Andrade, Mariza de

Abstract The role of genes that influence the risk of developing pancreatic cancer (PC) has not been well studied. The mitochondrion, conventionally thought to be an organelle specific to energy metabolism, is in fact multifunctional and has been implicated in many diseases, including cancer. To evaluate whether single nucleotide polymorphisms in mitochondrial DNA (mtSNP) are associated with increased risk of PC, we screened Caucasian cases diagnosed or seen at the Mayo Clinic with primary pancreatic adenocarcinoma (n = 955), and healthy clinic-based Caucasian controls (n = 1,102). A total of 24 mtSNPs, including 10 of the most common tagSNPs, 7 non-tagSNPs in the coding region, and 7 common SNPs in the regulatory region were genotyped. For analysis, these samples were grouped into two phases, the “testing” set (474 cases and 615 controls), and the “validation” set (481 cases and 487 controls). In the testing set, one mtSNP (SNP11719) suggested an association in single SNP analysis, with an odds ratio of 1.34 (95% confidence intervals, 1.05-1.72; P = 0.020), but did not remain statistically significant after correction for multiple testing. In the validation set, none of the 24 variants indicated any association with PC. For haplogroup analysis, 10 core SNPs that form common haplogroups in Caucasians (1719, 4580, 7028, 8251, 9055, 10398, 12308, 13368, 13708, and 16391) were evaluated. No significant associations with PC were identified either by analyzing the two sets separately or combined (combined global P = 0.17). Overall, these results do not support a significant involvement of mitochondrial DNA variation in the risk of developing PC. Investigation of other mitochondrial genetic variations (i.e., nuclear-encoded mitochondrial proteins) would be necessary to elucidate any role of mitochondrial DNA variation in PC. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1455–9)

Abstract The use of tyrosine kinase inhibitors (TKI) has yielded great success in treatment of lung adenocarcinomas. However, patients who develop resistance to TKI treatment often acquire a somatic resistance mutation (T790M) located in the catalytic cleft of the epidermal growth factor receptor (EGFR) enzyme. Recently, a report describing EGFR-T790M as a germ-line mutation suggested that this mutation may be associated with inherited susceptibility to lung cancer. Contrary to previous reports, our analysis indicates that the T790M mutation confers increased Y992 and Y1068 phosphorylation levels. In a human bronchial epithelial cell line, overexpression of EGFR-T790M displayed a growth advantage over wild-type (WT) EGFR. We also screened 237 lung cancer family probands, in addition to 45 bronchoalveolar tumors, and found that none of them contained the EGFR-T790M mutation. Our observations show that EGFR-T790M provides a proliferative advantage with respect to WT EGFR and suggest that the enhanced kinase activity of this mutant is the basis for rare cases of inherited susceptibility to lung cancer. [Cancer Res 2007;67(10):4665–70]

AbstractMutations in the BRCA2 gene have been implicated in pancreatic cancer susceptibility through studies of high-risk breast and ovarian cancer families. To determine the contribution of mutations in BRCA2 to familial pancreatic cancer, we screened affected probands from 151 high-risk families identified through pancreatic cancer clinics for germ-line BRCA2 mutations. Of these families, 118 had two or more first- and second-degree relatives with pancreatic cancer, and an additional 33 had two or more affected second-degree relatives. The average age of onset for pancreatic cancer was 62.8 years. Five BRCA2 truncating mutations were identified, three in families with two or more first- and second-degree relatives with pancreatic cancer. Three of the families with mutations had a history of breast cancer but not ovarian cancer. Four of five families with mutations were identified through probands with early-onset (<55 years) pancreatic cancer. The results of this study were combined with those from a BRCA2 mutation study of 29 other families from the same Johns Hopkins University National Familial Pancreatic Tumor Registry to estimate the frequency of BRCA2 mutations. A total of 10 carriers from 180 families were identified, suggesting that BRCA2 mutations account for 6% of moderate and high-risk pancreatic cancer families. (Cancer Epidemiol Biomarkers Prev 2007;16(2):342–6)

