Epidemiological study of the role of vitamin D in the aetiology of ovarian cancer

Johtuen oireiden salakavaluudesta useimmat munasarjasyöpätapaukset todetaan pitkälle edenneinä ja munasarjasyöpä on hyvin tappava gynekologinen syöpä. Maantieteellisesti taudin ilmaantuvuus ja tautiin kuolleisuus vaihtelevat huomattavasti. Munasarjasyövän syyksi on esitetty gonadotropiinia, muuta hormonaalista syytä, keskeytymättömiä ovulaatioita ja tulehdusta. Vaikka jokaisen hypoteesin tueksi on esittää epidemiologista todistusaineistoa muiden, toistaiseksi vähän tutkittujen, tekijöiden osuutta ei voi sulkea pois. Ekologisten, kokeellisten ja ravitsemustutkimusten perusteella D-vitamiini voi suojata munasarjasyövältä, mutta tutkimukset, jotka hyödyntävät parasta D-vitamiinin mittaustapaa, seerumin 25-hydroksi D (25-OHD) vitamiinimääritystä, puuttuvat. Tämän väitöskirjatutkimuksen tarkoituksena oli tutkia D-vitamiinin ja munasarjasyövän yhteyttä käyttäen hyväksi seerumin 25-OHD -tasoja - luotettavinta tapaa määrittää yksilön D-vitamiinistatus. Tässä väitöskirjassa esitettävät työt ovat sarja Äitikohorttiin (Finnish Maternity Cohort, FMC) upotettuja tapaus-verrokkitutkimuksia. FMC-seerumipankki on väestöpohjainen seerumipankki, jossa lähes kaikkien Suomessa vuodesta 1983 raskaana olleiden naisten ensimmäisen raskauskolmanneksen seeruminäytettä säilytetään -25 °C:ssa. Munasarjasyöpätapaukset ja kaltaistetut verrokit identifioitiin yhdistämällä tietoja Syöpärekisterin ja Tilastokeskuksen kanssa. Tulostemme oikeellisuus riippuu paljolti siitä, miten hyvin D-vitamiinin 25-OHD -aineenvaihduntatuote on säilynyt ja mitattavissa vuoden ajan säilytetyissä seeruminäytteissä. Sen vuoksi välttääksemme virheluokitusta ensimmäinen tavoitteemme oli määrittää 25-OHD:n ja androstenedionin säilyminen seeruminäytteissä, joita oli säilytetty jopa 24 vuotta. Havaitsimme odotetut vuodenajasta johtuvat seerumin 25-OHD tasojen erot kaikkina seurantavuosina. Keskimääräinen seerumin 25-OHD -taso oli merkitsevästi korkeampi kesällä (44.0 nmol/l) talveen (33.4 nmol/l) verrattuna (p Toisessa tutkimuksessa, joka koski 201 munasarjasyöpätapausta, jotka oli diagnosoitu 10 vuoden kuluessa seeruminäytteen ottamisesta, ja 398 vuodenajan, iän ja raskauksien määrän suhteen kaltaistettua verrokkia, emme havainneet yhteyttä seerumin 25-OHD -pitoisuuden ja munasarjasyöpäriskin välillä (OR 1.8, 95% CI 0.9 3.5) vertailtaessa alimman ja ylimmän neljänneksen D-vitamiinitason omanneita tutkittavia. Naisilla, joilla oli suositusten mukaan riittämätön 25-OHD -taso ( 75 nmol/l) omanneisiin naisiin. Kolmannessa tutkimuksessa selvitimme toimivatko kalsium ja D-vitamiini riippumattomasti vai muuntelevatko ne toistensa vaikutusta munasarjasyöpäriskiin. Naisilla, jotka olivat kalsiumtasojensa suhteen korkeimmassa neljänneksessä, oli merkitsevästi vähentynyt munasarjasyöpäriski, kun taas naisten, jotka olivat korkeimmassa D-vitamiinineljänneksessä, munasarjasyöpäriskin vähenemisen tilastollinen merkitsevyys jäi rajalle. Naisilla, joilla oli riittävät 25-OHD -tasot oli merkitsevästi alentunut munasarjasyöpäriski (OR 0.32, 95% CI 0.12 0.91). Kalsiumiin tilastollisesti merkitsevästi liittyvä alentunut munasarjasyöpäriski oli riippumaton seerumin 25-OHD -tasoista (OR 0.41, 95% CI 0.19 0.87). D-vitamiiniin liittyvä alentunut munasarjasyöpäriski (OR 0.51, 95% CI 0.29 1.05) oli riippumaton. Emme havainneet, että kalsium ja D-vitamiini muuntelisivat toistensa vaikutusta suhteessa munasarjasyöpään. D-vitamiinia ja munasarjasyöpää koskeneiden epidemiologisten tutkimusten todettu heikkous on ollut yhden seeruminäytteen käyttö arvioitaessa elimistön D-vitamiinistatusta yli ajan. Toistaiseksi ainoassa tutkimuksessa, jossa seerumin 25-OHD -tasoja on mitattu kaksi kertaa pitkällä aikavälillä, havaitsimme, että korkean seerumi 25-OHD -tason säilyttäminen pitkän aikaa voi liittyä alentuneeseen munasarjasyöpäriskiin. Naisilla, joiden seerumin 25-OHD -tasot olivat vuodenajan keskimääräisiä tasoja korkeammat molemmissa näytteissä, oli alentunut riski sairastua munasarjasyöpään (OR 0.21, 95 % CI 0.05 0.99). Tätä tilastollisen merkitsevyyden rajalla ollutta vaikutusta ei havaittu naisilla, joiden näytteet oli otettu talvella.Ovarian cancer is a very lethal gynaecological cancer because its symptoms are insidious and majority of