Monica Cipollini

Genome-wide association study on differentiated thyroid cancer.

CONTEXT Genome-wide association studies (GWASs) of differentiated thyroid cancer (DTC) have identified associations with polymorphisms at 2q35 (DIRC3), 8p12 (NRG1), 9q22.33 (FOXE1), and 14q13.2 (NKX2-1). However, most of the inherited genetic risk factors of DTC remain to be discovered. OBJECTIVE Our objective was to identify additional common DTC susceptibility loci. DESIGN We conducted a GWAS in a high-incidence Italian population of 690 cases and 497 controls and followed up the most significant polymorphisms in 2 additional Italian series and in 3 low-incidence populations totaling 2958 cases and 3727 controls. RESULTS After excluding the most robust previously identified locus (9q22.33), the strongest association was shown by rs6759952, confirming the recently published association in DIRC3 (odds ratio [OR] = 1.21, P = 6.4 × 10(-10), GWAS and all replications combined). Additionally, in the combined analysis of the Italian series, suggestive associations were attained with rs10238549 and rs7800391 in IMMP2L (OR = 1.27, P = 4.1 × 10(-6); and OR = 1.25, P = 5.7 × 10(-6)), rs7617304 in RARRES1 (OR = 1.25, P = 4.6 × 10(-5)) and rs10781500 in SNAPC4/CARD9 (OR = 1.23, P = 3.5 × 10(-5)). CONCLUSIONS Our findings provide additional insights into the genetic and biological basis of inherited genetic susceptibility to DTC. Additional studies are needed to determine the role of the identified polymorphisms in the development of DTC and their possible use in the clinical practice.

Obesity and the risk of papillary thyroid cancer: a pooled analysis of three case-control studies.

BACKGROUND There is a correlation between temporal trends of obesity prevalence and papillary thyroid cancer (PTC) incidence in the United States. Obesity is a well-recognized risk factor for many cancers, but there are few studies on the association between obesity and PTC risk. We investigated the association between anthropometric measurements and PTC risk using pooled individual data from three case-control populations. METHODS Height and weight information were obtained from three independent case-control studies, including 1917 patients with PTC (1360 women and 557 men) and 2127 cancer-free controls from the United States, Italy, and Germany. Body mass index (BMI), body fat percentage, and body surface area (BSA) were calculated. An unconditional logistic regression model was used to calculate odds ratios (ORs) and confidence intervals (CIs) with respect to risk of PTC, adjusted by age, sex, race/ethnicity, and study site. RESULTS In the pooled population, for both men and women, an increased risk of PTC was found to be associated with greater weight, BMI, body fat percentage, and BSA, whereas a reduced risk of PTC was associated with greater height, in the pooled population for both men and women. Compared with normal-weight subjects (BMI 18.5-24.9 kg/m2), the ORs for overweight (BMI 25-29.9 kg/m2) and obese (BMI≥30 kg/m2) subjects were 1.72 [CI 1.48-2.00] and 4.17 [CI 3.41-5.10] respectively. Compared with the lowest quartile of body fat percentage, the ORs for the highest quartile were 3.83 [CI 2.85-5.15] in women and 4.05 [CI 2.67-6.15] in men. CONCLUSION Anthropometric factors, especially BMI and body fat percentage, were significantly associated with increased risk of PTC. Future studies of anthropometric factors and PTC that incorporate intermediate factors, including adiposity and hormone biomarkers, are essential to help clarify potential mechanisms of the relationship.

Evidences that the polymorphism Pro-282-Ala within the tumor suppressor gene WWOX is a new risk factor for differentiated thyroid carcinoma

We report a hypothesis‐driven study aimed to detect genetic markers of susceptibility to differentiated thyroid carcinomas (DTC). A large number of candidate genes were first selected through literature search (genome‐wide studies were also included). To restrict the analysis to single nucleotide polymorphisms (SNPs) with a high likelihood to be associated with increased risk, each SNP must comply with several a priori hypotheses. Only one SNP, the rs3764340 encoding for the aminoacidic substitution proline‐to‐alanine at codon 282 of the tumor suppressor gene WWOX, passed the selection. A case–control association study was carried out, involving a total of 1,741 cases and 1,042 controls. The logistic regression analysis revealed an increased risk of DTC for the carriers of the G‐allele (crude odds ratio, OR = 1.53; 95% confidence interval, CI = 1.18–1.99; p = 1.38 × 10−3). When we controlled for covariates, the adjusted OR was 1.48 with a 95% CI of 1.08–2.03 (p = 8.0 × 10−3). The association was confirmed after stratification for histology (for papillary thyroid carcinoma the adjusted OR was 1.43; 95% CI 1.02–2.00; p = 0.037), incident cases and smokers, but was also at the limit of statistical significance in all the other categories considered. In silico analyses showed that when alanine substitutes proline, subtle changes of the proteic structure can be predicted. These findings together with other observations from literature on human cancers and the fact that the proline at codon 282 is extremely conserved in phylogenetically distant organisms (including Drosophila) suggest that the variant allele‐282 could affect the biological function of WWOX, thereby predisposing individuals to thyroid cancer.

