by larger studies, aCGH could become the first-line test to detect chromosomal abnormalities. The authors performed aCGH on 300 samples of either amniotic fluid or chorionic villus sampling and found that 58 (19.3%) had copy number variants. Of these, 13.3% were determined to be benign inherited variants, 5% were pathologically significant, and 1% were of uncertain clinical significance. aCGH contributed important new information in 2.3% of cases, and in two instances, the abnormality would not have been detected via karyotype or FISH.

The current prenatal diagnostic strategy, which is focused primarily on detecting trisomy 21, identifies approximately 95% of fetuses with Down syndrome, and provides risk evaluation for trisomy 18, neural tube defects, and Smith-Lemli-Opitz syndrome. However, it typically does not detect deletions and duplications associated with moderate to severe disabilities that result from submicroscopic chromosomal abnormalities below the resolution of karotype analysis. FISH can detect these disorders, but it is not feasible to perform FISH for all possible deletion and duplication syndromes, or to identify all pregnancies at increased risk. In contrast, the authors contend that aCGH detects genetic deletions and duplications quickly and accurately. The technique has been used extensively in pediatric populations to detect chromosomal abnormalities, but not in clinical prenatal diagnosis.