the patients present with advanced stage disease. There is considerable geographic variation in the incidence and mortality of the disease. The gonadotrophin, hormonal, incessant ovulation and inflammation hypotheses have all been proposed to explain its aetiology and while epidemiological studies offer some support for aspects of each hypothesis, the contribution of other hitherto under-investigated factors cannot be discountenanced. Ecological, experimental and dietary studies suggest that vitamin D may offer some protection against ovarian cancer but there is dearth of epidemiological studies investigating this association using the best marker for vitamin D; serum 25-hydroxyvitamin D (25-OHD). The aim of this thesis was to investigate the association between vitamin D and ovarian cancer utilizing serum 25-OHD concentrations which is the most reliable way to determine an individual s vitamin D status. The studies in the thesis are a series of case-control studies nested within the Finnish Maternity Cohort (FMC) which is a population-based serum biorepository, maintained at -25oC, containing the first trimester serum samples of almost all pregnant Finnish women since 1983. Ovarian cancer cases and suitably matched controls were identified after linkages with the nation-wide Finnish Cancer Registry (FCR) and Statistics, Finland. The validity of our results depends to a large extent on how measurable and preserved the vitamin D metabolite, 25-OHD, is within serum samples that have been stored for many years. Therefore, in order to avoid differential misclassification in our studies, our first objective was to determine the stability of 25-OHD and androstenedione in serum samples that had been stored for up to 24 years. We observed the expected marked seasonal differences in serum 25-OHD concentrations for all the years studied. The mean serum 25-OHD levels were significantly higher in summer (44.0 nmol/L) compared to winter (33.4 nmol/L, p-value ? 0.001). There was no evidence to suggest systematic degradation of 25-OHD in stored sera, implying that 25-OHD is very stable in serum samples stored at-25oC for many years. In the second study involving 201 ovarian cancer cases diagnosed within 10 years of serum sampling and 398 season, age and parity-matched controls, we observed no overall association between serum 25-OHD concentrations and ovarian cancer risk (OR 1.8, 95% CI 0.9 3.5 comparing lowest to highest quintile) but women with insufficient serum 25-OHD concentrations ( In study III, we sought to determine whether calcium and vitamin D act independently or jointly and whether each modifies the action of the other on ovarian cancer risk. Women within the highest quartile of calcium concentration had significantly reduced risk of ovarian cancer while women within the highest quartile of serum 25-OHD concentration had borderline reduced risk of ovarian cancer compared to those within the lowest. Women with sufficient serum 25-OHD levels had a significantly reduced risk of ovarian cancer compared to women with insufficient serum levels (OR 0.32, 95% CI 0.12-0.91). While calcium was independently associated with a reduced risk of ovarian cancer regardless of serum 25-OHD levels, (OR 0.41, 95% CI 0.19-087), vitamin D was independently associated with a non-significantly reduced risk of ovarian cancer (OR 0.51, 95% CI 0.29-1.05). We observed no evidence of effect modification between calcium and vitamin D with regards to ovarian cancer. A perceived weakness in epidemiological studies of vitamin D and ovarian cancer is the use of one time serum 25-OHD measurement to indicate over time vitamin D status. In the only study so far that has measured serum 25-OHD twice, over a long period of time, among cases and controls; we found evidence to suggest that maintaining consistently high serum 25-OHD levels over many years during summer may be associated with a reduced risk of ovarian cancer. Women whose serum 25-OHD levels were above the season specific median values on both sampling occasions had a borderline reduced risk of ovarian cancer (OR 0.21 95% CI 0.05-0.99) compared to other women with consistently low or fluctuating serum 25-OHD levels. No such protective effect was however observed among women who donated their samples during winter

