Genetic factors for differentiated thyroid cancer in French Polynesia: new candidate loci.

Background: Populations of French Polynesia (FP), where France performed atmospheric tests between 1966 and 1974, experience a high incidence of differentiated thyroid cancer (DTC). However, up to now, no sufficiently large study of DTC genetic factors in this population has been performed to reach definitive conclusion. This research aimed to analyze the genetic factors of DTC risk among the native FP populations. Methods: We analyzed more than 300 000 single nucleotide polymorphisms (SNPs) genotyped in 283 DTC cases and 418 matched controls born in FP, most being younger than 15 years old at the time of the first nuclear tests. We analyzed the genetic profile of our cohort to identify population subgroups. We then completed a genome-wide analysis study on the whole population. Results: We identified a specific genetic structure in the FP population reflecting admixture from Asian and European populations. We identified three regions associated with increased DTC risk at 6q24.3, 10p12.2, and 17q21.32. The lead SNPs at these loci showed respective p-values of 1.66 × 10-7, 2.39 × 10-7, and 7.19 × 10-7 and corresponding odds ratios of 2.02, 1.89, and 2.37. Conclusion: Our study results suggest a role of the loci 6q24.3, 10p12.2 and 17q21.32 in DTC risk. However, a whole genome sequencing approach would be better suited to characterize these factors than genotyping with microarray chip designed for the Caucasian population. Moreover, the functional impact of these three new loci needs to be further explored and validated.

Assessment of Differentiated Thyroid Carcinomas in French Polynesia After Atmospheric Nuclear Tests Performed by France.

Importance: Due to the amount of iodine 131 released in nuclear tests and its active uptake by the thyroid, differentiated thyroid carcinoma (DTC) is the most serious health risk for the population living near sites of nuclear tests. Whether low doses to the thyroid from nuclear fallout are associated with increased risk of thyroid cancer remains a controversial issue in medicine and public health, and a misunderstanding of this issue may be associated with overdiagnosis of DTCs. Design, Setting, and Participants: This case-control study was conducted by extending a case-control study published in 2010 that included DTCs diagnosed between 1984 and 2003 by adding DTCs diagnosed between 2004 and 2016 and improving the dose assessment methodology. Data on 41 atmospheric nuclear tests conducted by France between 1966 and 1974 in French Polynesia (FP) were assessed from original internal radiation-protection reports, which the French military declassified in 2013 and which included measurements in soil, air, water, milk, and food in all FP archipelagos. These original reports led to an upward reassessment of the nuclear fallout from the tests and a doubling of estimates of the mean thyroid radiation dose received by inhabitants from 2 mGy to nearly 5 mGy. Included patients were diagnosed from 1984 to 2016 with DTC at age 55 years or younger and were born in and resided in FP at diagnosis; 395 of 457 eligible cases were included, and up to 2 controls per case nearest by birthdate and matched on sex were identified from the FP birth registry. Data were analyzed from March 2019 through October 2021. Exposure: The radiation dose to the thyroid gland was estimated using recently declassified original radiation-protection service reports, meteorological reports, self-reported lifestyle information, and group interviews of key informants and female individuals who had children at the time of these tests. Main Outcomes and Measures: The lifetime risk of DTC based on Biological Effects of Ionizing Radiation (BEIR) VII models was estimated. Results: A total of 395 DTC cases (336 females [85.1%]; mean [SD] age at end of follow-up, 43.6 [12.9] years) and 555 controls (473 females [85.2%]; mean [SD] age at end of follow-up, 42.3 [12.5] years) were included. No association was found between thyroid radiation dose received before age 15 years and risk of DTC (excess relative risk [ERR] per milligray, 0.04; 95% CI, -0.09 to 0.17; P = .27). When excluding unifocal noninvasive microcarcinomas, the dose response was significant (ERR per milligray, 0.09; 95% CI, -0.03 to 0.02; P = .02), but several incoherencies with the results of the initial study reduce the credibility of this result. The lifetime risk for the entire FP population was 29 cases of DTC (95% CI, 8-97 cases), or 2.3% (95% CI, 0.6%-7.7%) of 1524 sporadic DTC cases in this population. Conclusions and Relevance: This case-control study found that French nuclear tests were associated with an increase in lifetime risk of PTC in FP residents of 29 cases of PTC. This finding suggests that the number of thyroid cancer cases and the true order of magnitude of health outcomes associated with these nuclear tests were small, which may reassure populations of this Pacific territory.

