The role of pregnancy, perinatal factors and hormones in maternal cancer risk: a review of the evidence.

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 foetal 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, whilst 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 aetiology 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, is expected to affect the incidence of pregnancy-associated cancer.

HPV genotype profile in a Norwegian cohort with ASC-US and LSIL cytology with three year cumulative risk of high grade cervical neoplasia.

OBJECTIVE: To explore the HPVgenotype profile in Norwegian women with ASC-US/LSIL cytology and the subsequent risk of high-grade cervical neoplasia (CIN 3+). METHODS: In this observational study delayed triage of ASC-US/LSIL of 6058 women were included from 2005 to 2010. High-risk HPV detection with Hybrid Capture 2 (HC2) was used and the HC2+ cases were genotyped with in-house nmPCR. Women were followed-up for histologically confirmed CIN3+ within three years of index HPV test by linkage to the screening databases at the Cancer Registry of Norway. RESULTS: HC2 was positive in 45% (2756/6058) of the women. Within 3years CIN3+ was diagnosed in 26% of women<34year and in 15%≥34year. HC2 was positive at index in 94% of CIN3+ cases and negative in 64 cases including three women with cervical carcinomas. Women<34years with single infections of HPV 16, 35, 58 or 33 or multiple infections including HPV 16, 52, 33 or 31 were associated with highest proportions of CIN 3+. Older women with single infection with HPV 16, 33, 31 or 35 or multiple infections including HPV 16, 33, 31 or 18/39 were more likely to develop CIN 3+. CONCLUSIONS: HPV 16 and HPV 33 at baseline both as single or multiple infections, were associated with the highest risk for CIN3+. Among older women, all 13 high-risk genotypes as single infection were associated with >20% risk of CIN3+. Further studies are necessary to risk stratify the individual genotypes to reduce the number of colposcopies in Norway.

Reproduction and marriage among male survivors of cancer in childhood, adolescence and young adulthood: a national cohort study.

BACKGROUND: Increased survival after cancer in young age has made long-term follow-up studies of high external validity important. In this national cohort study, we explored the impact of cancer in young age on reproduction and marital status in male survivors. METHODS: Hazard ratios (HRs) and relative risks (RRs) of reproductive and marital outcomes were studied for male survivors of cancer in young age (<25 years) and cancer-free male comparisons, born during 1965-1985, by linking compulsory national registries in Norway. RESULTS: Male cancer survivors (n=2687) had reduced paternity (HR: 0.72, 95% confidence interval (CI): 0.68-0.76). This was most apparent in survivors of testicular cancer, brain tumours, lymphoma, leukemia and bone tumours, and when diagnosed with cancer before 15 years of age. Male cancer survivors were more likely to avail of assisted reproduction (RR: 3.32, 95% CI: 2.68-4.11). There was no increased risk of perinatal death, congenital malformations, being small for gestational age, of low birth weight or preterm birth in their first offspring. Male cancer survivors were less likely to marry (HR: 0.93, 95% CI: 0.86-1.00), in particular brain tumour survivors. CONCLUSIONS: In this national cohort study, we demonstrated reduced paternity and increased use of assisted reproduction among male cancer survivors, but no adverse outcome for their first offspring at birth.

Plasma methionine, choline, betaine, and dimethylglycine in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).

