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Supplementary Figure Legend from Age-Period-Cohort Analysis of Primary Bone Cancer Incidence Rates in the United States (1976–2005)

Supplementary Figure 1 from Age-Period-Cohort Analysis of Primary Bone Cancer Incidence Rates in the United States (1976–2005)

Supplementary Table 1. Per minor allele associations between breast cancer SNPs and mammographic density by breast cancer risk factors and confidence intervals, identified by lower (lowerCL) and upper (upperCL) confidence limits

Background: Primary bone cancer comprises three major histologic types: osteosarcoma (OS), Ewing sarcoma (ES), and chondrosarcoma (CS). Given the limited knowledge about the etiology of primary bone cancer, we undertook an age-period-cohort (APC) analysis to determine whether incidence varied by birth cohort or calendar period. The purpose was to examine the temporal development of each bone cancer type and generate etiologic hypotheses via the observed birth cohort-related changes.Methods: An APC model was fitted to incidence data for U.S. whites for OS, ES, and CS obtained from nine registries of the Surveillance, Epidemiology, and End Results program, which covers about 10% of the U.S. population, 1976–2005.Results: The incidence of OS decreased between 1976 and 2005 among those aged over 60 years, a decline that occurred among patients with OS as their primary malignancy only. From 1986–1995 to 1996–2005, the incidence rate of CS among females of 20 to 69 years rose by about 50%, with rates increasing among consecutive cohorts born during 1935–1975. CS rates among males were stable, as were rates of ES.Conclusion: The risk reduction in OS as a primary malignancy at older ages could possibly be related to diminished exposure over time to bone-seeking radionuclides. The CS increase among females corresponds to birth cohorts with rising exposures to oral contraceptives and menopausal hormonal therapy.Impact: As the estrogen signaling pathway has been shown to stimulate proliferation of normal and malignant chondrocytes, estrogen exposure may increase the risk for CS. Further studies are warranted to clarify its possible etiological significance. Cancer Epidemiol Biomarkers Prev; 20(8); 1770–7. ©2011 AACR.

Background: Mammographic density (MD) is one of the strongest known breast cancer risk factors. Twin studies have suggested that a large part of the variation in MD is genetically determined. We hypothesized that breast cancer susceptibility variants may affect MD, and that their effects may be modified by nongenetic factors.Methods: We assessed MD, using a computer-assisted method, on 2,348 postmenopausal Caucasian women (50–69 years) who participated in the Norwegian Breast Cancer Screening Program (NBCSP) in 2004 or 2006–07. We used linear regression (additive models) to determine the association between each SNP and MD, adjusting for age, body mass index (BMI), and study. We evaluated MD associations with 17 established breast cancer SNPs, overall, and by strata defined by non-genetic factors.Results: Two variants, 6q25.1-rs9383938 and TXNRD2-rs8141691, were statistically significantly associated with percent MD (P = 0.019 and 0.03, respectively), with the 6q25.1-rs9383938 association being consistent with the SNP effect on breast cancer risk. The effect of 6q25.1-rs3734805 on percent MD varied between parous and nulliparous women (Pinteraction = 0.02), whereas the effects of 9q31.2-rs865686 and MRPS30:FGF10-rs4415084 differed across strata of BMI (Pinteraction = 0.01 and 0.005, respectively). There was no evidence of effect modification by estrogen and progestin therapy use or alcohol consumption.Conclusion: This study provides novel evidence of shared genetic risk factors between MD and breast cancer and of possible MD genetic–environmental interactions.Impact: Although the results may be chance findings, they nevertheless highlight the need to investigate interactions with nongenetic factors in studies on the genetics of MD. Cancer Epidemiol Biomarkers Prev; 23(9); 1752–63. ©2014 AACR.

Thyroid cancer incidence is higher in women than men, especially during the reproductive years, for reasons that remain poorly understood. Using population-based registry data from 4 Nordic countries through 2015, we examined associations of perinatal characteristics with risk of maternal thyroid cancer. Cases were women diagnosed with thyroid cancer ≥2 years after last birth (n = 7,425, 83% papillary). Cases were matched to controls (n = 67,903) by mother’s birth year, country, and county of residence. Odds ratios (ORs) were estimated using conditional logistic regression models adjusting for parity. Older age at first pregnancy, postpartum hemorrhage (OR = 1.18, 95% (confidence interval) CI: 1.08, 1.29), and benign thyroid conditions (ORs ranging from 1.64 for hypothyroidism to 10.35 for thyroid neoplasms) were associated with increased thyroid cancer risk, as were higher offspring birth weight (per 1-kg increase, OR = 1.17, 95% CI: 1.12, 1.22) and higher likelihood of offspring being large for gestational age (OR = 1.26, 95% CI: 1.11, 1.43). Unmarried/noncohabiting status (OR = 0.91, 95% CI: 0.84, 0.98), maternal smoking (OR = 0.75, 95% CI: 0.67, 0.84), and preterm birth (OR = 0.90, 95% CI: 0.83, 0.98) were associated with reduced risk. Several factors (e.g., older age at first pregnancy, maternal smoking, goiter, benign neoplasms, postpartum hemorrhage, hyperemesis gravidarum, and neonatal jaundice) were associated with advanced thyroid cancer. These findings suggest that some perinatal exposures may influence maternal thyroid cancer risk.

Summary Background Thyroid cancer tends to be diagnosed at a younger age (median age 51 years) compared with most other malignancies (such as breast cancer [62 years] or lung cancer [71 years]). The incidence of thyroid cancer is higher in women than men diagnosed from early adolescence. However, few in-utero and early life risk exposures associated with increased risk of thyroid cancer have been identified. Methods In this population-based nested case-control study we used registry data from four Nordic countries to assess thyroid cancer risk in offspring in relation to maternal medical history, pregnancy complications, and birth characteristics. Patient with thyroid cancer (cases) were individuals born and subsequently diagnosed with first primary thyroid cancer from 1973 to 2013 in Denmark, 1987 to 2014 in Finland, 1967 to 2015 in Norway, or 1973 to 2014 in Sweden. Each case was matched with up to ten individuals without thyroid cancer (controls) based on birth year, sex, country, and county of birth. Cases and matched controls with a previous diagnosis of any cancer, other than non-melanoma skin cancer, at the time of thyroid cancer diagnosis were excluded. Cases and matched controls had to reside in the country of birth at the time of thyroid cancer diagnosis. Conditional logistic regression models were used to calculate odds ratios (ORs) with 95% CIs. Results Of the 2437 cases, 1967 (81·4%) had papillary carcinomas, 1880 (77·1%) were women, and 1384 (56·7%) were diagnosed before age 30 years (range 0–48). Higher birth weight (OR per kg 1·14 [95% CI 1·05–1·23]) and congenital hypothyroidism (4·55 [1·58–13·08]); maternal diabetes before pregnancy (OR 1·69 [0·98–2·93]) and postpartum haemorrhage (OR 1·28 [1·06–1·55]); and (from registry data in Denmark) maternal hypothyroidism (18·12 [10·52–31·20]), hyperthyroidism (11·91 [6·77–20·94]), goiter (67·36 [39·89–113·76]), and benign thyroid neoplasms (22·50 [6·93–73·06]) were each associated with an increased risk of thyroid cancer in offspring. Interpretation In-utero exposures, particularly those related to maternal thyroid disorders, might have a long-term influence on thyroid cancer risk in offspring. Funding Intramural Research Program of the National Cancer Institute (National Institutes of Health).

