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Novel genetic variants in differentiated thyroid cancer and assessment of the cumulative risk.

ABSTRACT: A genome-wide association study (GWAS) performed on a high-incidence Italian population followed by replications on low-incidence cohorts suggested a strong association of differentiated thyroid cancer (DTC) with single nucleotide polymorphisms (SNPs) at 9q22.33, 2q35, 20q11.22-q12 and 14q24.3. Moreover, six additional susceptibility loci were associated with the disease only among Italians. The present study had two aims, first to identify loci involved in DTC risk and then to assess the cumulative effect of the SNPs identified so far in the Italian population. The combined analysis of the previous GWAS and the present Italian study provided evidence of association with rs7935113 (GALNTL4, OR = 1.36, 95%CI 1.20-1.53, p-value = 7.41 × 10(-7)) and rs1203952 (FOXA2, OR = 1.29, 95%CI 1.16-1.44, p-value = 4.42 × 10(-6)). Experimental ENCODE and eQTL data suggested that both SNPs may influence the closest genes expression through a differential recruitment of transcription factors. The assessment of the cumulative risk of eleven SNPs showed that DTC risk increases with an increasing number of risk alleles (p-trend = 3.13 × 10(-47)). Nonetheless, only a small fraction (about 4% on the disease liability scale) of DTC is explained by these SNPs. These data are consistent with a polygenic model of DTC predisposition and highlight the importance of association studies in the discovery of the disease hereditability.

SUBMITTER: Figlioli G

PROVIDER: S-EPMC4354074 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Novel genetic variants in differentiated thyroid cancer and assessment of the cumulative risk.

Figlioli Gisella G Chen Bowang B Elisei Rossella R Romei Cristina C Campo Chiara C Cipollini Monica M Cristaudo Alfonso A Bambi Franco F Paolicchi Elisa E Hoffmann Per P Herms Stefan S Kalemba Michał M Kula Dorota D Pastor Susana S Marcos Ricard R Velázquez Antonia A Jarząb Barbara B Landi Stefano S Hemminki Kari K Gemignani Federica F Försti Asta A

Scientific reports 20150310

A genome-wide association study (GWAS) performed on a high-incidence Italian population followed by replications on low-incidence cohorts suggested a strong association of differentiated thyroid cancer (DTC) with single nucleotide polymorphisms (SNPs) at 9q22.33, 2q35, 20q11.22-q12 and 14q24.3. Moreover, six additional susceptibility loci were associated with the disease only among Italians. The present study had two aims, first to identify loci involved in DTC risk and then to assess the cumula ...[more]

PMID: 25753578

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Project description:Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other risk factors. A risk prediction model was built and applied to the Scottish population using available data.Nine populations of European descent were studied to develop and validate CRC risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence CRC risk. Risk models were generated from case-control data incorporating genotypes alone (n=39,266) and in combination with gender, age and FH (n=11,324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4187 independent samples. The 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks.The median number of risk alleles was greater in cases than controls (10 vs 9, p<2.2 × 10(-16)), confirmed in external validation sets (Sweden p=1.2 × 10(-6), Finland p=2 × 10(-5)). The mean per-allele increase in risk was 9% (OR 1.09; 95% CI 1.05 to 1.13). Discriminative performance was poor across the risk spectrum (area under curve for genotypes alone 0.57; area under curve for genotype/age/gender/FH 0.59). However, modelling genotype data, FH, age and gender with Scottish population data shows the practicalities of identifying a subgroup with >5% predicted 10-year absolute risk.Genotype data provide additional information that complements age, gender and FH as risk factors, but individualised genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance.

Project description:BackgroundIt is difficult to reliably distinguish between American Thyroid Association (ATA) low-risk and intermediate-risk differentiated thyroid cancer (DTC) before surgery. Therefore, physicians are faced with a dilemma regarding the necessity and timing of completion total thyroidectomy (CT) after thyroid lobectomy (TL). We evaluated proper surgical methods by analyzing oncologic outcomes of TL in patients with DTC whose risk had been upgraded after surgery.MethodsWe retrospectively reviewed the medical records of 1,702 patients with DTC who underwent TL and ipsilateral central lymph node (LN) dissection between January 2006 and December 2011. The patients were classified into Group A (n=1,159; low risk; ≤5 central LN metastases or the absence of pathologic microscopic capsular invasion) and Group B (n=543; upgraded intermediate risk after surgery; >5 central LN metastases or the presence of pathologic microscopic capsular invasion). We analyzed their clinicopathological characteristics and recurrence-free survival.ResultsAll 32 patients who experienced recurrence underwent CT. After the first operation, the duration until reoperation in Groups A and B were 8.00±2.74 (range, 3.42-12.17) and 5.10±3.09 (range, 1.25-11.67) years, respectively. There was no significant difference in recurrence rates, disease-related mortality rates, or 10-year recurrence-free survival rates between the two groups. The mean follow-up durations in Groups A and B were 10.22±1.58 and 10.13±1.47 years, respectively. Univariate analysis showed that sex, age, tumor size, multifocality, extrathyroidal extension (ETE), and number of central LN metastases were not associated with recurrence after TL, although the rate of central LN metastases was. Multivariate analysis showed that sex, age, tumor size, multifocality, ETE, central LN metastases, and the number of central LN metastases were not associated with recurrence after TL, although multifocality was.ConclusionsTL with prophylactic central compartment neck dissection (CCND) is sufficient for patients with DTC whose risk is upgraded after surgery because they have a good prognosis at long-term follow-up. Larger-scale randomized clinical trials are required to confirm our findings.

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Novel genetic variants in differentiated thyroid cancer and assessment of the cumulative risk.

Publications

Novel genetic variants in differentiated thyroid cancer and assessment of the cumulative risk.

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