BACKGROUND: Disturbances in one carbon metabolism may contribute to carcinogenesis by affecting methylation and synthesis of DNA. Choline and its oxidation product betaine are involved in this metabolism and can serve as alternative methyl group donors when folate status is low. PATIENTS AND METHODS: We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), to investigate plasma concentrations of the methyl donors methionine, choline, betaine (trimethylglycine), and dimethylglycine (DMG) in relation to colorectal cancer (CRC) risk. Our study included 1367 incident CRC cases (965 colon and 402 rectum) and 2323 controls matched by gender, age group, and study center. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for CRC risk were estimated by conditional logistic regression, comparing the fifth to the first quintile of plasma concentrations. RESULTS: Overall, methionine (OR: 0.79, 95% CI: 0.63-0.99, P-trend = 0.05), choline (OR: 0.77, 95% CI: 0.60-0.99, P-trend = 0.07), and betaine (OR: 0.85, 95% CI: 0.66-1.09, P-trend = 0.06) concentrations were inversely associated with CRC risk of borderline significance. In participants with folate concentration below the median of 11.3 nmol/l, high betaine concentration was associated with reduced CRC risk (OR: 0.71, 95% CI: 0.50-1.00, P-trend = 0.02), which was not observed for those having a higher folate status. Among women, but not men, high choline concentration was associated with decreased CRC risk (OR: 0.62, 95% CI: 0.43-0.88, P-trend = 0.01). Plasma DMG was not associated with CRC risk. CONCLUSIONS: Individuals with high plasma concentrations of methionine, choline, and betaine may be at reduced risk of CRC.

Increased uptake of social security benefits among long-term survivors of cancer in childhood, adolescence and young adulthood: a Norwegian population-based cohort study.

BACKGROUND: As the number of cancer survivors increases, their health and welfare have come into focus. Thus, long-term medical consequences of cancer at a young age (<25 years), obtained from social security benefit records, were studied. METHODS: Standardised incidence ratios (SIRs) of long-term medical consequences for 5-year cancer survivors, born during 1965-1985, were explored by linking population-based registries in Norway. RESULTS: Among the 5-year cancer survivors (4031 individuals), 29.7% received social security benefits. The survivors had an overall 4.4 times (95% confidence interval (95% CI): 4.1-4.6) higher risk of social security benefit uptake than the cancer-free population. Survivors of malignancies of bone and connective tissues (SIR: 10.8; 95% CI: 9.1-12.9), CNS tumours (SIR: 7.7; 95% CI: 6.9-8.6) and malignancies of the haematopoietic system (SIR: 6.1; 95% CI: 5.3-7.0) had the highest risks of social security benefits uptake. The most notified causes of social security benefit uptake were diseases of the nervous system, and injury and poisoning. CONCLUSION: The uptake of social security benefits among 5-year cancer survivors increased substantially and it may represent a solid outcome measure for the burden of the most severe late effects, especially in countries with comparable social welfare systems.

Metabolic risk factors and skin cancer in the Metabolic Syndrome and Cancer Project (Me-Can).

BACKGROUND: Little is known about the associations of metabolic aberrations with malignant melanoma (MM) and nonmelanoma skin cancer (NMSC). OBJECTIVES: To assess the associations between metabolic factors (both individually and combined) and the risk of skin cancer in the large prospective Metabolic Syndrome and Cancer Project (Me-Can). METHODS: During a mean follow-up of 12 years of the Me-Can cohort, 1728 (41% women) incident MM, 230 (23% women) fatal MM and 1145 (33% women) NMSC were identified. Most NMSC cases (76%) were squamous cell carcinoma (SCC) (873, 33% women). Hazard ratios (HRs) were estimated by Cox proportional hazards regression for quintiles and standardized z-scores (with a mean of 0 and SD of 1) of body mass index (BMI), blood pressure, glucose, cholesterol, triglycerides and for a combined metabolic syndrome score. Risk estimates were corrected for random error in the measurements. RESULTS: Blood pressure per unit increase of z-score was associated with an increased risk of incident MM cases in men and women [HR 1·17, 95% confidence interval (CI) 1·04-1·31 and HR 1·18, 95% CI 1·03-1·36, respectively] and fatal MM cases among women (HR 2·39, 95% CI 1·58-3·64). In men, all quintiles for BMI above the reference were associated with a higher risk of incident MM. In women, SCC NMSC risk increased across quintiles for glucose levels (P-trend 0·02) and there was a trend with triglyceride concentration (P-trend 0·09). CONCLUSION: These findings suggest that mechanisms linked to blood pressure may be involved in the pathogenesis of MM. SCC NMSC in women could be related to glucose and lipid metabolism.

Maternal birth characteristics and perinatal mortality in twin offspring. An intergenerational population-based study in Norway, 1967-2008.