Background Childhood cancer is more common among children with birth defects, suggesting a common aetiology. Whether this association differs by sex is unclear. Methods We performed a population-based nested case-control study using nationwide health registries in four Nordic countries. We included 21 898 cancer cases (0–19 years) and 218 980 matched population controls, born 1967–2014. Associations between childhood cancer and major birth defects were calculated as odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression models. Effect modification was evaluated using a counterfactual framework to estimate confidence intervals and P-values for the natural indirect effects. Results Birth defects were present for 5.1% (1117/21 898) of childhood cancer cases and 2.2% (4873/218 980) of controls; OR of cancer was higher for chromosomal (OR = 10, 95% CI = 8.6–12) than for non-chromosomal defects (OR = 1.9, 95% CI = 1.8–2.1), strongest between genetic syndromes/microdeletion and renal tumours, Down syndrome and leukaemia, and nervous system defects and central nervous system tumours. The association between birth defects and cancer was stronger among females (OR = 2.8, 95% CI = 2.6–3.1) than males (OR = 2.1, 95% CI = 1.9–2.2, Pinteraction Conclusions The birth defect–cancer associations were generally stronger among females than males. Birth defects did not act as a strong mediator for the modest differences in childhood cancer risk by sex, suggesting that other biological pathways are involved.

OBJECTIVE To identify minimally invasive biomarkers to help differentiate dogs with gastric carcinoma from those with chronic gastritis. DESIGN Prospective study. ANIMALS 15 dogs with gastric carcinoma, 29 dogs with chronic gastritis, and 7 healthy dogs. PROCEDURES Dogs with clinical signs of upper gastrointestinal tract disease for > 14 days that underwent gastroscopy or necropsy for collection of gastric biopsy specimens for histologic evaluation were prospectively enrolled. Gastric carcinoma and chronic gastritis were diagnosed on the basis of histologic findings. Additionally, gastric biopsy specimens were collected endoscopically from 7 healthy (control) dogs while they were anesthetized for a routine neutering procedure. Prior to being anesthetized for gastroscopy or euthanized, all dogs underwent a physical examination, and a blood sample was collected for quantification of select serum biomarker concentrations. Histologic findings, body condition score (BCS), and serum biomarker concentrations were compared among the 3 groups. RESULTS Dogs with gastric carcinoma were significantly older and had a significantly lower BCS, lower serum folate concentration, and greater serum C-reactive protein (CRP) concentration, compared with dogs with chronic gastritis and control dogs. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that age > 8 years, BCS < 4, serum CRP concentration > 25 mg/L, and an abnormally low serum folate concentration might be useful noninvasive biomarkers for identification of dogs with gastric carcinoma. For underweight older dogs with signs of upper gastrointestinal tract disease and high serum CRP and low serum folate concentrations, gastric biopsy specimens should be obtained and evaluated so that a prompt definitive diagnosis can be made and appropriate treatment initiated.

Background: Studies evaluating the association between peripheral blood leukocyte telomere length (LTL) and testicular germ cell tumor (TGCT) risk have produced conflicting results. Methods: Using available genotype data from the Testicular Cancer Consortium (TECAC), polygenic risk score and Mendelian randomization analyses of genetic variants previously associated with LTL were used to assess potential etiologic associations between telomere length and TGCT risk. Results: Genetically inferred telomere length was not associated with TGCT risk among 2,049 cases and 6,921 controls with individual-level genotype data (OR, 1.02; 95% confidence interval, 0.97–1.07). Mendelian randomization analyses using summary statistic data further indicated no evidence for an association between telomere length and TGCT risk among all available TECAC participants (3,558 cases and 13,971 controls). Conclusions: Our analyses in the largest molecular genetic testicular cancer study to date provide no evidence for an association between genetically inferred peripheral blood LTL and TGCT risk. Impact: The lack of evidence for an overall association indicates that peripheral blood LTL is likely not a strong biomarker for TGCT risk.

Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation., Testicular germ cell tumors are highly heritable, and the authors present the largest genome association study, identifying 22 novel loci, which account for a third of those identified to date. Implicated pathways include male germ cell development and differentiation, and chromosomal segregation.

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence., In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.

Background Non-epithelial ovarian cancers are divided into sex cord-stromal tumours (SCSTs) and germ cell tumours (GCTs). Whereas parity and other pregnancy-related factors are protective for epithelial ovarian cancer, their associations with SCSTs and GCTs remains unclear. Methods Using data from the medical birth registries from Denmark, Finland, Norway and Sweden, we compared all parous women with a diagnosis of SCSTs (n = 420) or GCTs (n = 345) 1970–2013 with up to 10 parous controls (SCSTs n = 4041; GCTs n = 2942) matched on the cases’ birth year and country. We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) of associations between pregnancy-related factors and SCSTs and GCTs. Results The risk of SCSTs, but not GCTs, decreased with higher age at last birth [≥40 versus Conclusions We found a decreased risk of SCSTs with higher age at last birth and shorter time since last birth. The risk of SCSTs (but not GCTs) may be influenced by the woman’s reproductive history.

ObjectiveTo examine associations between birth defects and cancer from birth into adulthood.DesignPopulation based nested case-control study.SettingNationwide health registries in Denmark, Finland, Norway, and Sweden.Participants62 295 cancer cases (0-46 years) and 724 542 frequency matched controls (matched on country and birth year), born between 1967 and 2014.Main outcome measuresRelative risk of cancer in relation to major birth defects, estimated as odds ratios with 99% confidence intervals from logistic regression models.ResultsAltogether, 3.5% (2160/62 295) of cases and 2.2% (15 826/724 542) of controls were born with major birth defects. The odds ratio of cancer for people with major birth defects compared with those without was 1.74 (99% confidence interval 1.63 to 1.84). For individuals with non-chromosomal birth defects, the odds ratio of cancer was 1.54 (1.44 to 1.64); for those with chromosomal anomalies, the odds ratio was 5.53 (4.67 to 6.54). Many structural birth defects were associated with later cancer in the same organ system or anatomical location, such as defects of the eye, nervous system, and urinary organs. The odds ratio of cancer increased with number of defects and decreased with age, for both non-chromosomal and chromosomal anomalies. The odds ratio of cancer in people with any non-chromosomal birth defect was lower in adults (≥20 years: 1.21, 1.09 to 1.33) than in adolescents (15-19 years: 1.58, 1.31 to 1.90) and children (0-14 years: 2.03, 1.85 to 2.23). The relative overall cancer risk among adults with chromosomal anomalies was markedly reduced from 11.3 (9.35 to 13.8) in children to 1.50 (1.01 to 2.24). Among adults, skeletal dysplasia (odds ratio 3.54, 1.54 to 8.15), nervous system defects (1.76, 1.16 to 2.65), chromosomal anomalies (1.50, 1.01 to 2.24), genital organs defects (1.43, 1.14 to 1.78), and congenital heart defects (1.28, 1.02 to 1.59) were associated with overall cancer risk.ConclusionsThe increased risk of cancer in individuals with birth defects persisted into adulthood, both for non-chromosomal and chromosomal anomalies. Further studies on the molecular mechanisms involved are warranted.