Epidemiological study of the role of vitamin D in the aetiology of ovarian cancer

Väitöskirja, liitteenä alkuperäisartikkelit (ei verkkoversiossa). Suomenkielinen tiivistelmä vain verkkoversioss

Multiplatform urinary metabolomics profiling to discriminate cachectic from non-cachectic colorectal cancer patients: Pilot results from the ColoCare Study

Cachexia is a multifactorial syndrome that is characterized by loss of skeletal muscle mass in cancer patients. The biological pathways involved remain poorly characterized. Here, we compare urinary metabolic profiles in newly diagnosed colorectal cancer patients (stage I-IV) from the ColoCare Study in Heidelberg, Germany. Patients were classified as cachectic

The role of CT-quantified body composition on longitudinal health-related quality of life in colorectal cancer patients: The Colocare Study

BACKGROUND: Obesity, defined by body mass index (BMI), measured at colorectal cancer (CRC) diagnosis has been associated with postoperative complications and survival outcomes. However, BMI does not allow for a differentiation between fat and muscle mass. Computed tomography (CT)-defined body composition more accurately reflects different types of tissue and their associations with health-related quality of life (HRQoL) during the first year of disease, but this has not been investigated yet. We studied the role of visceral and subcutaneous fat area (VFA and SFA) and skeletal muscle mass (SMM) on longitudinally assessed HRQoL in CRC patients. METHODS: A total of 138 newly diagnosed CRC patients underwent CT scans at diagnosis and completed questionnaires prior to and six and twelve months post-surgery. We investigated the associations of VFA, SFA, and SMM with HRQoL at multiple time points. RESULTS: A higher VFA was associated with increased pain six and twelve months post-surgery (β = 0.06, CONCLUSIONS: CT-quantified body composition is associated with HRQoL scales post-surgery. Intervention strategies targeting a reduction in VFA and maintaining SMM might improve HRQoL in CRC patients during the first year post-surgery

Does circulating progesterone mediate the associations of single nucleotide polymorphisms in progesterone receptor (PGR)-related genes with mammographic breast density in premenopausal women?

UNLABELLED: Progesterone is a proliferative hormone in the breast but the associations of genetic variations in progesterone-regulated pathways with mammographic breast density (MD) in premenopausal women and whether these associations are mediated through circulating progesterone are not clearly defined. We, therefore, investigated these associations in 364 premenopausal women with a median age of 44 years. We sequenced 179 progesterone receptor (PGR)-related single nucleotide polymorphisms (SNPs). We measured volumetric percent density (VPD) and non-dense volume (NDV) using Volpara. Linear regression models were fit on circulating progesterone or VPD/NDV separately. We performed mediation analysis to evaluate whether the effect of a SNP on VPD/NDV is mediated through circulating progesterone. All analyses were adjusted for confounders, phase of menstrual cycle and the Benjamini-Hochberg false discovery (FDR) adjusted p-value was applied to correct for multiple testing. In multivariable analyses, only PGR rs657516 had a direct effect on VPD (averaged direct effect estimate = - 0.20, 95%CI = - 0.38 ~ - 0.04, p-value = 0.02) but this was not statistically significant after FDR correction and the effect was not mediated by circulating progesterone (mediation effect averaged across the two genotypes = 0.01, 95%CI = - 0.02 ~ 0.03, p-value = 0.70). Five SNPs (PGR rs11571241, rs11571239, rs1824128, rs11571150, PGRMC1 rs41294894) were associated with circulating progesterone but these were not statistically significant after FDR correction. SNPs in PGR-related genes were not associated with VPD, NDV and circulating progesterone did not mediate the associations, suggesting that the effects, if any, of these SNPs on MD are independent of circulating progesterone. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-021-00438-1

