Associations between pregnancy-related factors and birth characteristics with risk of rare uterine cancer subtypes: a Nordic population-based case-control study.

PURPOSE: Uterine sarcomas are a rare group of uterine malignancies. Due to the low incidence and changes in uterine sarcoma classification, risk factors are not well characterized. Our objective was to evaluate risk factors for uterine sarcoma and compare risk factors between uterine sarcoma, malignant mixed Mullerian tumors (MMMTs), and type I endometrial carcinomas. METHODS: This nested case-control study utilized linked data from population-based medical birth and cancer registries in Denmark, Finland, Norway, and Sweden. Up to 10 controls were matched on country and birth year for each uterine cancer case. Using multivariable adjusted multinomial logistic regression, estimates of the associations between pregnancy-related factors and risk of uterine sarcoma, MMMTs, and type I endometrial carcinomas were determined. RESULTS: Having a very-low-birth-weight infant (< 1500 vs. 2500-3999 g: OR [95% CI] 2.83 [1.61-4.96]) was associated with an increased risk of uterine sarcoma. Whereas, having a more recent pregnancy was associated with reduced risks of MMMT (< 10 vs. ≥ 30 years: 0.66 [0.20-2.23]) and type 1 endometrial carcinomas (0.35 [0.30-0.41]) but not uterine sarcomas (1.33 [0.90-1.98], p-heterogeneity < 0.01). CONCLUSION: Our study provides evidence that risk factors for uterine sarcoma and MMMT, previously grouped with uterine sarcomas, vary substantially. Additionally, MMMT and type I endometrial carcinomas are more similar than uterine sarcoma in that pregnancy complications like gestational hypertension and preeclampsia were associated with reduced risks of both but not uterine sarcoma, suggesting different etiologies.

Cancer risk in the siblings of individuals with major birth defects: a large Nordic population-based case-control study.

BACKGROUND: Individuals with major birth defects are at increased risk of developing cancer, indicating a common aetiology. However, whether the siblings of individuals with birth defects are also at an increased risk of cancer is unclear. METHODS: We used nationwide health registries in four Nordic countries and conducted a nested case-control study. We included 40 538 cancer cases (aged 0-46 years) and 481 945 population controls (matched by birth year and country), born between 1967 and 2014. The relative risk of cancer among individuals whose siblings had birth defects was computed with odds ratios (OR) and 95% confidence intervals (CIs), using logistic regression models. RESULTS: In the total study population (aged 0-46 years), we observed no overall difference in cancer risk between individuals whose siblings had birth defects and those who had unaffected siblings (OR 1.02; 95% CI 0.97-1.08); however, the risk of lymphoid and haematopoietic malignancies was elevated (1.16; 1.05-1.28). The overall risk of childhood cancer (0-19 years) was increased for siblings of individuals who had birth defects (1.09; 1.00-1.19), which was mainly driven by lymphoma (1.35; 1.09-1.66), neuroblastoma (1.51; 1.11-2.05) and renal carcinoma (5.03; 1.73-14.6). The risk of cancer also increased with the number of siblings with birth defects (Ptrend = 0.008). CONCLUSION: Overall risk of cancer among individuals (aged 0-46 years) whose siblings had birth defects was not elevated, but the risk of childhood cancer (ages 0-19 years) was increased. Our novel findings are consistent with the common aetiologies of birth defects and cancer, such as shared genetic predisposition and environmental factors.

A lean additive frailty model: With an application to clustering of melanoma in Norwegian families.

Additive frailty models are used to model correlated survival data. However, the complexity of the models increases with cluster size to the extent that practical usage becomes increasingly challenging. We present a modification of the additive genetic gamma frailty (AGGF) model, the lean AGGF (L-AGGF) model, which alleviates some of these challenges by using a leaner additive decomposition of the frailty. The performances of the models were compared and evaluated in a simulation study. The L-AGGF model was used to analyze population-wide data on clustering of melanoma in 2 391 125 two-generational Norwegian families, 1960-2015. Using this model, we could analyze the complete data set, while the original model limited the analysis to a restricted data set (with cluster sizes ≤ 7 $$ \le 7 $$ ). We found a substantial clustering of melanoma in Norwegian families and large heterogeneity in melanoma risk across the population, where 52% of the frailty was attributed to the 10% of the population at highest unobserved risk. Due to the improved scalability, the L-AGGF model enables a wider range of analyses of population-wide data compared to the AGGF model. Moreover, the methods outlined here make it possible to perform these analyses in a computationally efficient manner.

Sex differences in childhood cancer risk among children with major birth defects: a Nordic population-based nested case-control study.

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 <0.001). Male sex was an independent risk factor for childhood cancer, but very little of the overall association between sex and childhood cancer was mediated through birth defects (4.8%, PNIE <0.001), although more at younger ages (10% below years and 28% below 1 year). 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.

Maternal Health, Pregnancy and Offspring Factors, and Maternal Thyroid Cancer Risk: A Nordic Population-Based Registry Study.

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.

Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk.