MicroRNA binding site polymorphisms as biomarkers in cancer management and research.

MicroRNAs (miRNAs) are important regulators of eukaryotic gene expression. They have been implicated in a broad range of biological processes, and miRNA-related genetic alterations probably underlie several human diseases. Single nucleotide polymorphisms of transcripts may modulate the posttranscriptional regulation of gene expression by miRNAs and explain interindividual variability in cancer risk and in chemotherapy response. On the basis of recent association studies published in the literature, the present review mainly summarizes the potential role of miRNAs as molecular biomarkers for disease susceptibility, diagnosis, prognosis, and drug-response prediction in tumors. Many clues suggest a role for polymorphisms within the 3′ untranslated regions of KRAS rs61764370, SET8 rs16917496, and MDM4 rs4245739 as SNPs in miRNA binding sites highly promising in the biology of human cancer. However, more studies are needed to better characterize the composite spectrum of genetic determinants for future use of markers in risk prediction and clinical management of diseases, heading toward personalized medicine.

Novel Genome-Wide Association Study-Based Candidate Loci for Differentiated Thyroid Cancer Risk

CONTEXT Genome-wide association studies (GWASs) on differentiated thyroid cancer (DTC) have identified robust associations with single nucleotide polymorphisms (SNPs) at 9q22.33 (FOXE1), 14q13.3 (NKX2-1), and 2q35 (DIRC3). Our recently published GWAS suggested additional susceptibility loci specific for the high-incidence Italian population. OBJECTIVE The purpose of this study was to identify novel Italian-specific DTC risk variants based on our GWAS and to test them further in low-incidence populations. DESIGN We investigated 45 SNPs selected from our GWAS first in an Italian population. SNPs that showed suggestive evidence of association were investigated in the Polish and Spanish cohorts. RESULTS The combined analysis of the GWAS and the Italian replication study (2260 case patients and 2218 control subjects) provided strong evidence of association with rs10136427 near BATF (odds ratio [OR] =1.40, P = 4.35 × 10(-7)) and rs7267944 near DHX35 (OR = 1.39, P = 2.13 × 10(-8)). A possible role in DTC susceptibility in the Italian populations was also found for rs13184587 (ARSB) (P = 8.54 × 10(-6)) and rs1220597 (SPATA13) (P = 3.25 × 10(-6)). Only the associations between rs10136427 and rs7267944 and DTC risk were replicated in the Polish and the Spanish populations with little evidence of population heterogeneity (GWAS and all replications combined, OR = 1.30, P = 9.30 × 10(-7) and OR = 1.32, P = 1.34 × 10(-8), respectively). In silico analyses provided new insights into the possible functional consequences of the SNPs that showed the strongest association with DTC. CONCLUSIONS Our findings provide evidence for novel DTC susceptibility variants. Further studies are warranted to identify the specific genetic variants responsible for the observed associations and to functionally validate our in silico predictions.

Risk of malignant pleural mesothelioma and polymorphisms in genes involved in the genome stability and xenobiotics metabolism.

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer mostly attributable to asbestos exposure. Many polymorphic genes encoding for xenobiotic and oxidative metabolism enzymes (XME) or involved in genome stability (GS) can modulate individual MPM risk in exposed populations. An association study was carried out in a case-control setting including 119 MPM patients and two groups of referent subjects (104 with and 695 without documented asbestos exposure). Forty-eight polymorphisms in XME genes and 75 in GS-genes were evaluated. Statistical analysis revealed some significant associations of studied polymorphisms with MPM risk, but most of them disappeared after applying Bonferroni correction (new threshold for statistical significance: p=4.07 x 10(-4)). On the other hand, the nucleotidic change 282C>T within NAT2 held the statistical significance (OR=3.54; 95% CI 1.75-7.16; p=0.0002), reinforcing existing evidences that describe genetic polymorphisms of NAT2 possibly involved in the etiology of the MPM.

TPO genetic variants and risk of differentiated thyroid carcinoma in two European populations

Thyroid cancer risk involves the interaction of genetic and environmental factors. The thyroperoxidase (TPO) has a key role in the iodine metabolism, being essential for the thyroid function. Mutations in the TPO gene are common in congenital hypothyroidism, and there are also signs of the implication of TPO in thyroid cancer. We performed a case–control association study of genetic variants in TPO and differentiated thyroid carcinoma (DTC) in 1,586 DTC patients and 1,769 controls including two European populations (Italy: 1,190 DTC and 1,290 controls; Spain: 396 DTC and 479 controls). Multivariate logistic regression analyses were performed separately for each population and each single‐nucleotide polymorphism (SNP). From the three studied polymorphisms, significant associations were detected between DTC and rs2048722 and rs732609 in both populations (p <  0.05). In the Italian population, both SNPs showed a negative association (rs2048722, odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.63–1.00, p = 0.045; rs732609, OR = 0.72, 95% CI = 0.55–0.94, p = 0.016), whereas in the Spanish population, these SNPs showed a positive association (rs2048722, OR = 1.39, 95% CI = 1.03–1.89, p = 0.033; rs732609, OR = 1.41, 95% CI = 1.06–1.87, p = 0.018). The corresponding associations for papillary or follicular thyroid cancer were similar to those for all DTC, within population. No association was detected for the third TPO polymorphism in the Italian and the Spanish populations. Our results, for the first time, point to TPO as a gene involved in the risk of DTC, and suggest the importance of interactions between TPO variants and other unidentified population‐specific factors in determining thyroid cancer risk.