Background Cisplatin-based chemotherapy (CBCT) is part of standard treatment of several cancers. In testicular cancer (TC) survivors, an increased risk of developing metabolic syndrome (MetS) is observed. In this epigenome-wide association study, we investigated if CBCT relates to epigenetic changes (DNA methylation) and if epigenetic changes render individuals susceptible for developing MetS later in life. We analyzed methylation profiles, using the MethylationEPIC BeadChip, in samples collected ~ 16 years after treatment from 279 Norwegian TC survivors with known MetS status. Among the CBCT treated (n = 176) and non-treated (n = 103), 61 and 34 developed MetS, respectively. We used two linear regression models to identify if (i) CBCT results in epigenetic changes and (ii) epigenetic changes play a role in development of MetS. Then we investigated if these changes in (i) and (ii) links to genes, functional networks, and pathways related to MetS symptoms. Results We identified 35 sites that were differentially methylated when comparing CBCT treated and untreated TC survivors. The PTK6–RAS–MAPk pathway was significantly enriched with these sites and infers a gene network of 13 genes with CACNA1D (involved in insulin release) as a network hub. We found nominal MetS-associations and a functional gene network with ABCG1 and NCF2 as network hubs. Conclusion Our results suggest that CBCT has long-term effects on the epigenome. We could not directly link the CBCT effects to the risk of developing MetS. Nevertheless, since we identified differential methylation occurring in genes associated with conditions pertaining to MetS, we hypothesize that epigenomic changes may also play a role in the development of MetS in TC survivors. Further studies are needed to validate this hypothesis.

Epithelial ovarian cancer is a fatal disease of largely unknown etiology. Higher parity is associated with reduced risk of ovarian cancer. However, among parous women, the impact of pregnancy-related factors on risk is not well understood. This population-based case–control study included all parous women with epithelial ovarian cancer in Denmark, Finland, Norway and Sweden during 1967–2013 (n = 10,957) and up to 10 matched controls (n = 107,864). We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for pregnancy-related factors and ovarian cancer risk by histological subtype. Preterm delivery was associated with an increased risk [pregnancy length (last pregnancy) ≤30 vs. 39–41 weeks, OR 1.33 (95% CI 1.06–1.67), adjusted for number of births]; the OR increased as pregnancy length decreased (p for trend < 0.001). Older age at first and last birth was associated with a decreased risk [first birth: 30–39 vs. heterogeneity < 0.001]. No associations were observed for multiple pregnancies, preeclampsia or offspring size. In conclusion, in addition to high parity, full-term pregnancies and pregnancies at older ages were associated with decreased risk of ovarian cancer. Our findings favor the cell clearance hypothesis, i.e. a recent pregnancy provides protection by clearing of precancerous cells from the epithelium of the ovary/fallopian tubes, mediated by placental or ovarian hormones.

Kidney transplantation in recipients with a previous malignancy is often deferred 2 to 5 years after cancer treatment due to fear of cancer recurrence. In Norway, the required waiting period has been 1 year.We compared patient and graft survival of recipients with pretransplant cancer to the outcomes of matched recipients without such cancer (comparators) using Cox regression.From 1963 to 2010, 377 (6.4%) of 5867 recipients had a pretransplant cancer. During a median follow-up of 6.8 years, 256 recipients died, 35 (13.7%) from recurrent cancer and 27 (10.5%) from de novo cancer. Uncensored and death-censored graft loss occurred in 263 and 46 recipients, respectively. All-cause mortality was similar as in comparators (hazard ratio [HR], 1.06; 95% confidence interval [CI], 0.93-1.20]; P = 0.40), death-censored graft loss was lower (HR, 0.63; 95% CI, 0.47-0.84; P = 0.002), and uncensored graft loss was similar (HR, 0.99; 95% CI, 0.87-1.12; P = 0.87). Cancer mortality was higher than in comparators (HR, 1.97; 95% CI, 1.51-2.56; P0.001), particularly during the first 5 years of follow-up (HR, 3.44; 95% CI, 2.36-5.03; P0.01). Waiting period was not associated with recurrent cancer mortality or all-cause mortality (both P0.45). Results were similar within cancer subgroups, with most data in patients with a history of kidney cancer, prostate cancer, urothelial cancer, and skin squamous cell carcinoma.Kidney transplant recipients with a pretransplant cancer had a similar overall patient and graft survival as recipients without such cancer. Cancer mortality was increased, particularly during the first 5 years after transplantation. A short waiting period was not associated with mortality.

Introduction/Background Non-epithelial ovarian cancers are rare but affect women of all ages. The etiology is unknown. Non-epithelial ovarian cancers are divided into two major subgroups: sex cord-stromal tumors (SCSTs) and germ cell tumors (GCTs). Whereas parity is protective for epithelial ovarian cancer, its association with non-epithelial ovarian cancer and its subtypes remains less clear, as are associations with other pregnancy-related factors. Methodology All parous women with births recorded in the medical birth registries from the Nordic countries with a subsequent diagnosis of SCSTs (n=420) and GCTs (n=345) during 1967–2013 were compared with up to 10 controls (SCSTs n=4041; GCTs n=2942) matched on the cases’ birth year and country. We used conditional logistic regression to estimate odds ratios (ORs)with 95% confidence intervals (CI)of associations of pregnancy-related factors. Results Number of births was not associated with risk of SCSTs or GCTs. Older age at last birth was inversely associated with the risk of SCSTs (age 30–39 versus Conclusion In this large population-based case-control study among parous women, number of births was not protective for risk of SCSTs and GCTs.The inverse associations with greater age at last birth and shorter time since last birth observed for SCSTs, however, suggest that these subtypes may be influenced by the woman’s reproductive history. Disclosure Ingrid Glimelius have received Honoraria from Janssen for projects unrelated to the current study.

Many pregnancy‐related factors are associated with reduced endometrial cancer risk. However, it remains unclear whether pregnancy‐related complications (e.g., hypertensive conditions) are associated with risk and whether these associations vary by endometrial cancer subtype. Thus, we evaluated the risk of endometrial cancer, overall and by subtype, in relation to pregnancy‐related factors, pregnancy complications and birth characteristics. Utilizing population‐based register data from four Nordic countries, we conducted a nested case–control analysis of endometrial cancer risk. We included 10,924 endometrial cancer cases and up to 10 matched controls per case. Odds ratios (ORs) with 95% confidence intervals (CIs) were derived from unconditional logistic regression models. We further evaluated associations by individual histology (i.e., endometrioid, serous, etc.) or, for rare exposures (e.g., pregnancy complications), by dualistic type (Type I [n = 10,343] and Type II [n = 581]). Preexisting and pregnancy‐related hypertensive conditions were associated with increased endometrial cancer risk (OR [95% CI]: preexisting hypertension 1.88 [1.39–2.55]; gestational hypertension 1.47 [1.33–1.63]; preeclampsia 1.43 [1.30–1.58]), with consistent associations across dualistic type. Increasing number of pregnancies (≥4 vs. 1 birth: 0.64 [0.59–0.69]) and shorter time since last birth (

An understanding of the origin of cancer is critical for cancer prevention and treatment. Complex biological mechanisms promote carcinogenesis, and there is increasing evidence that pregnancy-related exposures influence fetal growth cell division and organ functioning and may have a long-lasting impact on health and disease susceptibility in the mothers and offspring. Nulliparity is an established risk factor for breast, ovarian, endometrial, and possibly pancreatic cancer, while the risk of kidney cancer is elevated in parous compared with nulliparous women. For breast, endometrial and ovarian cancer, each pregnancy provides an additional risk reduction. The associations of parity with thyroid and colorectal cancers are uncertain. The timing of reproductive events is also recognized to be important. Older age at first birth is associated with an increased risk of breast cancer and older age at last birth is associated with a reduced risk of endometrial cancer. The risks of breast and endometrial cancers increase with younger age at menarche and older age at menopause. The mechanisms, and hormone profiles, that underlie alterations in maternal cancer risk are not fully understood and may differ by malignancy. Linking health-registries and pooling of data in the Nordic countries have provided opportunities to conduct epidemiologic research of pregnancy exposures and subsequent cancer. We review the maternal risk of several malignancies, including those with a well-known hormonal etiology and those with less established relationships. The tendency for women to have fewer pregnancies and at later ages, together with the age-dependent increase in the incidence of most malignancies, are expected to affect the incidence of pregnancy-associated cancer. This article is protected by copyright. All rights reserved.