BACKGROUND: Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. SNPs in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation. METHODS: In this pathway-focused investigation, we evaluated the association between 273 selected tag SNPs from 28 DNA methylation-related genes and TGCT risk. We carried out association analysis at individual SNP and gene-based level using summary statistics from the Genome Wide Association Study meta-analysis recently conducted by the international Testicular Cancer Consortium on 10,156 TGCT cases and 179,683 controls. RESULTS: In individual SNP analyses, seven SNPs, four mapping within MTHFR, were associated with TGCT risk after correction for multiple testing (q ≤ 0.05). Queries of public databases showed that three of these SNPs were associated with MTHFR changes in enzymatic activity (rs1801133) or expression level in testis tissue (rs12121543, rs1476413). Gene-based analyses revealed MTHFR (q = 8.4 × 10-4), methyl-CpG-binding protein 2 (MECP2; q = 2 × 10-3), and ZBTB4 (q = 0.03) as the top TGCT-associated genes. Stratifying by tumor histology, four MTHFR SNPs were associated with seminoma. In gene-based analysis MTHFR was associated with risk of seminoma (q = 2.8 × 10-4), but not with nonseminomatous tumors (q = 0.22). CONCLUSIONS: Genetic variants within MTHFR, potentially having an impact on the DNA methylation pattern, are associated with TGCT risk. IMPACT: This finding suggests that TGCT pathogenesis could be associated with the folate cycle status, and this relation could be partly due to hereditary factors.

Identification of 22 susceptibility loci associated with testicular germ cell tumors.

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.

Ultralow amounts of DNA from long-term archived serum samples produce high-quality methylomes.

BACKGROUND: Long-term stored serum is considered challenging for epigenomic analyses: as there are no cells, circulating DNA is scarce, and amplification removes epigenetic signals. Additionally, pre-analytical treatments and storage might introduce biases and fragmentation to the DNA. In particular, starting with low-input DNA can result in low-diversity libraries. However, successful whole-genome bisulphite sequencing (WGBS) of such serum samples has the potential to open biobanks for epigenetic analyses and deliver novel prediagnostic biomarkers. Here, we perform WGBS using the Accel-NGS library preparation kit on ultralow amounts of DNA from long-term archived samples with diverse pretreatments from the Janus Serum Bank. RESULTS: Ninety-four of the 96 samples produced satisfactory methylation calls; an average of 578 M reads per sample generated a mean coverage of 17× and mean duplication level of 35%. Failed samples were related to poor bisulphite conversion rather than to sequencing or library preparation. We demonstrate the feasibility of WGBS on ultralow DNA yields from serum samples stored up to 48 years. CONCLUSIONS: Our results show the potential of large serum biobank collections for future epigenomic studies and biomarker discovery.

Genetically Inferred Telomere Length and Testicular Germ Cell Tumor Risk.

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.

Maternal health, in-utero, and perinatal exposures and risk of thyroid cancer in offspring: a Nordic population-based nested case-control study.

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).

Cancer risk in individuals with major birth defects: large Nordic population based case-control study among children, adolescents, and adults.

OBJECTIVE: To examine associations between birth defects and cancer from birth into adulthood. DESIGN: Population based nested case-control study. SETTING: Nationwide health registries in Denmark, Finland, Norway, and Sweden. PARTICIPANTS: 62 295 cancer cases (0-46 years) and 724 542 frequency matched controls (matched on country and birth year), born between 1967 and 2014. MAIN OUTCOME MEASURES: Relative risk of cancer in relation to major birth defects, estimated as odds ratios with 99% confidence intervals from logistic regression models. RESULTS: Altogether, 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. CONCLUSIONS: The 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.

Serum RNA Profiling in the 10-Years Period Prior to Diagnosis of Testicular Germ Cell Tumor.

Although testicular germ cell tumor (TGCT) overall is highly curable, patients may experience late effects after treatment. An increased understanding of the mechanisms behind the development of TGCT may pave the way for better outcome for patients. To elucidate molecular changes prior to TGCT diagnosis we sequenced small RNAs in serum from 69 patients who were later diagnosed with TGCT and 111 matched controls. The deep RNA profiles, with on average 18 million sequences per sample, comprised of nine classes of RNA, including microRNA. We found that circulating RNA signals differed significantly between cases and controls regardless of time to diagnosis. Different levels of TSIX related to X-chromosome inactivation and TEX101 involved in spermatozoa production are among the interesting findings. The RNA signals differed between seminoma and non-seminoma TGCT subtypes, with seminoma cases showing lower levels of RNAs and non-seminoma cases showing higher levels of RNAs, compared with controls. The differentially expressed RNAs were typically associated with cancer related pathways. Our results indicate that circulating RNA profiles change during TGCT development according to histology and may be useful for early detection of this tumor type.

Pregnancy-related risk factors for sex cord-stromal tumours and germ cell tumours in parous women: a registry-based study.