Abstract In this study, we observed loss of heterozygosity (LOH) in human chromosomal fragment 6q25.1 in sporadic lung cancer patients. LOH was observed in 65% of the 26 lung tumors examined and was narrowed down to a 2.2-Mb region. Single-nucleotide polymorphism (SNP) analysis of genes located within this region identified a candidate gene, termed p34. This gene, also designated as ZC3H12D, C6orf95, FLJ46041, or dJ281H8.1, carries an A/G nonsynonymous SNP at codon 106, which alters the amino acid from lysine to arginine. Nearly 73% of heterozygous lung cancer tissues with LOH and the A/G SNP also exhibited loss of the A allele. In vitro clonogenic and in vivo nude mouse studies showed that overexpression of the A allele exerts tumor suppressor function compared with the G allele. p34 is located within a recently mapped human lung cancer susceptibility locus, and association of the p34 A/G SNP was tested among these families. No significant association between the less frequent G allele and lung cancer susceptibility was found. Our results suggest that p34 may be a novel tumor suppressor gene involved in sporadic lung cancer but it seems not to be the candidate familial lung cancer susceptibility gene linked to chromosomal region 6q23-25. [Cancer Res 2007;67(1):93–9]

Abstract Despite numerous studies showing that mutagen sensitivity is a cancer predisposition factor, the heritability of mutagen sensitivity has not been clearly established. In this report, we used a classic twin study design to examine the role of genetic and environmental factors on the mutagen sensitivity phenotype. Mutagen sensitivity was measured in peripheral blood lymphocytes from 460 individuals [148 pairs of monozygotic (MZ) twins, 57 pairs of dizygotic (DZ) twins, and 50 siblings]. The intraclass correlation coefficients were all significantly higher in MZ twins than in dizygotes (DZ pairs and MZ-sibling pairs combined) for sensitivity to four different mutagen challenges. Applying biometric genetic modeling, we calculated a genetic heritability of 40.7%, 48.0%, 62.5%, and 58.8% for bleomycin, benzo[a]pyrene diol epoxide, γ-radiation, and 4-nitroquinoline-1-oxide sensitivity, respectively. This study provides the strongest and most direct evidence that mutagen sensitivity is highly heritable, thereby validating the use of mutagen sensitivity as a cancer susceptibility factor. (Cancer Res 2006; 66(12): 5993-6)

Background and Purpose— Genetic factors that influence interindividual variation in levels of plasma homocysteine, a risk factor for vascular disease, are not fully understood. We performed linkage analyses to identify genomic regions that influence homocysteine levels in blacks and non-Hispanic whites. Methods— Subjects (n=2283) belonged to hypertensive sibships and included 1319 blacks (63±10 years, 70% women) and 964 non-Hispanic whites (61±7 years, 57% women). Fasting plasma homocysteine was measured by high-pressure liquid chromatography. Genotypes were measured at 366 microsatellite marker loci distributed across the 22 autosomes. Plasma homocysteine adjusted for age, sex, body mass index, serum creatinine, and estrogen use (in women) was used in the genetic analyses. Heritability and linkage analyses were performed using a variance components approach. Results— Mean (±SD) homocysteine levels were 10.4±5.27 μmol/L in blacks and 10.0±2.84 μmol/L in non-Hispanic whites ( P =0.58 for difference). Homocysteine levels were significantly ( P <0.0001) heritable in blacks ( h 2 =0.70) and in non-Hispanic whites ( h 2 =0.49). Linkage analyses demonstrated significant evidence of linkage (multipoint logarithm of odds≥3.0) for homocysteine on chromosomes 1q42, 14q32, and 19p13 in blacks and on chromosomes 9q34 and 12q24 in non-Hispanic whites. Tentative evidence of linkage (logarithm of odds 1.3 to 2.0) was present on chromosomes 2q32, 7p15, 8q24, 18q21, and 20p12 in blacks and chromosomes 6q26 and 18q21 in non-Hispanic whites. Four genes in the homocysteine metabolism pathway ( MTR , DNMT1 , GAMT , and CARM1 ) were present under 2 of the significant linkage signals in blacks (chromosomes 1q42 and 19p13). Conclusions— Plasma homocysteine is a significantly heritable trait. Linkage analyses reveal several unique genomic loci that may influence circulating levels of homocysteine and therefore susceptibility to vascular diseases including stroke.