Genome-wide association (GWA) studies have reported 19 distinct susceptibility loci for testicular germ cell tumor (TGCT). A GWA study for TGCT was performed by genotyping 610 240 single-nucleotide polymorphisms (SNPs) in 1326 cases and 6687 controls from Sweden and Norway. No novel genome-wide significant associations were observed in this discovery stage. We put forward 27 SNPs from 15 novel regions and 12 SNPs previously reported, for replication in 710 case-parent triads and 289 cases and 290 controls. Predefined biological pathways and processes, in addition to a custom-built sex-determination gene set, were subject to enrichment analyses using Meta-Analysis Gene Set Enrichment of Variant Associations (M) and Improved Gene Set Enrichment Analysis for Genome-wide Association Study (I). In the combined meta-analysis, we observed genome-wide significant association for rs7501939 on chromosome 17q12 (OR = 0.78, 95% CI = 0.72-0.84, P = 1.1 × 10(-9)) and rs2195987 on chromosome 19p12 (OR = 0.76, 95% CI: 0.69-0.84, P = 3.2 × 10(-8)). The marker rs7501939 on chromosome 17q12 is located in an intron of the HNF1B gene, encoding a member of the homeodomain-containing superfamily of transcription factors. The sex-determination gene set (false discovery rate, FDRM < 0.001, FDRI < 0.001) and pathways related to NF-κB, glycerophospholipid and ether lipid metabolism, as well as cancer and apoptosis, was associated with TGCT (FDR < 0.1). In addition to revealing two new TGCT susceptibility loci, our results continue to support the notion that genes governing normal germ cell development in utero are implicated in the development of TGCT.

Reproductive factors have been shown to influence cancer risk. Several pathological conditions during pregnancy have also been associated with subsequent altered cancer risk in the mother. Hyperemesis gravidarum (hyperemesis) is an early pregnancy condition characterized by severe nausea and vomiting resulting in weight loss and metabolic disturbances. Studies have reported associations between hyperemesis and cancer, but results are inconsistent. In this nested case-control study we linked the population-based medical birth registries and cancer registries in Norway, Sweden and Denmark in order to examine overall cancer risk and risk of specific cancer types in women with a history of hyperemesis, using conditional logistic regression. In total, 168,501 cases of cancer in addition to up to 10 cancer-free controls per case were randomly sampled, matched on year of birth and birth registry (n 5 1,721,626). Hyperemesis was defined through the International Classification of Diseases. Analyses were adjusted for potential confounders. Hyperemesis was inversely associated with overall cancer risk with adjusted relative risk (aRR) of 0.93 (95% CI: 0.88–0.99), with cancer in the lungs (aRR: 0.60, 95% CI: 0.44–0.81), cervix (aRR: 0.66, 95% CI: 0.49–0.91) and rectum (aRR: 0.48, 95% CI: 0.29–0.78). Thyroid cancer was positively associated with hyperemesis (aRR 1.45, 95% CI: 1.06–1.99) and risk increased with more than one hyperemetic pregnancy (aRR 1.80, 95% CI: 1.23–2.63). Hormonal factors, in particular human chorionic gonadotropin, are likely to be involved in mediating these effects. This study is the first to systematically address these associations and provides valuable knowledge on potential long-term consequences of hyperemesis.

Summary Observational studies have suggested anthropometric traits, particularly increased height are associated with an elevated risk of testicular cancer (testicular germ cell tumour). However, there is an inconsistency between study findings, suggesting the possibility of the influence of confounding factors. To examine the association between anthropometric traits and testicular germ cell tumour using an unbiased approach, we performed a Mendelian randomisation study. We used genotype data from genome wide association studies of testicular germ cell tumour totalling 5518 cases and 19,055 controls. Externally weighted polygenic risk scores were created and used to evaluate associations with testicular germ cell tumour risk per one standard deviation (s.d) increase in genetically-defined adult height, adult BMI, adult waist hip ratio adjusted for BMI (WHRadjBMI), adult hip circumference adjusted for BMI (HIPadjBMI), adult waist circumference adjusted for BMI (WCadjBMI), birth weight (BW) and childhood obesity. Mendelian randomisation analysis did not demonstrate an association between any anthropometric trait and testicular germ cell tumour risk. In particular, despite good power, there was no global evidence for association between height and testicular germ cell tumour. However, three SNPs for adult height individually showed association with testicular germ cell tumour (rs4624820: OR = 1.47, 95% CI: 1.41–1.55, p = 2.7 × 10−57; rs12228415: OR = 1.17, 95% CI: 1.11–1.22, p = 3.1 × 10−10; rs7568069: OR = 1.13, 95% CI: 1.07–1.18, p = 1.1 × 10−6). This Mendelian randomisation analysis, based on the largest testicular germ cell tumour genome wide association dataset to date, does not support a causal etiological association between anthropometric traits and testicular germ cell tumour aetiology. Our findings are more compatible with confounding by shared environmental factors, possibly related to prenatal growth with exposure to these risk factors occurring in utero.

Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta- A nalysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.

Background: Mammographic density (MD) is one of the strongest known breast cancer risk factors. Twin studies have suggested that a large part of the variation in MD is genetically determined. We hypothesized that breast cancer susceptibility variants may affect MD, and that their effects may be modified by nongenetic factors. Methods: We assessed MD, using a computer-assisted method, on 2,348 postmenopausal Caucasian women (50–69 years) who participated in the Norwegian Breast Cancer Screening Program (NBCSP) in 2004 or 2006–07. We used linear regression (additive models) to determine the association between each SNP and MD, adjusting for age, body mass index (BMI), and study. We evaluated MD associations with 17 established breast cancer SNPs, overall, and by strata defined by non-genetic factors. Results: Two variants, 6q25.1-rs9383938 and TXNRD2-rs8141691, were statistically significantly associated with percent MD (P = 0.019 and 0.03, respectively), with the 6q25.1-rs9383938 association being consistent with the SNP effect on breast cancer risk. The effect of 6q25.1-rs3734805 on percent MD varied between parous and nulliparous women (Pinteraction = 0.02), whereas the effects of 9q31.2-rs865686 and MRPS30:FGF10-rs4415084 differed across strata of BMI (Pinteraction = 0.01 and 0.005, respectively). There was no evidence of effect modification by estrogen and progestin therapy use or alcohol consumption. Conclusion: This study provides novel evidence of shared genetic risk factors between MD and breast cancer and of possible MD genetic–environmental interactions. Impact: Although the results may be chance findings, they nevertheless highlight the need to investigate interactions with nongenetic factors in studies on the genetics of MD. Cancer Epidemiol Biomarkers Prev; 23(9); 1752–63. ©2014 AACR.