High prevalence of chromosome 10 rearrangements in human lymphocytes after in vitro X-ray irradiation

Purpose : To evaluate the chromosome symmetric or asymmetric rearrangement (CR) frequency for chromosome 10 compared to chromosomes 1 and 3 induced in vitro in human lymphocytes by low doses of X-rays. Materials and methods : Blood samples obtained from three young and healthy volounteers were irradiated in G0 with 0.25, 0.50 and 1 Gy X-rays. Chromosome painting analysis was used on preparations of peripheral lymphocytes for the identification of CR. Results : It was found that radiation-induced CR levels were non-randomly distributed among the three painted chromosomes. Chromosome 10 CR frequencies were significantly greater than those involving chromosomes 1 (at all the doses tested) or 3 (at 0.25 and 1 Gy), with frequency ratios ranging from 2.2 to 5.2. Conclusions : In comparison to chromosomes 1 and 3, chromosome 10 appeared to be involved in exchanging at a significantly greater extent than expected according to its DNA content.PURPOSE To evaluate the chromosome symmetric or asymmetric rearrangement (CR) frequency for chromosome 10 compared to chromosomes 1 and 3 induced in vitro in human lymphocytes by low doses of X-rays. MATERIALS AND METHODS Blood samples obtained from three young and healthy volunteers were irradiated in G0 with 0.25, 0.50 and 1 Gy X-rays. Chromosome painting analysis was used on preparations of peripheral lymphocytes for the identification of CR. RESULTS It was found that radiation-induced CR levels were nonrandomly distributed among the three painted chromosomes. Chromosome 10 CR frequencies were significantly greater than those involving chromosomes 1 (at all the doses tested) or 3 (at 0.25 and 1 Gy), with frequency ratios ranging from 2.2 to 5.2. CONCLUSIONS In comparison to chromosomes 1 and 3, chromosome 10 appeared to be involved in exchanging at a significantly greater extent than expected according to its DNA content.

Runs of homozygosity and inbreeding in thyroid cancer

BackgroundGenome-wide association studies (GWASs) have identified several single-nucleotide polymorphisms (SNPs) influencing the risk of thyroid cancer (TC). Most cancer predisposition genes identified through GWASs function in a co-dominant manner, and studies have not found evidence for recessively functioning disease loci in TC. Our study examines whether homozygosity is associated with an increased risk of TC and searches for novel recessively acting disease loci.MethodsData from a previously conducted GWAS were used for the estimation of the proportion of phenotypic variance explained by all common SNPs, the detection of runs of homozygosity (ROH) and the determination of inbreeding to unravel their influence on TC.ResultsInbreeding coefficients were significantly higher among cases than controls. Association on a SNP-by-SNP basis was controlled by using the false discovery rate at a level of q* < 0.05, with 34 SNPs representing true differences in homozygosity between cases and controls. The average size, the number and total length of ROHs per person were significantly higher in cases than in controls. A total of 16 recurrent ROHs of rather short length were identified although their association with TC risk was not significant at a genome-wide level. Several recurrent ROHs harbor genes associated with risk of TC. All of the ROHs showed significant evidence for natural selection (iHS, Fst, Fay and Wu’s H).ConclusionsOur results support the existence of recessive alleles in TC susceptibility. Although regions of homozygosity were rather small, it might be possible that variants within these ROHs affect TC risk and may function in a recessive manner.

Expression status of candidate genes in mesothelioma tissues and cell lines.

In order to broaden knowledge on the pathogenesis of malignant pleural mesothelioma (MPM), we reviewed studies on the MPM-transcriptome and identified 119 deregulated genes. However, there was poor consistency among the studies. Thus, the expression of these genes was further investigated in the present work using reverse transcriptase-quantitative PCR (RT-qPCR) in 15 MPM and 20 non-MPM tissue samples. Fifty-nine genes showed a statistically significant deregulation and were further evaluated in two epithelioid MPM cell lines (compared to MET-5A, a non-MPM cell line). Nine genes (ACSL1, CCNO, CFB, PDGFRB, SULF1, TACC1, THBS2, TIMP3, XPOT) were deregulated with statistical significance in both cell lines, 12 (ASS1, CCNB1, CDH11, COL1A1, CXADR, EIF4G1, GALNT7, ITGA4, KRT5, PTGIS, RAN, SOD1) in at least one cell line, whereas 7 (DSP, HEG1, MCM4, MSLN, NME2, NMU, TNPO2) were close but did not reach the statistical significance in any of the cell line. Patients whose MPM tissues expressed elevated mRNA levels of BIRC5, DSP, NME2, and THBS2 showed a statistically significant shorter overall survival. Although MPM is a poorly studied cancer, some features are starting to emerge. Novel cancer genes are suggested here, in particular those involved in cell-cell and cell-matrix interactions.