Family history of breast cancer and mammographic breast density in premenopausal women

Importance: Family history of breast cancer (FHBC) and mammographic breast density are independent risk factors for breast cancer, but the association of FHBC and mammographic breast density in premenopausal women is not well understood. Objectives: To investigate the association of FHBC and mammographic breast density in premenopausal women using both quantitative and qualitative measurements. Design, Setting, and Participants: This single-center cohort study examined 2 retrospective cohorts: a discovery set of 375 premenopausal women and a validation set of 14 040 premenopausal women. Data from women in the discovery set was collected between December 2015 and October 2016, whereas data from women in the validation set was collected between June 2010 and December 2015. Data analysis was performed between June 2018 and June 2020. Exposures: Family history of breast cancer (FHBC). Main Outcomes and Measures: The primary outcomes were mammographic breast density measured quantitatively as volumetric percent density using Volpara (discovery set) and qualitatively using BI-RADS (Breast Imaging Reporting and Data System) breast density (validation set). Multivariable regressions were performed using a log-transformed normal distribution for the discovery set and a logistic distribution for the validation set. Results: Of 14 415 premenopausal women included in the study, the discovery set and validation set had similar characteristics (discovery set with FHBC: mean [SD] age, 47.1 [5.6] years; 15 [17.2%] were Black or African American women and 64 [73.6%] were non-Hispanic White women; discovery set with no FHBC: mean [SD] age, 47.7 [4.5] years; 87 [31.6%] were Black or African American women and 178 [64.7%] were non-Hispanic White women; validation set with FHBC: mean [SD] age, 46.8 [7.3] years; 720 [33.4%] were Black or African American women and 1378 [64.0%] were non-Hispanic White women]; validation set with no FHBC: mean [SD] age, 47.5 [6.1] years; 4572 [38.5%] were Black or African American women and 6632 [55.8%] were non-Hispanic White women]). In the discovery set, participants who had FHBC were more likely to have a higher mean volumetric percent density compared with participants with no FHBC (11.1% vs 9.0%). In the multivariable-adjusted model, volumetric percent density was 25% higher (odds ratio [OR], 1.25 ;95% CI, 1.12-1.41) in women with FHBC compared with women without FHBC; and 24% higher (OR, 1.24; 95% CI, 1.10-1.40) in women who had 1 affected relative, but not significantly higher in women who had at least 2 affected relatives (OR, 1.40; 95% CI, 0.95-2.07) compared with women with no relatives affected. In the validation set, women with a positive FHBC were more likely to have dense breasts (BI-RADS 3-4) compared with women with no FHBC (BI-RADS 3: 41.1% vs 38.8%; BI-RADS 4: 10.5% vs 7.7%). In the multivariable-adjusted model, the odds of having dense breasts (BI-RADS 3-4) were 30% higher (OR, 1.30; 95% CI, 1.17-1.45) in women with FHBC compared with women without FHBC; and 29% higher (OR, 1.29; 95% CI, 1.14-1.45) in women who had 1 affected relative, but not significantly higher in women who had at least 2 affected relatives (OR, 1.38; 95% CI, 0.85-2.23) compared with women with no relatives affected. Conclusions and Relevance: In this cohort study, having an FHBC was positively associated with mammographic breast density in premenopausal women. Our findings highlight the heritable component of mammographic breast density and underscore the need to begin annual screening early in premenopausal women with a family history of breast cancer