Introduction Testicular germ cell tumour (TGCT) is a malignancy present in males with the highest incidence rates in younger age ranges. The aetiology is still largely unknown; however, several genome-wide association studies have identified up to 30 independent loci influencing TGCT risk, confirming its inherited genetic susceptibility. Machine learning can be utilised as a modelling technique to identify patterns within genetic and lifestyle data that allows classification and identification of biomarkers. We aim to identify potential biomarkers and perform accurate classifications in the small non-coding RNAs (sncRNAs) of 147 pre-diagnostic serum samples. Material and methods The serum samples were obtained from the Janus Serum Bank, with life-style covariates, such as smoking habits, BMI and exercise habits also recorded for each sample. A total of 69 TGCT samples and 78 control sample sncRNA reads were used to train machine learning algorithms including linear regression, LASSO, decision trees and neural networks. These cases and controls are matched by age at blood sampling. Results and discussions Preliminary results from LASSO and decision tree methods show differentiation in the miRNA/piRNA patterns between the control and the TGCT samples after adjusting individual read counts for age at sampling. Classification performance was better when trained using piRNAs, 58% of control samples were classified as normal and 60% of TGCT cases being classified as TGCT patients. Further inclusion of life-style covariates in the model as well as age and time of diagnosis is still to be performed to increase classification performance further. By using interpretable machine learning methods, we aim to identify biomarkers that allow the accurate classification of the samples. Conclusion These results show that the piRNA composition seen in pre-diagnostic serum samples may contain potential biomarkers that can lead to accurate classification of whether a patient was at increased risk of testicular cancer before the initial diagnosis. Preliminary results should be further expanded with different sncRNA datasets and lifestyle covariates.

Testicular germ cell tumors (TGCT) are ideally suited to agnostic genome-wide association methods because of their known high heritability and homogeneous cell of origin. Here we report the most updated results from the international Testicular Cancer Consortium (TECAC) that extends published findings from our recent meta-analysis, which included 3,558 cases and 13,970 controls from five centers. To these existing samples, we added summary statistics from 300 cases and 151,991 controls provided by deCODE combined with imputed genotypes from an additional 5,602 cases and 5,006 controls assembled from 15 TECAC centers, almost all (97%) of which were centrally genotyped using the Illumina Human Core array. A total of 9,458 TGCT cases were included in our current meta-analysis, representing a 66% increase since our last publication. We identified 14 new and confirmed 41 previously reported loci that surpassed genome-wide significance (5 × 10-8). Fifteen previously reported loci did not reach this threshold, although one did so in subgroup analysis. In addition, 57 new loci attained nominal significance (5 × 10-8 ≤ p ≤ 1 × 10-5). As expected, a substantial proportion of top hits continue to map to genetic regions belonging to biological pathways essential to male germ cell development, sex determination, and chromosomal segregation. For example, newly identified genes include anaphase promoting complex subunit 2 (ANAPC2), BCL2 like 11 (BCL211), anti-Mullerian hormone receptor type 2 (AMHR2), and DEP domain containing mTOR interacting protein (DEPTOR). Our findings also further implicate genes located on the X chromosome, specifically the androgen receptor (AR). In analyses stratified by tumor subtype, we identified GATA-binding protein 4 (GATA4) as a susceptibility locus among men diagnosed with seminoma. Despite a similar effect size observed among men diagnosed solely with non-seminoma (i.e. excluding cases with a mixture of both seminoma and non-seminoma tumors), this marker did not surpass genome-wide significance in this subtype likely because of the smaller case sample size. GATA4 previously has been associated with overall risk of TGCT (Litchfield et al., Nat Genet. 2017). Biological mechanisms for all genome-wide significant loci are currently being explored using publicly available data sets, ATAC-seq of four TGCT cell lines, and SPATIaL-Seq (a novel high-resolution chromatin conformation capture (3C) assay) of the NTERA2 pluripotent human embryonal carcinoma cell line. Additional genotyping of top hits in an independent sample set of 1,103 TGCT cases and 1,210 controls is currently ongoing. Citation Format: Louise C. Pyle, John Pluta, Kevin T. Nead, Nandita Mitra, Javier Benitez, D. Timothy Bishop, Victoria Cortessis, Alberto Ferlin, Jourik Gietema, Mark Greene, Tom Grotmol, Ramneek Gupta, Rob Hamilton, Michelle A. Hildebrandt, Trine B. Haugen, Lambertus Kiemeney, Christian Kubisch, Davor Lessel, Paloma Martin, Thorunn Rafnar, Lorenzo Richiardi, Rolf Skotheim, Clare Turnbull, Fredrik Wiklund, Tongzhang Zheng, Ewa Rajpert-De Meyts, Stephen M. Schwartz, Katherine A. McGlynn, Peter A. Kanetsky, Katherine L. Nathanson, Testicular Cancer Consortium (TECAC). Identification of 14 novel genetic loci for testicular germ cell tumor susceptibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2684.

Using a 2-level hierarchical frailty model, we analyzed population-wide data on testicular germ-cell tumor (TGCT) status in 1,135,320 two-generational Norwegian families to examine the risk of TGCT in family members of patients. Follow-up extended from 1954 (cases) or 1960 (unaffected persons) to 2008. The first-level frailty variable was compound Poisson-distributed. The underlying Poisson parameter was randomized to model the frailty variation between families and was decomposed additively to characterize the correlation structure within a family. The frailty relative risk (FRR) for a son, given a diseased father, was 4.03 (95% confidence interval (CI): 3.12, 5.19), with a borderline significantly higher FRR for nonseminoma than for seminoma (P = 0.06). Given 1 affected brother, the lifetime FRR was 5.88 (95% CI: 4.70, 7.36), with no difference between subtypes. Given 2 affected brothers, the FRR was 21.71 (95% CI: 8.93, 52.76). These estimates decreased with the number of additional healthy brothers. The estimated FRRs support previous findings. However, the present hierarchical frailty approach allows for a very precise definition of familial risk. These FRRs, estimated according to numbers of affected/nonaffected family members, provide new insight into familial TGCT. Furthermore, new light is shed on the different familial risks of seminoma and nonseminoma.

Recent genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) associated with testicular germ cell tumor (TGCT) risk in the genes ATF7IP, BAK1, DMRT1, KITLG, SPRY4 and TERT. In the present study, we validate these associations in a Scandinavian population, and explore effect modification by parental sex and differences in associations between the major histological subtypes seminoma and non-seminoma. A total of 118 SNPs in the six genes were genotyped in a population-based Swedish-Norwegian sample comprising 831 TGCT case-parent triads, 474 dyads, 712 singletons and 3919 population controls. Seven hundred and thirty-four additional SNPs were imputed using reference haplotypes from the 1000 genomes project. SNP-TGCT association was investigated using a likelihood-based association test for nuclear families and unrelated subjects implemented in the software package UNPHASED. Forward stepwise regression within each gene was applied to determine independent association signals. Effect modifications by parent-of-origin and effect differences between histological subtypes were explored. We observed strong association between SNPs in all six genes and TGCT (lowest P-value per gene: ATF7IP 6.2 × 10(-6); BAK1 2.1 × 10(-10); DMRT1 6.7 × 10(-25); KITLG 2.1 × 10(-48); SPRY4 1.4 × 10(-29); TERT 1.8 × 10(-18)). Stepwise regression indicated three independent signals for BAK1 and TERT, two for SPRY4 and one each for DMRT1, ATF7IP and KITLG. A significant parent-of-origin effect was observed for rs10463352 in SPRY4 (maternal odds ratio = 1.72, paternal odds ratio = 0.99, interaction P = 0.0013). No significant effect differences between seminomas and non-seminomas were found. In summary, we validated previously reported genetic associations with TGCT in a Scandinavian population, and observed suggestive evidence of a parent-of-origin effect in SPRY4.