OBJECTIVE: To investigate the relationship between maternal preterm birth and fetal growth in one generation and perinatal mortality of twin offspring in the next generation. DESIGN: Population-based cohort study. SETTING: The Medical Birth Registry of Norway from 1967 to 2008. POPULATION: Linked generational data with 9426 mother-twin pair units. METHODS: Twin offspring were linked to their mothers by means of the unique national identification numbers. MAIN OUTCOME MEASURES: Perinatal mortality in twin offspring. RESULTS: The twin prevalence was not dependent on the mother's gestational age at birth, but increased with increasing birthweight in term mothers. Maternal gestational age was strongly and inversely associated with a risk of perinatal death in one or both of her twin offspring. Compared with term mothers, preterm mothers born at 27-31 and 32-34 weeks had relative risks (RRs) for perinatal loss of 3.83 [95% confidence interval (CI), 1.56-9.36] and 2.41 (95% CI, 1.29-4.50), respectively. This effect was even stronger after the use of assisted reproductive technologies (ART), with a significant interaction between maternal gestational age and ART (P = 0.03). Further, term mothers with birthweight-by-gestational age Z-scores of -2 or less had more than twice the risk of a perinatal loss in their twin offspring relative to mothers with the most favourable birthweight Z-scores (1-1.99) [RR, 2.42 (95% CI, 1.37-4.29)]. CONCLUSIONS: Women born preterm had an increased risk of perinatal mortality in their twin offspring, particularly after ART treatment. The same was true for women who were growth restricted at term. A twin pregnancy is a high-risk pregnancy in general, but even more so if the mother herself was born preterm or was growth restricted at birth.

High BMI is significantly associated with positive progesterone receptor status and clinico-pathological markers for non-aggressive disease in endometrial cancer.

BACKGROUND: Endometrial cancer incidence is increasing in industrialised countries. High body mass index (BMI, kg m(-2)) is associated with higher risk for disease. We wanted to investigate if BMI is related to clinico-pathological characteristics, hormone receptor status in primary tumour, and disease outcome in endometrial cancer. PATIENTS AND METHODS: In total, 1129 women primarily treated for endometrial carcinoma at Haukeland University Hospital during 1981-2009 were studied. Body mass index was available for 949 patients and related to comprehensive clinical and histopathological data, hormone receptor status in tumour, treatment, and follow-up. RESULTS: High BMI was significantly associated with low International Federation of Gynaecology and Obstetrics (FIGO) stage, endometrioid histology, low/intermediate grade, and high level of progesterone receptor (PR) mRNA by qPCR (n=150; P=0.02) and protein expression by immunohistochemistry (n=433; P=0.003). In contrast, oestrogen receptor (ERα) status was not associated with BMI. Overweight/obese women had significantly better disease-specific survival (DSS) than normal/underweight women in univariate analysis (P=0.035). In multivariate analysis of DSS adjusting for age, FIGO stage, histological subtype, and grade, BMI showed no independent prognostic impact. CONCLUSION: High BMI was significantly associated with markers of non-aggressive disease and positive PR status in a large population-based study of endometrial carcinoma. Women with high BMI had significantly better prognosis in univariate analysis of DSS, an effect that disappeared in multivariate analysis adjusting for established prognostic markers. The role of PR in endometrial carcinogenesis needs to be further studied.

Metabolic syndrome and rare gynecological cancers in the metabolic syndrome and cancer project (Me-Can).

