Genetic Variations, Exposure to Persistent Organic Pollutants and Breast Cancer Risk - A Greenlandic Case-Control Study.

This study investigated the effects of single nucleotide polymorphisms (SNPs) in xenobiotic and steroid hormone-metabolizing genes in relation to breast cancer risk and explored possible effect modifications on persistent organic pollutants (POPs) and breast cancer associations. The study also assessed effects of Greenlandic BRCA1 founder mutations. Greenlandic Inuit women (77 cases and 84 controls) were included. We determined two founder mutations in BRCA1: Cys39Gly (rs80357164) and 4684delCC, and five SNPs in xenobiotic and oestrogen-metabolizing genes: CYP17A1 -34T>C (rs743572), CYP19A1 *19C>T (rs10046), CYP1A1 Ile462Val (rs1048943), CYP1B Leu432Val (rs1056836) and COMT Val158Met (rs4680). We used chi-square test for comparison of categorical variables between groups. Odds ratio (OR) estimates with 95% confidence interval (95%CI) were obtained using logistic regression models. The variant allele of BRCA1 Cys39Gly increased breast cancer risk (Gly/Cys versus Cys/Cys, OR: 12.2, 95%CI: 1.53; 98.1), and carriers of the variant allele of CYP17A1 -34T>C had reduced risk (CT+CC versus TT, OR: 0.44, 95%CI: 0.21; 0.93). CYP17A1 -34T>C was an effect modifier on the association between perfluoroalkyl acids (PFAAs) and breast cancer risk (∑PFAA, ratio of OR: 0.18, 95%CI: 0.03; 0.97). Non-significant modifying tendencies were seen for the other SNPs on the effect of polychlorinated biphenyls, organochlorine pesticides and PFAAs. In summary, the BRCA1 Cys39Gly and CYP17A1 -34T>C genetic variations were associated with breast cancer risk. Our results indicate that the evaluated genetic variants modify the effects of POP exposure on breast cancer risk; however, further studies are needed to document the data from the relatively small sample size.

Receptor activities of persistent pollutant serum mixtures and breast cancer risk.

Studies on associations between persistent organic pollutants (POPs) and breast cancer risk are inconclusive. The majority of studies have evaluated the effect of single compounds, without considering multiple exposures to and interactions between different POPs. The present study aimed at evaluating breast cancer risk related to combined effects of serum POP mixtures on cellular receptor functions. Data on breast cancer cases (n = 77) and controls (n = 84) were collected among Greenlandic Inuit women. Serum mixtures of lipophilic POPs (lipPOPs), perfluoroalkyl acids (PFAAs) and dioxin-like POPs were extracted. The effect of the mixture extracts on the estrogen receptor (ER), androgen receptor (AR) and aryl hydrocarbon receptor (AhR) was determined using cell culture reporter gene assays. The serum mixtures were analyzed alone and upon co-exposure with natural receptor ligands to determine agonistic and antagonistic/competitive activity. We found that the frequency of lipPOP mixtures eliciting no, decreasing, or agonizing xenoandrogenic effect differed by breast cancer status. Using lipPOP mixtures with no effect on AR as reference, the mixtures with decreasing effects reduced breast cancer risk (OR: 0.30 (0.12; 0.76)). The AhR-toxic equivalent of serum mixtures was significantly lower in cases than in controls, and a reduced breast cancer risk was found when comparing the third tertile to the first (OR: 0.34 (0.14; 0.83)). We found no association between the xenoestrogenic activities of lipPOPs or PFAAs and breast cancer risk. Serum lipPOP mixtures are hormone disruptive and may influence breast cancer risk, whereas PFAAs seem to influence breast cancer risk through other pathways.

Serum levels of environmental pollutants is a risk factor for breast cancer in Inuit: a case control study.