The in utero origins of breast cancer are an increasing focus of research. However, the long time period between exposure and disease diagnosis, and the lack of standardized perinatal data collection makes this research challenging. We assessed perinatal factors, as proxies for in utero exposures, and breast cancer risk using pooled, population-based birth and cancer registry data. Birth registries provided information on perinatal exposures. Cases were females born in Norway, Sweden or Denmark who were subsequently diagnosed with primary, invasive breast cancer (n = 1419). Ten controls for each case were selected from the birth registries matched on country and birth year (n = 14,190). Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using unconditional regression models. Breast cancer risk rose 7% (95% CI 2–13%) with every 500 g (roughly 1 s.d.) increase in birth weight and 7% for every 1 s.d. increase in birth length (95% CI 1–14%). The association with birth length was attenuated after adjustment for birth weight, while the increase in risk with birth weight remained with adjustment for birth length. Ponderal index and small- and large-for-gestational-age status were not better predictors of risk than either weight or length alone. Risk was not associated with maternal education or age, gestational duration, delivery type or birth order, or with several pregnancy complications, including preeclampsia. These data confirm the positive association between birth weight and breast cancer risk. Other pregnancy characteristics, including complications such as preeclampsia, do not appear to be involved in later breast carcinogenesis in young women.

BACKGROUND: Data are conflicting regarding the role of endogenous sex hormones in colorectal carcinogenesis. In this large population-based study, we pooled data from birth and cancer registries in four Nordic countries, to evaluate the risk of colorectal adenocarcinoma in relation to women's reproductive history.METHODS: We conducted a population-based case-control study among women registered in Nordic birth registries. The study included colorectal adenocarcinoma cases diagnosed in Denmark, Finland, Norway, and Sweden during 1967-2013 and up to 10 matched controls per case, in total 22 185 cases and 220 246 controls. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were derived from conditional logistic regression models. We had limited information available on possible confounders.RESULTS: We found no evidence for associations between colorectal adenocarcinoma and parity, age at first and last birth, and time since first and last birth. The risk estimates were also close to unity for specific cancer subsites (proximal and distal colon and rectum). As well, when the analyses were stratified on menopausal status, parity, and mother's year of birth, no indication of associations was found.CONCLUSIONS: In this large, Nordic population-based study, no evidence for associations was found between women's reproductive history and colorectal adenocarcinoma in parous women.British Journal of Cancer advance online publication 4 October 2016; doi:10.1038/bjc.2016.315 www.bjcancer.com.

After the introduction of the prostate specific antigen (PSA) test in the 1980s, a sharp increase in the incidence rate of prostate cancer was seen in the United States. The age-specific incidence patterns exhibited remarkable shifts to younger ages, and declining rates were observed at old ages. Similar trends were seen in Norway. We investigate whether these features could, in combination with PSA testing, be explained by a varying degree of susceptibility to prostate cancer in the populations. We analyzed incidence data from the United States’ Surveillance, Epidemiology, and End Results program for 1973–2010, comprising 511,027 prostate cancers in men ≥40 years old, and Norwegian national incidence data for 1953–2011, comprising 113,837 prostate cancers in men ≥50 years old. We developed a frailty model where only a proportion of the population could develop prostate cancer, and where the increased risk of diagnosis due to the massive use of PSA testing was modelled by encompassing this heterogeneity in risk. The frailty model fits the observed data well, and captures the changing age-specific incidence patterns across birth cohorts. The susceptible proportion of men is $$39.9\,\%\,\left( {95\,\%\,{\text{CI}}\, 38.2, 41.6\,\% } \right)$$ in the United States and $$30.4\,\%\, \left( {95\,\%\, {\text{CI}} \,28.9, 32.0\,\% } \right)$$ in Norway. Cumulative incidence rates at old age are unchanged across birth cohort exposed to PSA testing at younger and younger ages. The peaking cohort-specific age-incidence curves of prostate cancer may be explained by the underlying heterogeneity in prostate cancer risk. The introduction of the PSA test has led to a larger number of diagnosed men. However, no more cases are being diagnosed in total in birth cohorts exposed to the PSA era at younger and younger ages, even though they are diagnosed at younger ages. Together with the earlier peak in the age-incidence curves for younger cohorts, and the strong familial association of the cancer, this constitutes convincing evidence that the PSA test has led to a higher proportion, and an earlier timing, of diagnoses in a limited pool of susceptible individuals.

The Armitage–Doll model with random frailty can fail to describe incidence rates of rare cancers influenced by an accelerated biological mechanism at some, possibly short, period of life. We propose a new model to account for this influence. Osteosarcoma and Ewing sarcoma are primary bone cancers with characteristic age–incidence patterns that peak in adolescence. We analyze Surveillance, Epidemiology and End Result program incidence data for whites younger than 40 years diagnosed during the period 1975–2005, with an Armitage–Doll model with compound Poisson frailty. A new model treating the adolescent growth spurt as the accelerated mechanism affecting cancer development is a significant improvement over that model. We also model the incidence rate conditioning on the event of having developed the cancers before the age of 40 years and compare the results with those predicted by the Armitage–Doll model. Our results support existing evidence of an underlying susceptibility for the two cancers among a very small proportion of the population. In addition, the modeling results suggest that susceptible individuals with a rapid growth spurt acquire the cancers sooner than they otherwise would have if their growth had been slower. The new model is suitable for modeling incidence rates of rare diseases influenced by an accelerated biological mechanism. Copyright © 2012 John Wiley & Sons, Ltd.

BACKGROUND Testicular germ cell tumour (TGCT) is the most common cancer in young men, and an imbalance between the estrogen and androgen levels in utero is hypothesized to influence TGCT risk. Thus, polymorphisms in genes involved in the action of sex hormones may contribute to variability in an individual's susceptibility to TGCT. METHODS We conducted a Norwegian–Swedish case–parent study. A total of 105 single-nucleotide polymorphisms (SNPs) in 20 sex hormone pathway genes were genotyped using Sequenom MassArray iPLEX Gold, in 831 complete triads and 474 dyads. To increase the statistical power, the analysis was expanded to include 712 case singletons and 3922 Swedish controls, thus including triads, dyads and the case–control samples in a single test for association. Analysis for allelic associations was performed with the UNPHASED program, using a likelihood-based association test for nuclear families with missing data, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. False discovery rate (FDR) was used to adjust for multiple testing. RESULTS Five genetic variants across the ESR2 gene [encoding estrogen receptor beta (ERβ)] were statistically significantly associated with the risk of TGCT. In the case–parent analysis, the markers rs12434245 and rs10137185 were associated with a reduced risk of TGCT (OR = 0.66 and 0.72, respectively; both FDRs