BACKGROUND: Risk factors for rare gynecological cancers are largely unknown. Initial research has indicated that the metabolic syndrome (MetS) or individual components could play a role. MATERIALS AND METHODS: The Metabolic syndrome and Cancer project cohort includes 288,834 women. During an average follow-up of 11 years, 82 vulvar, 26 vaginal and 43 other rare gynecological cancers were identified. Hazard ratios (HRs) were estimated fitting Cox proportional hazards regression models for tertiles and standardized z-scores [with a mean of 0 and a standard deviation (SD) of 1] of body mass index (BMI), blood pressure, glucose, cholesterol, triglycerides and MetS. Risk estimates were corrected for random error in the measurement of metabolic factors. RESULTS: The MetS was associated with increased risk of vulvar [HR 1.78, 95% confidence interval (CI) 1.30-2.41) and vaginal cancer (HR 1.87, 95% CI 1.07-3.25). Among separate MetS components, 1 SD increase in BMI was associated with overall risk (HR 1.43, 95% CI 1.23-1.66), vulvar (HR 1.36, 95% CI 1.11-1.69) and vaginal cancer (HR 1.79, 95% CI 1.30-2.46). Blood glucose and triglyceride concentrations were associated with increased risk of vulvar cancer (HR 1.98, 95% CI 1.10-3.58 and HR 2.09, 95% CI 1.39-3.15, respectively). CONCLUSION: The results from this first prospective study on rare gynecological cancers suggest that the MetS and its individual components may play a role in the development of these tumors.

Trends in incidence and mortality for triplets in Norway 1967-2006: the influence of assisted reproductive technologies.

OBJECTIVE: To assess changes in incidence rates and outcomes of triplets over 40 years with a particular focus on the influence of assisted reproductive technology (ART). DESIGN: Population-based cohort study. SETTING: The Medical Birth Registry of Norway. POPULATION: 2.18 million pregnancies, including 448 sets of triplets and 27,575 twin pairs, covering the years 1967-2006. Since 1988, pregnancies from ART have been available through a separate registry and linked with the birth record. METHODS: Incidence rates and outcomes for triplets were analysed and compared with those for singletons and twins. Relative risks were estimated between time periods and between ART and non-ART pregnancies. MAIN OUTCOME MEASURES: Incidence rates, birthweight, gestational age and perinatal mortality. RESULTS: The total triplet rate per 10,000 pregnancies increased from 1.0 during 1967-71 to 3.5 during 1987-92, followed by a decline to 2.7 during 2002-06. After excluding ART pregnancies, the incidence was more than doubled at the end of the study period. The mean gestational age and birthweight of triplets were significantly lower during 1988-2006 than 1967-87, but similar for ART and non-ART triplets in the last period. The caesarean rate in triplets increased from 47 to 92%. The relative risk of perinatal death in triplets relative to singletons did not change after the introduction of ART [before: relative risk, 8.9 (95% confidence interval, 6.8-11.7); after: relative risk, 10.4 (95% confidence interval, 8.3-13.0)]. CONCLUSIONS: The triplet incidence rate in Norway has more than doubled during the last 40 years, even after excluding ART pregnancies. The risk of perinatal death in triplets is ten times higher relative to singletons and has not changed during this 40-year period, independent of the introduction of ART.

Birth and parental characteristics and risk of neuroblastoma in a population-based Norwegian cohort study.

In this population-based Norwegian cohort study (2.1 million children), the impact of birth and parental characteristics on the risk of neuroblastoma (178 cases) was evaluated. In children below the age of 18 months, there was an increased neuroblastoma risk among those with congenital malformations and suggestion of increased risk when the mother had pre-eclampsia.

Body size and thyroid cancer in two million Norwegian men and women.

We investigated relations between measured body mass index (BMI) and stature and thyroid cancer (3046 cases) in a large Norwegian cohort of more than two million individuals. The risk of thyroid cancer, especially of the papillary and follicular types, increased moderately with increasing BMI and height in both sexes.

Height and body mass index in relation to cancer of the small intestine in two million Norwegian men and women.

The present study aimed at exploring the relations between body mass index (BMI, (weight in kilograms)/(height in meters)(2)) and stature and cancer of the small intestine (1162 cases) in a large Norwegian cohort (of two million) with measured height and weight. Elevated BMI in males and increasing height in both sexes were associated with a moderately increased risk of cancer of the small intestine.

BRCA1 mutations in ovarian cancer and borderline tumours in Norway: a nested case-control study.