Gene network and biological pathways associated with susceptibility to differentiated thyroid carcinoma.

Variants identified in earlier genome-wide association studies (GWAS) on differentiated thyroid carcinoma (DTC) explain about 10% of the overall estimated genetic contribution and could not provide complete insights into biological mechanisms involved in DTC susceptibility. Integrating systems biology information from model organisms, genome-wide expression data from tumor and matched normal tissue and GWAS data could help identifying DTC-associated genes, and pathways or functional networks in which they are involved. We performed data mining of GWAS data of the EPITHYR consortium (1551 cases and 1957 controls) using various pathways and protein-protein interaction (PPI) annotation databases and gene expression data from The Cancer Genome Atlas. We identified eight DTC-associated genes at known loci 2q35 (DIRC3), 8p12 (NRG1), 9q22 (FOXE1, TRMO, HEMGN, ANP32B, NANS) and 14q13 (MBIP). Using the EW_dmGWAS approach we found that gene networks related to glycogenolysis, glycogen metabolism, insulin metabolism and signal transduction pathways associated with muscle contraction were overrepresented with association signals (false discovery rate adjusted p-value < 0.05). Additionally, suggestive association of 21 KEGG and 75 REACTOME pathways with DTC indicate a link between DTC susceptibility and functions related to metabolism of cholesterol, amino sugar and nucleotide sugar metabolism, steroid biosynthesis, and downregulation of ERBB2 signaling pathways. Together, our results provide novel insights into biological mechanisms contributing to DTC risk.

Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 2q35 and 8p12 in Europeans, Melanesians and Polynesians.

Differentiated thyroid carcinoma (DTC) incidence is characterized by wide ethnic and geographic variations, with high incidence rates observed in Oceanian populations. Genome-wide association studies (GWAS) identified mainly four DTC susceptibility loci at 9q22.33, 14q13.3, 2q35 and 8p12. Here we performed fine-mapping of the 2q35 and 8p12 loci in the population of the EPITHYR consortium that includes Europeans, Melanesians and Polynesians to identify likely causal variants for DTC risk. We conducted a colocalization analysis using eQTLs data to determine the SNPs with the highest probability of causality. At 2q35, we highlighted rs16857609 located in DIRC3. This SNP has a high probability of causality in the three populations, and a significant association in Europeans (OR = 1.4, p = 1.9 x 10-10). It is also associated with expression of DIRC3 and of the nearby gene IGFBP5 in thyroid tumour cells. At 8p12, we identified rs7844425 which was significantly associated with DTC in Europeans (OR = 1.32, p = 7.6 x 10-8) and rs2439304, which was highlighted by the colocalization analysis but only moderately associated with DTC in our dataset (OR = 1.2, p = 0.001). These SNPs are linked to the expression of NRG1 in thyroid tissue. Hence, our study identified novel variants at 2q35 and 8p12 to be prioritized for further functional studies.

Multiethnic genome-wide association study of differentiated thyroid cancer in the EPITHYR consortium.

Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. DTC is one of the cancers with the highest familial risk suggesting a major role of genetic risk factors, but only few susceptibility loci were identified so far. In order to assess the contribution of known DTC susceptibility loci and to identify new ones, we conducted a multiethnic genome-wide association study (GWAS) in individuals of European ancestry and of Oceanian ancestry from Pacific Islands. Our study included 1554 cases/1973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from seven population-based case-control studies participating to the EPITHYR consortium. All participants were genotyped using the OncoArray-500K Beadchip (Illumina). We confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 and 16q23.2, which were associated with thyroid-stimulating hormone levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. We also observed that the frequencies of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans. However, additional GWAS and epidemiological studies in Oceanian populations are needed to fully understand the highest incidence observed in these populations.