The etiology of testicular germ cell cancer (TGCC) is still poorly understood, but biological and epidemiological evidence suggest that TGCC originates early in life. The aim of the present study was to analyze heterogeneity in TGCC risk within Norway, comparing county of birth to county of diagnosis, in order to assess the relative contribution of risk factors acting early and later in life. A further aim was to present the Norwegian TGCC incidence rates (1958-2007).All TGCC cases (n = 7130) reported to the Cancer Registry of Norway, 1958-2007, were analyzed by county of diagnosis in 10-year intervals. The relative risk of TGCC based on county of birth, was estimated by Poisson regression analysis of all new TGCC cases (n = 1943), based on the mother's county of residence at the time of the son's birth, 1967-2007, obtained by linkage between the Cancer Registry and the Medical Birth Registry of Norway.Between the first (1958-67) and last (1998-2007) 10-year period, the average incidence rate more than tripled from 3.3 to 10.5 per 100 000 person-years (world adjusted), respectively. The average incidence rate during 1968-2007 was highest in the county of Rogaland (8.6) and lowest in Hedmark (5.3), the ratio between them being 1.6. The relative risk of TGCC based on county of birth (1967-2007) varied between 1.43 (Møre og Romsdal) and 0.95 (Buskerud), giving a ratio of 1.5.The ratio between the relative risk in the highest and lowest county was basically similar when comparing counties of birth with counties of diagnosis. Thus, our data do not shed light on the relative contribution of risk factors acting early versus later in life. The incidence rate of TGCC in Norway is among the highest in the world, and the increase in incidence rate does not seem to level off.

Testicular cancer (TC) survival rates have increased substantially over the last decades, largely due to the introduction of cisplatin (CP) chemotherapy. This treatment is, however, associated with increased risk of developing metabolic syndrome (MetS), defined according to the National Cholesterol Education Program. We aimed to investigate if CP treatment were associated with epigenetic changes, and whether these changes render TC survivors susceptible for developing MetS later in life. We included 279 Norwegian TC survivors with and without CP treatment and MetS, matched on age at blood sampling (Table 1). The TC survivors were re-examined on average 16 years after the orchiectomy, and for some patients, CP treatment. Whole genome DNA methylation profiles were measured with MethylationEPIC BeadChip and analyzed with the R package minfi. We used a linear regression model adjusting for smoking, age and cell type composition to identify CP differentially methylated CpG sites and logistic regression adjusting for smoking and age to identify differentially methylated CpG sites associated with MetS. Gene enrichment analyses were based on Fisher's exact test using KEGG and Reactome pathways. 32 and 15 differentially methylated CpG sites were associated with CP treatment after adjusting for multiple testing with False Discovery Rate (FDR) and Bonferroni correction, respectively. The PTK6-RAS-MAPk pathway was significantly enriched with the FDR significant CpGs (p-value < 0.1). We could not identify FDR significant differentially methylated CpGs associated with MetS with our sample size. In conclusion, our results suggest that CP treatment has long-term effects on the epigenome. Genes involved in double-strand break repair, consistent with the cytotoxicity of CP treatment, are among the differentially methylated CpGs. Our top list of differentially methylated CpGs associated with MetS (lowest unadjusted p-values), should be further explored in a larger sample set of TC survivors. Table 1: Overview of sample characteristicsCP+ MetS+CP- MetS+CP+ MetS-CP- MetS-N613411569Mean age at surgery31312730Mean age at sample collection49484443Time between surgery and sample collection17181714 Citation Format: Trine B. Rounge, Cecilie Bucher-Johannessen, Christian M. Page, Trine B. Haugen, Sophie D. Fosså, Hege S. Haugnes, Tom Grotmol. Cisplatin treatment of testicular cancer introduces long-term changes to the epigenome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4325.

Both subtypes of estrogen receptor (ER), ERalpha and ERbeta, are normally present in the mammary gland. The role of ERalpha as a prognostic marker in breast cancer is well established due to the beneficial effect of providing tamoxifen as adjuvant therapy. The role of ERbeta, however, is less clear. To gain insight into the importance of ERbeta in breast cancer, 145 primary breast cancers were examined by immunohistochemistry for ERbeta, and the expression level was compared with ERalpha and progesterone receptor (PR) status. Especially, we wanted to examine the significance of ERbeta in the contrasting ERalpha+/PR+ and ERalpha-/PR- subgroups. In the ERalpha+/PR+ subgroup (dual positive), the survival difference between patients with low, medium and high ER beta level was statistically significant (p = 0.004), with more than 70% of patients with medium and high ERbeta levels surviving 100 months, compared with less than 30% in the group with low ERbeta level. Further, for ERalpha+/PR+ patients there was a reduced risk of fatal outcome by multivariate analysis with increasing ERbeta levels (p(trend) < 0.01 [univariate analysis]; p(trend) = 0.05 [multivariate analysis]). The risk was 31% and 27% for medium and high ERbeta levels, respectively, compared with low ERbeta level, adjusting for standard prognostic factors such as tumor diameter, nuclear tumor grade (quantified by mean nuclear area), lymph node status, and patient age at operation. For patients with ERalpha-/PR- tumors (dual negative), however, there was no association between ERbeta levels and patient outcome. Our findings indicate that ERbeta expression provides independent prognostic information for breast cancers with ERalpha/PR-positive status, a feature typical among screen-detected breast cancers. The role of ERbeta needs to be further evaluated especially in this group of breast cancers.

The distinct geographic variation in the global incidence of nasopharyngeal carcinoma reflects a complex etiology involving viral, environmental, and genetic components. The high to intermediate rates observed in endemic areas contrast markedly with the uniformly low rates seen in much of the world. An interesting epidemiologic observation is the early peak in age-incidence curves observed in certain geographically disparate populations, suggestive of distinct causal entities and the possible exhaustion of susceptible individuals from the population at a certain age. The aim of this study was to systematically evaluate the age-incidence profiles of NPC worldwide on partitioning populations according to level of risk, in an effort to provide clues about the importance of early-in-life factors and genetic susceptibility. Using data from 23 high-quality population-based cancer registries for the period 1983-1997, a key finding was the consistent pattern of bimodality that emerged across low-risk populations, irrespective of geographic location. Continual increases in NPC risk by age up to a first peak in late adolescence/early adulthood (ages 15-24 years) were observed, followed by a second peak later in life (ages 65-79 years). No such early peak in NPC incidence by age group was evident among the high-risk populations studied. These findings are discussed according to existing lines of biological and epidemiologic evidence related to level of population risk, age at diagnosis, and histologic subtype. A modified model for NPC tumor development is proposed on the basis of these observations. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2356–65)