The aims of the present study were to find the frequency of the most common BRCA1 mutations in women with ovarian tumours identified from a population-based cancer registry and in the general population, to estimate the relative risk of ovarian tumours among the mutation carriers, and to explore the value of using CA125 as a prediagnostic test. The study was designed as a nested case-control study within a cohort mainly consisting of participants in population-based health examinations. The data files of The Cancer Registry of Norway and the Janus serum bank were linked to identify cases with ovarian cancer and borderline tumours. Hereditary BRCA1 mutations were determined using archived serum samples and capillary electrophoresis. Altogether 478 ovarian cancer patients and 190 patients with borderline tumours were identified, and 1421 and 568 matching controls were selected. Odds ratios (OR) of developing ovarian cancer and borderline tumours in the presence of BRCA1 mutations and CA125 level were derived from conditional logistic regression models. Among the 478 ovarian cancer patients, 19 BRCA1 mutations were identified (1675delA, 1135insA, 816delGT and 3347delAG), none among the patients with borderline tumours. Only two of the 1989 controls were BRCA1 mutation carriers (0.10%). The risk of ovarian cancer among the mutation carriers was strongly elevated (OR=29, 95% CI=6.6-120). CA125 was a marker for ovarian cancer, but the sensitivity was low. This study showed that BRCA1 mutation carriers have a very high risk of ovarian cancer. However, since the prevalence of BRCA1 mutations in the Norwegian population was low, the proportion of ovarian cancers due to BRCA1 mutations seemed to be low, about 4%. The sensitivity of using CA125 only as a screening test for ovarian cancer was low.

Joint effects of different human papillomaviruses and Chlamydia trachomatis infections on risk of squamous cell carcinoma of the cervix uteri.

This case-control study based in Nordic serum banks evaluated the joint effects of infections with genital human papillomavirus (HPV) types, and Chlamydia trachomatis in the aetiology of cervical squamous cell carcinoma. Through a linkage with the cancer registries, 144 cases were identified and 420 controls matched to them. Exposure to past infections was defined by the presence of specific IgG antibodies. The odds ratio (OR) for the second-order interaction of HPV16, HPV6/11 and C. trachomatis was small (1.0) compared to the expected multiplicative OR, 57, and the additive OR, 11. The interactions were not materially different among HPV16 DNA-positive squamous cell carcinomas. When HPV16 was replaced with HPV18/33 in the analysis of second-order interactions with HPV6/11 and C. trachomatis, there was no evidence of interaction, the joint effect being close to the expected additive OR. Possible explanations for the observed antagonism include misclassification, selection bias or a true biological phenomenon with HPV6/11 and C. trachomatis exposures antagonizing the carcinogenic effects of HPV16.

Height, body mass index, and prostate cancer: a follow-up of 950000 Norwegian men.

The present study explored body mass index (BMI), height, and risk of prostate cancer in a large Norwegian cohort of 950000 men aged 20-74 years, whose height and weight were measured in a standardised way in the period 1963-1999. These were followed for an average of 21 years. The Cox proportional hazard models were used in the analyses. During follow-up, 33 300 histologically verified cases of prostate cancer were registered. The risk of prostate cancer increased by both BMI and height. The magnitude of the increase by BMI was modest, the relative risk (RR) of obese men (BMI>or=30) compared with normal weighted was 1.09 (95% CI: 1.04-1.15). However, the RR at age 50-59 years was 1.58 (95% CI: 1.29-1.94) in men being obese at about age 45 years compared with normal weighted men. The tallest men had an RR of 1.72 (95% CI: 1.46-2.04) compared with the shortest men. The overall effect of BMI on the incidence of prostate cancer was modest. The larger effect found in men aged 50-59 years might partly explain the previous inconsistent findings.

Gestational trophoblastic tumors in Norway, 1968-1997: patient characteristics, treatment, and prognosis.

