Deficient H2A.Z deposition is associated with genesis of uterine leiomyoma.

One in four women suffers from uterine leiomyomas (ULs)-benign tumours of the uterine wall, also known as uterine fibroids-at some point in premenopausal life. ULs can cause excessive bleeding, pain and infertility1, and are a common cause of hysterectomy2. They emerge through at least three distinct genetic drivers: mutations in MED12 or FH, or genomic rearrangement of HMGA23. Here we created genome-wide datasets, using DNA, RNA, assay for transposase-accessible chromatin (ATAC), chromatin immunoprecipitation (ChIP) and HiC chromatin immunoprecipitation (HiChIP) sequencing of primary tissues to profoundly understand the genesis of UL. We identified somatic mutations in genes encoding six members of the SRCAP histone-loading complex4, and found that germline mutations in the SRCAP members YEATS4 and ZNHIT1 predispose women to UL. Tumours bearing these mutations showed defective deposition of the histone variant H2A.Z. In ULs, H2A.Z occupancy correlated positively with chromatin accessibility and gene expression, and negatively with DNA methylation, but these correlations were weak in tumours bearing SRCAP complex mutations. In these tumours, open chromatin emerged at transcription start sites where H2A.Z was lost, which was associated with upregulation of genes. Furthermore, YEATS4 defects were associated with abnormal upregulation of bivalent embryonic stem cell genes, as previously shown in mice5. