Maureen Sadim

Germline Allele-specific Expression of TGFBR1 Confers an Increased Risk of Colorectal Cancer

Much of the genetic predisposition to colorectal cancer (CRC) in humans is unexplained. Studying a Caucasian-dominated population in the United States, we showed that germline allele-specific expression (ASE) of the gene encoding transforming growth factor–β (TGF-β) type I receptor, TGFBR1, is a quantitative trait that occurs in 10 to 20% of CRC patients and 1 to 3% of controls. ASE results in reduced expression of the gene, is dominantly inherited, segregates in families, and occurs in sporadic CRC cases. Although subtle, the reduction in constitutive TGFBR1 expression alters SMAD-mediated TGF-β signaling. Two major TGFBR1 haplotypes are predominant among ASE cases, which suggests ancestral mutations, but causative germline changes have not been identified. Conservative estimates suggest that ASE confers a substantially increased risk of CRC (odds ratio, 8.7; 95% confidence interval, 2.6 to 29.1), but these estimates require confirmation and will probably show ethnic differences.

Variants of the adiponectin and adiponectin receptor 1 genes and breast cancer risk.

Breast cancer risk is higher among obese women and women with diabetes. Adiponectin is a protein exclusively secreted by adipose tissue, circulating levels of which have been associated with breast cancer risk. Whether genetic variants within the adiponectin pathway are associated with breast cancer risk is unknown. To explore the association of genetic variants of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) genes with breast cancer risk, we conducted a case control study of female patients with breast cancer and healthy female controls from New York City recruited between 1999 and 2004. We genotyped 733 hospital-based breast cancer cases and 839 controls for 10 haplotype-tagging single nucleotide polymorphisms (SNP) of ADIPOQ and ADIPOR1. Two ADIPOQ SNPs (rs2241766 and rs1501299), which have been associated with circulating levels of adiponectin, were associated with breast cancer risk [rs1501299*GG: odd ratios (OR), 1.80; 95% confidence interval (95% CI), 1.14-2.85; rs2241766*TG: OR, 0.61; 95% CI, 0.46-0.80]. One ADIPOR1 SNP (rs7539542), which modulates expression of adiponectin receptor 1 mRNA, was also associated with breast cancer risk (OR, 0.51; 95% CI, 0.28-0.92). Based on the known function of rs2241766 and rs1501299, we categorized individuals by adiponectin signaling status and found that, when compared with high signalers, intermediate signalers had a 4.16-fold increase in breast cancer risk (95% CI, 0.49-35.19), and low signalers had a 6.56-fold increase in breast cancer risk (95% CI, 0.78-54.89; P(trend) = 0.001). This is the first report of an association between functionally relevant variants of the adiponectin pathway and breast cancer risk. The results warrant further studies of the adiponectin pathway in breast cancer.

The role of the fat mass and obesity associated gene (FTO) in breast cancer risk.

BackgroundObesity has been shown to increase breast cancer risk. FTO is a novel gene which has been identified through genome wide association studies (GWAS) to be related to obesity. Our objective was to evaluate tissue expression of FTO in breast and the role of FTO SNPs in predicting breast cancer risk.MethodsWe performed a case-control study of 354 breast cancer cases and 364 controls. This study was conducted at Northwestern University. We examined the role of single nucleotide polymorphisms (SNPs) of intron 1 of FTO in breast cancer risk. We genotyped cases and controls for four SNPs: rs7206790, rs8047395, rs9939609 and rs1477196. We also evaluated tissue expression of FTO in normal and malignant breast tissue.ResultsWe found that all SNPs were significantly associated with breast cancer risk with rs1477196 showing the strongest association. We showed that FTO is expressed both in normal and malignant breast tissue. We found that FTO genotypes provided powerful classifiers to predict breast cancer risk and a model with epistatic interactions further improved the prediction accuracy with a receiver operating characteristic (ROC) curves of 0.68.ConclusionIn conclusion we have shown a significant expression of FTO in malignant and normal breast tissue and that FTO SNPs in intron 1 are significantly associated with breast cancer risk. Furthermore, these FTO SNPs are powerful classifiers in predicting breast cancer risk.

Tgfbr1 haploinsufficiency is a potent modifier of colorectal cancer development

Transforming growth factor-beta (TGF-beta) signaling is frequently altered in colorectal cancer. Using a novel model of mice heterozygous for a targeted null mutation of Tgfbr1 crossed with Apc(Min/+) mice, we show that Apc(Min/+);Tgfbr1(+/-) mice develop twice as many intestinal tumors as Apc(Min/+);Tgfbr1(+/+) mice, as well as adenocarcinoma of the colon, without loss of heterozygosity at the Tgfbr1 locus. Decreased Smad2 and Smad3 phosphorylation and increased cellular proliferation are observed in the colonic epithelium crypts of Apc(Min/+); Tgfbr1(+/-) mice. Smad-mediated TGF-beta signaling is preserved in both Apc(Min/+);Tgfbr1(+/+) and Apc(Min/+);Tgfbr1(+/-) intestinal tumors, but cyclin D1 expression and cellular proliferation are significantly higher in Apc(Min/+);Tgfbr1(+/-) tumors. These results show that constitutively reduced Tgfbr1-mediated TGF-beta signaling significantly enhances colorectal cancer development and results in increased tumor cell proliferation. These findings provide a plausible molecular mechanism for colorectal cancer development in individuals with constitutively altered TGFBR1 expression, a recently identified common form of human colorectal cancer.