OBJECTIVES: The aim of this study was to give an overview of the Norwegian population of gestational trophoblastic tumors (GTT), diagnosed during 1968-1997 and treated with chemotherapy at the Norwegian Radium Hospital (NRH), with regard to patient characteristics, treatment, and prognosis. METHODS: The cases were grouped according to a modified version of the WHO scoring system. Staging was performed retrospectively according to the systems adopted by FIGO. Survival estimates were calculated by the method described by Kaplan and Meier. Cox regression models were used to find the best classification system with regard to prognosis (disease-free survival). RESULTS: A total of 141 cases, 106 invasive moles (IM) and 35 choriocarcinomas (CC), were diagnosed in Norway and treated with chemotherapy at the NRH in the period 1968-1997. Altogether, 56% of the patients were assigned to the low-risk category, 20% to the medium-risk category, and 15% to the high-risk category. Most cases were classified into the clinical stages I (69%) and III (23%). The overall 5-year survival rate was 96%. A more favorable prognosis was seen in patients diagnosed in the 1980s and 1990s compared with those diagnosed in the 1970s (P = 0.04). Five patients had progressive disease and died from the disease. Nine patients relapsed. The prognosis (disease-free survival) was more favorable for IM compared with CC (P < 0.01). The FIGO classification system seemed to be a better predictor of disease-free survival than the WHO scoring system. CONCLUSIONS: This study showed that the prognosis of patients with GTT improved in the 1980s and 1990s in Norway, and that the FIGO system might be the best predictor of disease-free survival.

Human papillomavirus infection as a risk factor for anal and perianal skin cancer in a prospective study.

Human papillomavirus has emerged as the leading infectious cause of cervical and other anogenital cancers. We have studied the relation between human papillomavirus infection and the subsequent risk of anal and perianal skin cancer. A case-cohort study within two large Nordic serum banks to which about 760 000 individuals had donated serum samples was performed. Subjects who developed anal and perianal skin cancer during follow up (median time of 10 years) were identified by registry linkage with the nationwide cancer registries in Finland and Norway. Twenty-eight cases and 1500 controls were analysed for the presence of IgG antibodies to HPV 16, 18, 33 or 73, and odds ratios of developing anal and perianal skin cancer were calculated. There was an increased risk of developing anal and perianal skin cancer among subjects seropositive for HPV 16 (OR=3.0; 95%CI=1.1-8.2) and HPV 18 (OR=4.4; 95%CI=1.1-17). The highest risks were seen for HPV 16 seropositive patients above the age of 45 years at serum sampling and for patients with a lag time of less than 10 years. This study provides prospective epidemiological evidence of an association between infection with HPV 16 and 18 and anal and perianal skin cancer.

[Can human papillomavirus testing and vaccination prevent cervical cancer?]. / Kan testing og vaksinering for humant papillomavirus forebygge livmorhalskreft?

BACKGROUND: Cervical cancer is the third most frequent cancer among women worldwide. Human papillomavirus (HPV) infection is a necessary risk factor and the first step in cervical carcinogenesis. MATERIAL AND METHODS: This article reviews the current literature concerning the possibility of preventing cervical cancer by HPV testing and vaccination. RESULTS: HPV testing cannot replace cytology, but will reduce false negative cytology and may improve the screening programme for cervical neoplasia. It has not yet been incorporated in any national cervical cancer screening program, but trials are ongoing in Scandinavia and in the Netherlands. The cost-effectiveness of HPV testing in screening has to be proven and whether it can affect the recommended screening-intervals. Therapeutic and prophylactic vaccines for HPV associated disease are in progress. Evaluating the clinical trials that are ongoing will take several years. Several anti-HPV vaccines are now in clinical trials; Norway will also participate. Therapeutic vaccines against cervical cancer have so far not been successful, but anogenital dysplasias and condylomas may be more susceptible. Prophylactic vaccines against HPV 6, 11, 16 and 18 have been evaluated in clinical phase I and II trials, and phase III trials are in progress. INTERPRETATION: HPV testing improves the specificity and sensitivity of cervical cytology and it can be used to clarify cases with atypical cells of undetermined significance (ASCUS) and low-grade intraepithelial neoplasia. In the near future it may also be included in the cervical cancer screening programme for women above the age of 30. The first results in clinical vaccine trials are encouraging, and final conclusions about the effectiveness of these vaccines may be achieved in five years' time.