Non-Essential Trace Elements Dietary Exposure in French Polynesia: Intake Assessment, Nail Bio Monitoring and Thyroid Cancer Risk

Background: In French Polynesia, thyroid cancer mortality and incidence is reported to be the highest in the world. Excessive levels of non-essential trace elements (nETE) in the body are associated with several types of cancer. Objective: The present study aims to provide quantitative information on food contamination by mercury (Hg), lead (Pb), arsenic (As) and cadmium (Cd) in French Polynesia and its potential correlation with measurements performed in fingernails of Polynesians, and then to investigate the potential association between these nETE and different thyroid cancer risks. Methods: The study population included 229 interviewed cases and 373 interviewed controls We performed a descriptive analysis of Polynesian food and examined the association between thyroid cancer risk and daily intake levels of nETE and with fingernail nETE levels. Results: Hg contamination was mainly present in sea products, Pb contamination was present in almost all samples, Cd was detectable in starchy food and As was detectable in all sea products. No patient exceeded dietary contamination WHO limits for Pb, 2 participants exceeded it for Hg and 3 individuals (0.5%) for cadmium. In fingernail clippings, the most detectable pollutant was Pb (553 participants), then Hg (543 participants) then Cd (only in 130 participants). Thyroid cancer risk was increased more than 4 times by Pb daily intake in patients with a history of cancer in first-degree relatives than in ones without (p for interaction =0.01), and 2 times more in women with more than 3 pregnancies than in those with none or less (p for interaction =0.005); it was also increased following As intake by more than 30% in patients with a history of cancer in first-degree relatives than in ones without (p for interaction =0.05). Conclusion: Locally produced foods are not a source of nETE exposure in French Polynesia. Dieatry nETE exposure and fingernail nETE concentration are not associated to differentiated thyroid cancer risk. No correlation found between nETE dietary exposure and fingernail nETE concentration.

Common variants at 9q22.33, 14q13.3, and ATM loci, and risk of differentiated thyroid cancer in the French Polynesian population.

BACKGROUND: French Polynesia has one of the highest incidence rates of thyroid cancer worldwide. Relationships with the atmospheric nuclear weapons tests and other environmental, biological, or behavioral factors have already been reported, but genetic susceptibility has yet to be investigated. We assessed the contribution of polymorphisms at the 9q22.33 and 14q13.3 loci identified by GWAS, and within the DNA repair gene ATM, to the risk of differentiated thyroid cancer (DTC) in 177 cases and 275 matched controls from the native population. PRINCIPAL FINDINGS: For the GWAS SNP rs965513 near FOXE1, an association was found between genotypes G/A and A/A, and risk of DTC. A multiplicative effect of allele A was even noted. An excess risk was also observed in individuals carrying two long alleles of the poly-alanine tract expansion in FOXE1, while no association was observed with rs1867277 falling in the promoter region of the gene. In contrast, the GWAS SNP rs944289 (NKX2-1) did not show any significant association. Although the missense substitution D1853N (rs1801516) in ATM was rare in the population, carriers of the minor allele (A) also showed an excess risk. The relationships between these five polymorphisms and the risk of DTC were not contingent on the body surface area, body mass index, ethnicity or dietary iodine intake. However, an interaction was evidenced between the thyroid radiation dose and rs944289. SIGNIFICANCE: A clear link could not be established between the high incidence in French Polynesia and the studied polymorphisms, involved in susceptibility to DTC in other populations. Important variation in allele frequencies was observed in the Polynesian population as compared to the European populations. For FOXE1 rs965513, the direction of association and the effect size was similar to that observed in other populations, whereas for ATM rs1801516, the minor allele was associated to an increased risk in the Polynesian population and with a decreased risk in the European population.

Lack of association between fingernail selenium and thyroid cancer risk: a case-control study in French Polynesia.

BACKGROUND: Numerous studies have suggested that selenium deficiency may be associated with an increased risk for several types of cancer, but few have focused on thyroid cancer. MATERIALS AND METHODS: We examined the association between post-diagnostic fingernail selenium levels and differentiated thyroid cancer risk in a French Polynesian matched case-control study. Conditional logistic regression models were used to estimate odds ratios and 95% confidence intervals. RESULTS: The median selenium concentration among controls was 0.76 µg/g. Significantly, we found no association between fingernail selenium levels and thyroid cancer risk after conditioning on year of birth and sex and additionally adjusting for date of birth (highest versus lowest quartile: odds-ratio=1.12, 95% confidence interval: 0.66-1.90; p-trend=0.30). After additional adjustment for other covariates, this association remained non-significant (p-trend=0.60). When restricting the analysis to thyroid cancer of 10 mm or more, selenium in nails was non-significantly positively linked to thyroid cancer risk (p-trend=0.09). Although no significant interaction was evidenced between iodine in nails and selenium in nails effect (p=0.70), a non-significant (p-trend =0.10) positive association between selenium and thyroid cancer risk was seen in patients with less than 3 ppm of iodine in nails. The highest fingernail selenium concentration in French Polynesia was in the Marquises Islands (M=0.87 µg/g) and in the Tuamotu-Gambier Archipelago (M=0.86 µg/g). CONCLUSIONS: Our results do not support, among individuals with sufficient levels of selenium, that greater long-term exposure to selenium may reduce thyroid cancer risk. Because these findings are based on post-diagnostic measures, studies with prediagnostic selenium are needed for corroboration.