Polymorphisms of ADIPOQ and ADIPOR1 and prostate cancer risk

Studies have linked prostate cancer risk with insulin resistance and obesity. Circulating levels of adiponectin, a protein involved in insulin resistance and obesity, have been associated with prostate cancer risk. We studied the association of prostate cancer risk with haplotype tagging single nucleotide polymorphisms (SNPs) of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) chosen based on their functional relevance or association with other types of cancer. DNA samples from 465 cases and 441 healthy volunteers from New York City were genotyped for ADIPOQ rs266729, rs822395, rs822396, rs1501299, and rs2241766 SNPs and ADIPOR1 rs12733285, rs1342387, rs7539542, rs2232853, and rs10920531 SNPs. We performed both single- and multiple-SNP analyses. We found that rs12733285, rs7539452, rs266729, rs822395, rs822396, and rs1501299 were significantly associated with prostate cancer risk. Haplotype analysis confirmed these results and identified 5 ADIPOQ 4-SNP haplotypes and 1 ADIPOR1 2-SNP haplotype tightly associated with prostate cancer risk. Importantly, 2 ADIPOQ SNPs, rs266729 and rs1501299, have been previously associated with colon and breast cancer risk, respectively, in the same direction as in this study. These findings suggest that variants of the adiponectin pathway may be associated with susceptibility to various forms of common cancers and warrant validation studies.

Tgfbr1 Haploinsufficiency Inhibits the Development of Murine Mutant Kras-Induced Pancreatic Precancer

To dissect the role of constitutively altered Tgfbr1 signaling in pancreatic cancer development, we crossed Elastase-Kras(G12D) (EL-Kras) mice with Tgfbr1 haploinsufficient mice to generate EL-Kras/Tgfbr1(+/-) mice. Mice were euthanized at 6 to 9 months to compare the incidence, frequency, and size of precancerous lesions in the pancreas. Only 50% of all EL-Kras/Tgfbr1(+/-) mice developed preinvasive lesions compared with 100% of EL-Kras (wild-type Tgfbr1) mice. The frequency of precancerous lesions was 4-fold lower in haploinsufficient than in control mice. Paradoxically, the precancerous lesions of EL-Kras/Tgfbr1(+/-) mice were considerably larger than those in EL-Kras mice. Yet, the mitotic index of precancerous cells and the observable levels of fibrosis, lipoatrophy, and lymphocytic infiltration were reduced in EL-Kras/Tgfbr1(+/-) mice. We conclude that Tgfbr1 signaling promotes the development of precancerous lesions in mice. These findings suggest that individuals with constitutively decreased TGFBR1 expression may have a decreased risk of pancreatic cancer.

Constitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs

PurposeConstitutively decreased TGFBR1 allelic expression is emerging as a potent modifier of colorectal cancer risk in mice and humans. This phenotype was first observed in mice, then in lymphoblastoid cell lines from patients with microsatellite stable colorectal tumors.Patients and MethodsWe assessed the frequency of constitutively decreased TGFBR1 allelic expression and association with SNPs covering the TGFBR1 locus using RNA and DNA extracted from the peripheral blood lymphocytes of 118 consecutive patients with biopsy-proven adenocarcinoma of the colon or the rectum.ResultsWe found that 11(9.3%) of 118 patients exhibited decreased TGFBR1 allelic expression (TGFBR1 ASE). TGFBR1 ASE was strongly associated with three SNPs in linkage disequilibrium with each other: rs7034462 (p = 7.2 × 10-4), TGFBR1* 6A (p = 1.6 × 10-4) and rs11568785 (p = 1.4 × 10-4).ConclusionThese results confirm the high prevalence of constitutively decreased TGFBR1 allelic expression among patients with colorectal cancer. The association of this phenotype with TGFBR1*6A, rs7034462 and rs1156875 suggests an association between TGFBR1 SNPs and colorectal cancer, which warrants additional studies.

Role of Polymorphisms in Adamantiades-Behçet’s Disease

Objective We previously showed that Adamantiades-Behçet’s disease (A-BD) is associated with a lower incidence of malignancy compared with the general population. Transforming growth factor-β (TGF-β) has been shown to play a role in cartilage regeneration and is increased in patients with A-BD. We also found 2 functional polymorphisms of the TGF-β pathway, TGFBR1*6A and TGFB1*CC, that are associated with risk of malignancy. We tested whether incidence of these polymorphisms would differ in patients with A-BD compared with healthy controls of similar age and geographic location. Methods We performed a case-control study including 139 cases and 128 controls from Greece. Cases and controls were genotyped for TGFBR1*6A and TGFB1*CC. Results We found that cases had lower incidence of TGFBR1*6A compared with controls (11.3% vs 13.3%, respectively). Also, the incidence of TGFB1*CC was lower in cases than controls (24.6% vs 27.0%, respectively). These differences were not statistically significant. Conclusion Although there is a suggestion that the lower incidence of TGFBR1*6A in A-BD patients may play a protective role against development of malignancy, larger studies would be needed to fully evaluate the role of TGF-β and its polymorphisms in A-BD.

A prospective evaluation of clinical and genetic predictors of weight changes in breast cancer survivors

Postdiagnosis weight gain in patients with breast cancer has been associated with increased cancer recurrence and mortality. This study was designed to identify risk factors for weight gain and create a predictive model to identify a high‐risk population for targeted interventions.

Clinical and genetic predictors of weight gain in patients diagnosed with breast cancer

Postdiagnosis weight gain in patients with breast cancer has been associated with increased cancer recurrence and mortality. This study was designed to identify risk factors for weight gain and create a predictive model to identify a high‐risk population for targeted interventions.