BACKGROUND: Environmental Persistent Organic Pollutants (POPs) can alter the hormone homeostasis by mimicking, interfering or blocking the function of hormones; moreover POPs are hypothesized to modify the risk of breast cancer. The association between POPs and breast cancer has been widely studied but the conclusions are inconsistent. The present study examined the associations between serum levels of POPs and breast cancer with focus on the highly exposed Greenlandic Inuit population. METHODS: The study design was a case-control study of Inuit women from Greenland. The participants were asked to complete a questionnaire with information on reproductive history and lifestyle and to provide a blood sample. The sampling was carried out in two time periods (2000-2003 and 2011-2014). The serum levels were determined of 14 polychlorinated biphenyls (PCBs), 11 organochlorine pesticides (OCPs), 16 perfluoroalkyl acids (PFAAs), 1 polybrominated biphenyl (PBB), and 9 polybrominated diphenyl ethers (PBDEs). Independent samples t-test was used to compare differences between cases and controls and odds ratios (OR) adjusted for identified confounders were obtained using logistic regression. RESULTS: The study population included 77 breast cancer cases and 84 controls. The majority of the measured compounds declined significantly from 2000 - 2003 to 2011-2014. However, for the perfluorinated carboxylic acids (PFCAs) an increase was observed. The serum levels were significantly higher in cases compared to controls for the majority of the compounds, and after adjusting for age the difference was maintained for ∑OCP, dichlorodiphenyldichloroethylene (p,p'-DDE), ∑PFAA, ∑perfluorinated sulfonic acids (PFSA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS). For the lipophilic POPs, high serum levels (middel/highest vs. lowest tertile) of ∑PCB, ∑estrgoenicPCB, PCB99, PCB138, PCB153, PCB170, PCB170, and PCB183 was associated with breast cancer risk; for the amphiphilic PFAAs, high serum levels of ∑PFAA, ∑PFCA, ∑PFSA, perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), PFHxS, and PFOS were associated with breast cancer risk. CONCLUSION: Significant, positive associations between breast cancer risk and PCBs and PFAAs were observed. The associations indicate that environmental exposure to POPs can be a factor increasing the risk for breast cancer in Inuit women.

Abdominal Wall Defects in Greenland 1989-2015.

BACKGROUND: In the last decades, an increasing rate of gastroschisis but not of omphalocele has been reported worldwide. Greenland is the world's largest island, but 80% is covered by an ice cap, it has a small population of around 56,000 peoples (as of 2016). The occurrence of abdominal wall defects has never been investigated in Greenland. METHODS: The present study is based on data retrieved from three nationwide and two local registries in the Greenlandic health care system over 27 years (1989-2015). RESULTS: We identified 33 infants with abdominal wall defects born in the study time period. All cases were reclassified to 28 cases of gastroschisis, four cases of omphalocele, and there was 1 infant in the indeterminate group. The point prevalence at birth for gastroschisis increased significantly from 8 to 35 (average 10.7) per 10,000 liveborn and -stillborn infants. Mothers below 20 years of age represented 23% of all cases and the prevalence for this group was 17 per 10,000 liveborn and stillborn. Perinatal mortality for infants with gastroschisis was high (18%), and 1 year survival was 71%. For omphalocele, the prevalence varied from 8 to 11 per 10,000 liveborn and stillborn infants. There was no increasing rate in the period, further highlighting an etiological difference between gastroschisis and omphalocele. CONCLUSION: This study confirms the increasing prevalence of gastroschisis in Greenland in the period from 1989 to 2015. The average was 10.7 per 10,000 liveborn and -stillborn infants and, to the best of our knowledge, this is the highest prevalence ever reported. Birth Defects Research 109:836-842, 2017. © 2017 Wiley Periodicals, Inc.

Cervical cancer screening in Greenland, 1997-2011: Screening coverage and trends in the incidence of high-grade cervical lesions.

OBJECTIVE: In spite of the high incidence of cervical cancer in Greenland, no assessment has been made of the impact of organized cervical screening, introduced in 1998, in relation to occurrence of high-grade cervical lesions. The objectives of the present study were to estimate coverage of the screening program and to examine possible changes in cervical intraepithelial neoplasia (CIN3) incidence in Greenland during 1997-2011 according to calendar period and age. METHODS: Using nationwide registries, we calculated age-standardized incidence rates for all women born and living in Greenland. To investigate whether possible variation in the incidence of CIN3 were related to differences in screening coverage, we further estimated relative risks of CIN3 within two years of screening among women who participated in the screening program using log-linear binomial regression. RESULTS: Coverage of the screening program was low during 1997-2011 with the highest level of 54% observed in 2011. Peaks in CIN3 incidence of around 300 per 100,000 person-years were observed in 1999 and between 2009 and 2011, while the incidence was lower of approximately 100 per 100,000 person-years between 2000 and 2008. During 2009-2011, the highest incidence was found among women aged 25-34 years. Similar patterns of CIN3 risk according to calendar period and age groups were observed among screened women. CONCLUSIONS: The great variations in CIN3 incidence and low screening coverage observed during 1997-2011 suggest that improvements in the Greenlandic screening program are warranted.