Differentiated thyroid carcinoma risk factors in French Polynesia.

BACKGROUND: To investigate differentiated thyroid cancer risk factors in natives of French Polynesia is of interest because of the very high incidence of this cancer in the archipelago. MATERIALS AND METHODS: To assess the role of various potential risk factors of thyroid cancer in the natives of French Polynesia we performed a case-control study. The study included almost all the French Polynesians diagnosed with differentiated thyroid carcinoma between 1981 and 2003 (n=229) and 373 French Polynesian control individuals from the general population without cancer. RESULTS: Thyroid radiation dose received from nuclear fallout before the age of 15, a personal history of neck or/and head medical irradiation, obesity, tallness, large number of children, an artificial menopause, a familial history of thyroid cancer, a low dietary iodine intake, and having a spring as the main source of drinking water were found to be significant risk factors. No roles of smoking habits, alcohol consumption, iodine containing drugs, and exposure to pesticides were evidenced. CONCLUSIONS: Except for smoking, differentiated thyroid carcinoma risk factors in natives of French Polynesia are similar to those in other populations. Our finding on the role of having a spring as a drinking water origin is coherent with some other studies and could be due to geological factors.

Dietary patterns, goitrogenic food, and thyroid cancer: a case-control study in French Polynesia.

French Polynesia has one of the world's highest thyroid cancer incidence rates. A case-control study among native residents of French Polynesia included 229 cases of differentiated thyroid cancer diagnosed between 1979 and 2004, and 371 population controls. Dietary patterns and goitrogenic food consumption (cabbage, cassava) were analyzed. We used a factor analysis to identify dietary patterns and a conditional logistic regression analysis to investigate the association between dietary patterns or food items and thyroid cancer risk. Two distinct dietary patterns were identified: traditional Polynesian and Western. A nonsignificant inverse association was observed between the traditional Polynesian dietary pattern and thyroid cancer risk. The Western pattern was not associated with thyroid cancer risk. Cassava consumption was significantly associated with a decreased risk of thyroid cancer. In conclusion, a traditional Polynesian dietary pattern led to a weak reduced risk of thyroid cancer in French Polynesia. The protective effect of cassava on this cancer does not seem to be substantially different from that of cabbage, which was the main goitrogenic food studied to date.

Dietary iodine and thyroid cancer risk in French Polynesia: a case-control study.

BACKGROUND: French Polynesia has one of the world's highest thyroid cancer incidence rates. Iodine is suspected to play a role in this high incidence. The objective of this study was to assess whether low dietary iodine is related to a higher risk of thyroid cancer in the French Polynesian population. METHODS: A case-control study was performed among native residents of French Polynesia. It included 229 cases of differentiated thyroid cancer diagnosed between 1979 and 2004 (203 women, 26 men) matched with 371 population controls (324 women, 47 men) on the date of birth. The current study is focused on dietary iodine intake and fish consumption (food rich in iodine) and analyzed by conditional logistic regression. RESULTS: Daily dietary iodine intake was insufficient (<150 µg/day) in 60% of both cases and controls. A decreased risk of thyroid cancer was observed with a higher consumption of fish (p(trend)=0.008) and shellfish (p(trend)=0.002), and also with a higher dietary iodine intake (p(trend)=0.03). There was no significant interaction between the effects of the thyroid radiation dose and the dietary iodine intake (p=0.2). CONCLUSION: French Polynesia is a mild iodine deficiency area in which a higher consumption of food from the sea and a higher dietary iodine intake are significantly associated with a decreased risk of thyroid cancer. The quantification of this reduction requires specific investigation of iodine intake in traditional Polynesian food.

Family history of thyroid cancer and the risk of differentiated thyroid cancer in French polynesia.