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 <25 years: OR 0.48 (95% CI 0.23-0.98)]. The risk of SCSTs (but not GCTs) also decreased with shorter time since last birth. Number of births, preterm birth, preeclampsia, and offspring size were not associated with risk of SCSTs or GCTs. 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.

Birthweight and all-cause mortality after childhood and adolescent leukemia: a cohort of children with leukemia from Denmark, Norway, Sweden, and Washington State.

Background: High birthweight may predispose children to acute lymphoid leukemia, whereas low birthweight is associated with childhood morbidity and mortality. Low and high birthweight have been inconsistently associated with mortality in children with leukemia.Material and methods: In a cohort of childhood and adolescent leukemia (0-19 years) patients from registries in Denmark, Norway, Sweden, and Washington State in the United States (1967-2015), five-year all-cause mortality was assessed by birthweight and other measures of fetal growth using the cumulative incidence function and Cox regression with adjustment for sex, diagnosis year, country, the presence of Down's syndrome or other malformations, and type of leukemia.Results: Among 7148 children and adolescents with leukemia (55% male), 4.6% were low (<2500 g) and 19% were high (≥4000 g) birthweight. Compared with average weight, hazard ratios (HRs) of death associated with low birthweight varied by age at leukemia diagnosis: 1.5 (95% confidence interval (CI): 0.7, 3.2) for patients 0-1 year old, 1.6 (95% CI: 1.0, 2.6) for >1-2 years old; 1.0 (95% CI: 0.6, 1.5) for 3-8 years old; 1.0 (95% CI: 0.6, 1.8) for 9-13 years old; and 1.2 (95% CI: 0.7, 2.1) for 14-19 years old, and were similar for size for gestational age and Ponderal index. In analyses restricted to children born full term (37-41 weeks of gestation), results were only slightly attenuated but risk was markedly increased for infants aged ≤1 year (HR for low birthweight = 3.2, 95% CI: 1.2, 8.8).Conclusion: This cohort study does not suggest that low birthweight or SGA is associated with increased five-year all-cause mortality risk among children with any type of childhood leukemia or acute lymphoblastic leukemia, specifically, beyond infancy.

Associations of pregnancy-related factors and birth characteristics with risk of endometrial cancer: A Nordic population-based case-control 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 (<10 vs. ≥30 years: 0.34 [0.29-0.40]) were associated with reduced endometrial cancer risk, with consistent associations across most subtypes. Our findings support the role for both hormonal exposures and cell clearance as well as immunologic/inflammatory etiologies for endometrial cancer. This research supports studying endometrial hyperplasia, a precursor condition of endometrial cancer, in the context of pregnancy-related exposures, as this may provide insight into the mechanisms by which pregnancy affects subsequent cancer risk.

Cisplatin treatment of testicular cancer patients introduces long-term changes in the epigenome.

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.

Comparison of body condition score and other minimally invasive biomarkers between dogs with gastric carcinoma and dogs with chronic gastritis.

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.

Preterm delivery is associated with an increased risk of epithelial ovarian cancer among parous women.

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. <25 years: adjusted OR 0.76 (95% CI 0.70-0.83); last birth 30-39 vs. <25 years: adjusted OR 0.76 (95% CI 0.71-0.82)]. Increasing number of births was protective [≥4 births vs. 1; OR 0.63 (95% CI 0.59-0.68)] for all subtypes, most pronounced for clear-cell tumors [OR 0.30, (95% CI 0.21-0.44), pheterogeneity < 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.

Pregnancy complications and subsequent breast cancer risk in the mother: a Nordic population-based case-control study.

Certain features of pregnancy are important risk factors for breast cancer, such as protection afforded by young age at first birth. Preeclampsia, a pregnancy complication, is associated with reduced maternal breast cancer risk. However, questions remain regarding causality, biological mechanisms and the relation of other hypertensive conditions to risk. We conducted a population-based case-control study of breast cancer cases (n = 116,196) in parous women identified through linkage of birth and cancer registries in Denmark, Finland, Norway and Sweden (1967-2013), including up to 10 matched controls per case (n = 1,147,192) sampled from the birth registries (complete data were not available on all variables). Odds ratios (ORs) with 95% confidence intervals (CIs) were derived from unconditional logistic regression models including matching factors (country, maternal birth year) and parity. Hypertension diagnosed before pregnancy (OR 0.87; 95% CI 0.78-0.97), gestational hypertension (OR 0.90; 95% CI 0.86-0.93) and preeclampsia (OR 0.91; 95% CI 0.88-0.95) were associated with reduced breast cancer risk. Results remained similar after adjustment for smoking and maternal body mass index before first pregnancy, and were generally similar stratified by parity, age at breast cancer diagnosis, time since first and last birth, sex of the offspring and calendar time. Except for retained placenta (OR 1.14; 95% CI 0.98-1.32), no other pregnancy complication appeared associated with breast cancer risk. The mechanisms mediating the modest risk reductions for history of preeclampsia or hypertension preceding or arising during pregnancy, and possible increased risk with history of retained placenta are unknown and warrant further laboratory, clinical and epidemiological investigation.