Vitamin D status in Greenland--dermal and dietary donations.

BACKGROUND: Vitamin D status influences skeletal health, the risk of falls and fractures, and muscle health, and it has been associated with inflammatory, infectious, cardiovascular and metabolic disorders in addition to some cancers. Prevailing intracellular infections such as tuberculosis are speculated to relate to vitamin D status. The vitamin D sources are dietary and dermal, the latter depending on UVB radiation exposure from the sun. Life in the Arctic influences vitamin D status because of dietary peculiarities, the polar night, waning of the ozone layer and maybe ethnic differences between Inuit and non-Inuit. OBJECTIVE AND DESIGN: Data on vitamin D status as estimated by plasma 25OHD in Inuit and non-Inuit in Greenland are reviewed. RESULTS: Decreasing intake of vitamin D-rich local food items associated with decreasing plasma 25OHD levels and insufficient vitamin D status is seen with low intake of traditional Inuit foods. Plasma 25OHD levels increase markedly during spring and summer in parallel with the high influx of sunlight while plasma 25OHD is not influenced by obesity in Greenland Inuit and no clear-cut association is seen between plasma 25OHD and the risk of tuberculosis. CONCLUSION: The frequency of vitamin D deficiency in populations in Greenland rises with the dietary transition and diseases related to low vitamin D status should be monitored.

Perfluorinated compounds are related to breast cancer risk in Greenlandic Inuit: a case control study.

BACKGROUND: Breast cancer (BC) is the most common cancer for women in the western world. From very few cases an extraordinary increase in BC was observed in the Inuit population of Greenland and Canada although still lower than in western populations. Previous data suggest that exposure to persistent organic pollutants (POPs) might contribute to the risk of BC. Rat studies showed that perfluorinated compounds (PFCs) cause significantly increase in mammary fibroadenomas. This study aimed at evaluating the association between serum levels of POPs/PFCs in Greenlandic Inuit BC cases and their controls, and whether the combined POP related effect on nuclear hormone receptors affect BC risk. METHODS: Thirty-one BC cases and 115 controls were sampled during 2000-2003 from various Greenlandic districts. The serum levels of POPs, PFCs, some metals and the combined serum POP related effect on estrogen- (ER), androgen- (AR) and Ah-receptor (AhR) transactivity were determined. Independent student t-test was used to compare the differences and the odds ratios were estimated by unconditional logistic regression models. RESULTS: We observed for the very first time a significant association between serum PFC levels and the risk of BC. The BC cases also showed a significantly higher concentration of polychlorinated biphenyls at the highest quartile. Also for the combined serum POP induced agonistic AR transactivity significant association to BC risk was found, and cases elicited a higher frequency of samples with significant POP related hormone-like agonistic ER transactivity. The AhR toxic equivalent was lowest in cases. CONCLUSIONS: The level of serum POPs, particularly PFCs, might be risk factors in the development of BC in Inuit. Hormone disruption by the combined serum POP related xenoestrogenic and xenoandrogenic activities may contribute to the risk of developing breast cancer in Inuit. Further investigations are needed to document these study conclusions.

A high frequent BRCA1 founder mutation identified in the Greenlandic population.

Approximately 10% of all breast and ovarian cancers are dominantly inherited and mutations are mainly found in the BRCA 1 and 2 genes. The penetrance of BRCA1 mutations is reported to be between 68 and 92% and confers a 36-92% life time risk of breast cancer. Most mutations in BRCA1 are uniquely occurring mutations, but founder mutations have been described. In this study we describe a founder mutation with wide spread presence in the Inuit population. We have screened 2,869 persons from Greenland for the presence of a BRCA1 mutation (p.Cys39Gly) only found in the Inuit population. The overall carrier frequency was 1.6% in the general population, but the frequency differs geographically from 0.6% on the West coast to 9.7% in the previously isolated population of the East coast. This is to our knowledge the highest population frequency of a BRCA1 mutation ever to be described. To determine the clinical relevance of the mutation, we have examined ten breast cancer patients and nine ovarian cancer patients from Greenland for the presence of the p.Cys39Gly mutation. We found three ovarian cancer patients (33%) and one breast cancer patient (10%) carrying the mutation. The high number of women carrying a BRCA1 mutation known to trigger the development of potentially lethal diseases leads us to recommend an offer of genetic counselling and test for the mutation to all females of Inuit origin, thereby hopefully preventing a number of breast and ovarian cancer deaths.