BACKGROUND: Differentiated thyroid carcinoma is considered to be the nonhereditary cancer for which familial inheritance is the highest. To date, no familial aggregation analysis of this cancer has been performed in Maohi populations, which exhibit a very high incidence rate. Therefore, we evaluate the risk of differentiated thyroid cancer associated with a family history of thyroid cancer in natives of French Polynesia. METHODS: We investigated thyroid cancer incidence in the first-degree relatives of 225 cases of differentiated thyroid carcinomas diagnosed between 1979 and 2004 in patients born in French Polynesia, and 368 randomly selected population controls matched for sex and age, born and residing in French Polynesia. All but five thyroid cancers declared among relatives were validated. RESULTS: Twenty-four cases declared a family history of thyroid cancer, when compared with 11 controls. Individuals with an affected first-degree relative had a 4.5-fold (95% confidence interval [CI], 1.9-10.6) increased risk of differentiated thyroid cancer. This odds ratio (OR) was not significantly higher when a male first-degree relative was affected (OR, 10.0; 95% CI, 1.3-74.8) compared with a female (OR, 4.0; 95% CI, 1.5-10.3) and was not different for patients who had a nonaggressive thyroid microcarcinoma (OR, 3.5; 95% CI, 0.6-16.4) than those who had a larger cancer (OR, 6.0; 95% CI, 1.8-20.5). This OR was borderline significantly (p, 0.07) higher in Maohis (OR, 11.0; 95% CI, 2.4-48.8) than in individuals of mixed origin (OR, 2.1; 95% CI, 0.8-5.9). CONCLUSION: Our study shows that the familial inheritance of differentiated thyroid cancer is particularly high in Maohi populations.

Anthropometric factors in differentiated thyroid cancer in French Polynesia: a case-control study.

OBJECTIVES: French Polynesia has one of the world's highest thyroid cancer incidence rates. A case-control study among native residents of French Polynesia included 219 cases of differentiated thyroid cancers diagnosed between 1979 and 2004 (195 women/24 men) matched with 359 population controls (315 women/44 men) on the date of birth. METHODS: Anthropometric factors were analyzed by conditional logistic regression. RESULTS: The risk of thyroid cancer for women in the highest quartile of body mass index (BMI) before diagnosis and at age 18 was 2.3-fold higher (95% CI, 1.1-4.7 p = 0.04) and 2.3-fold higher (95% CI, 1.2-4.4 p < 0.01), respectively, compared with the lowest. Women who were overweight (BMI = 25-29.9 kg/m2) or obese (BMI > or = 30 kg/m2) at age 18 and before diagnosis had an increased risk compared with those with a normal lifelong weight (OR = 6.2; 95% CI, 2.5-15.5 p < 0.01). Results for excess weight appeared in similar directions for men, although the number of cases was too small to provide reliable estimates. Height was positively associated with thyroid cancer among men and women. CONCLUSION: This study shows the role of excess body weight, especially if the onset is during early adulthood, and elevated height in the risk of differentiated thyroid cancer in populations born in French Polynesia.

Menstrual and reproductive factors in the risk of differentiated thyroid carcinoma in native women in French Polynesia: a population-based case-control study.

French Polynesia has one of the world's highest incidence rates of thyroid cancer. A case-control study among native residents of French Polynesia included 201 women diagnosed with differentiated thyroid cancer before the age of 56 years, between 1981 and 2004, matched to 324 population controls on date of birth. Face-to-face interviews were conducted from 2002 to 2004. Odds ratios were calculated by using conditional logistic regression and were reported in the total group and by ethnic group ("Polynesian" vs. "mixed"). The risk of thyroid cancer increased with natural (odds ratio = 1.9) or artificial (odds ratio = 4.5) menopause compared with that associated with a premenopausal status and with number of births (p for trend = 0.03): odds ratios for one, two, three, four or five, six or seven, and eight or more births were, respectively, 0.90, 1.6, 2.3, 2.2, 2.7, and 1.7 compared with a nulliparous status. Similar results were observed for Polynesian women. No association was observed with irregular menstrual cycles, age at menopause, history of miscarriage or induced abortion, time since last birth, age at and outcome of first pregnancy, or breastfeeding. This study confirms the role of menstrual and reproductive factors in the risk of differentiated thyroid cancer in Pacific island populations.