Several polymorphisms of genes involved in one-carbon metabolism have been identified. The reported metabolic phenotypes are often based on small studies providing inconsistent results. This large-scale study of 10,601 population-based samples was carried out to investigate the association between a panel of biochemical parameters and genetics variants related to one-carbon metabolism. Concentrations of total homocysteine (tHcy), folate, vitamin B(12) (cobalamin), methylmalonic acid (MMA), vitamin B(2) (riboflavin), vitamin B(6) (PLP), choline, betaine, dimethylglycine (DMG), cystathionine, cysteine, methionine, and creatinine were determined in serum/plasma. All subjects were genotyped for 13 common polymorphisms: methylenetetrahydrofolate reductase (MTHFR) c.665CT (known as 677CT; p.Ala222Val) and c.1286AC (known as 1298AC; p.Glu429Ala); methionine synthase (MTR) c.2756AG (p.Asp919Gly); methionine synthase reductase (MTRR) c.66AG (p.Ile22Met); methylenetetrahydrofolate dehydrogenase (MTHFD1) c.1958GA (p.Arg653Gln); betaine homocysteine methyltransferase (BHMT) c.716GA (known as 742GA; p.Arg239Gln); cystathionine beta-synthase (CBS) c.844_845ins68 and c.699CT (p.Tyr233Tyr); transcobalamin-II (TCN2) c.67AG (p.Ile23Val) and c.776CG (p.Pro259Arg); reduced folate carrier-1 (SLC19A1) c.80GA (p.Arg27His); and paraoxonase-1 (PON1) c.163TA (p.Leu55Met) and c.575AG (p.Gln192Arg). The metabolic profile in terms of the measured vitamins and metabolites were investigated for these 13 polymorphisms. We confirmed the strong associations of MTHFR c.665CT with tHcy and folate, but also observed significant (P0.01) changes in metabolite concentrations according to other gene polymorphisms. These include MTHFR c.1286AC (associations with tHcy, folate and betaine), MTR c.2756AG (tHcy), BHMT c.716GA (DMG), CBS c.844_845ins68 (tHcy, betaine), CBS c.699CT (tHcy, betaine, cystathionine) and TCN2 c.776CG (MMA). No associations were observed for the other polymorphisms investigated.

BACKGROUND: The role of vitamin D in breast cancer etiology is unclear. There is some, but inconsistent, evidence that vitamin D is associated with both breast cancer risk and mammographic density (MD). We evaluated the associations of MD with month the mammogram was taken, and with vitamin D intake, in a population of women from Norway--a country with limited sunlight exposure for a large part of the year. METHODS: 3114 women aged 50-69, who participated in the Norwegian Breast Cancer Screening Program (NBCSP) in 2004 or 2006/07, completed risk factor and food frequency (FFQ) questionnaires. Dietary and total (dietary plus supplements) vitamin D, calcium and energy intakes were estimated by the FFQ. Month when the mammogram was taken was recorded on the mammogram. Percent MD was assessed using a computer assisted method (Madena, University of Southern California) after digitization of the films. Linear regression models were used to investigate percent MD associations with month the mammogram was taken, and vitamin D and calcium intakes, adjusting for age, body mass index (BMI), study year, estrogen and progestin therapy (EPT), education, parity, calcium intakes and energy intakes. RESULTS: There was no statistical significant association between the month the mammogram was taken and percent MD. Overall, there was no association between percent MD and quartiles of total or dietary vitamin D intakes, or of calcium intake. However, analysis restricted to women aged

Some cancer types level off or decrease in incidence at older age groups, not following the Weibull hazard rate. This stagnation can be explained by the frailty model, which describes the population effect of mixing individuals who are susceptible, with high risk of cancer, with those that are "non-susceptible", with a low risk of cancer even in the oldest age groups. The aim of the study was to apply a frailty model on colorectal cancer incidence data for the Norwegian population aged 40-99 years, diagnosed 1956-2000. The model provided an acceptable fit to the data. The estimated proportion of susceptibles increased from about 5% to about 24% from the first cohort (1851-1855) to the last cohort (1946-1950), in line with the rise in incidence of the disease during this period. According to the frailty modelling, the estimated number of genetic events necessary for a malignant lesion to develop in the colorectum is seven to eight, which accords with the present knowledge regarding colorectal carcinogenesis. The frailty phenomenon may thus be present in this cancer form. The findings indicate that it is possible to model the development of colorectal cancer in the population based on large heterogeneity in risk between individuals, in such a manner that a small group of individuals are susceptible to develop the disease, whereas the remaining majority have a low susceptibility.

The origin of testicular germ cell cancer (TGCC) is believed to be carcinoma in situ cells developed in utero. Clinically, TGCCs are divided into two major histological groups, seminomas and non-seminomas, where the latter group includes non-seminomatous TGCCs with seminomatous components (mixed S/NS TGCC). Recent studies, however, have suggested that non-seminomas and mixed S/NS TGCCs could have certain differences in aetiology, and in this study the TGCCs were divided into three, rather than the conventional two histological groups. A large case-control study was undertaken on data on all live-born boys registered in the Medical Birth Registry of Norway during the period 1967-1998 (n=961 396). Among these were 1087 TGCC cases registered in the Cancer Registry of Norway until February 2004. We found several risk factors for TGCC, including low parity, low gestational age, epilepsy and retained placenta. Several of the variables studied seemed to be risk factors for specific histological groups, e.g. parity 0 vs. 2 and low gestational age being associated with increased risk of non-seminomas, but not of mixed S/NS TGCC, and low maternal age being associated with increased risk of mixed S/NS TGCC, but not of non-seminomatous TGCC. Therefore, our results might suggest that non-seminomas and mixed S/NS TGCCs have partially different risk factors, whose associations may be obscured by combining these two histological groups. The histological groups were not significantly different, however. Most of our findings on risk factors for TGCC are in agreement with at least some previous studies. An unexplainable exception is low birth weight being associated with reduced risk of TGCC in our study.

Between 1955 and 1963, an estimated number of 150 million people in various parts of the world, including Norway, received poliomyelitis vaccine possibly contaminated with infectious simian virus 40 (SV40). Human studies have investigated the hypothesised association between SV40 and various cancers, but the results have so far been contradicting. The aim of the present study was to examine Norwegian cancer incidence data to assess a possible association between birth cohorts assumed to have been subjected to the vaccine and the incidence rate of lymphoproliferative disorders (excluding Hodgkin's lymphoma), further subdivided into non-Hodgkin's lymphoma (NHL), lymphocytic leukemia and plasma cell neoplasms. Between 1953 and 1997, the incidence rate of lymphoproliferative diseases combined increased about 3-fold in both males and females. Subgroup analysis showed that this increase was largely attributable to NHL. Age-period-cohort modelling of the subgroups, as well as of all groups combined, showed that the cohort effect was more prominent than the period effect. However, the variations in incidence patterns across the birth cohorts did not fit with the trends that would be expected if a SV40 contaminated vaccine did play a causative role. Thus, our data do not support the hypothesis of an association between the vaccine and any subgroup of lymphoproliferative diseases.

Seasonal, daylight-dependent variation in human spermatozoa counts, with lowest values during summer, has been suggested. To test this hypothesis, we performed a longitudinal study of semen quality and reproductive hormone levels in Norwegian men living north and south of the Arctic Circle. An ejaculate and a serum specimen were obtained both in summer and in winter from 92 volunteers in Tromsoe (69° north latitude) and 112 in Oslo (60° north latitude). Semen analyses were performed, and serum was assayed for FSH and inhibin B. The median spermatozoa concentration in Tromsoe after adjustment for abstinence period length was 49 10 6 /ml in summer and 54 10 6 /ml in winter. Corresponding values for Oslo were 59 10 6 /ml and 54 10 6 /ml. The seasonal differences in spermatozoa concentration were not statistically significant, nor were significant differences observed in median total spermatozoa count, semen volume, percentage progressive motile spermatozoa, or FSH. In Tromsoe, but not Oslo, inhibin B concentration was slightly, but significantly (P 0.02) higher in winter than summer (229 ng/liter vs. 223 ng/liter). The length of the daylight period may have a slight impact on hormonal markers of spermatogenesis but does not cause substantial changes in spermatozoa numbers and motility. (J Clin Endocrinol Metab 89: 4397– 4402, 2004)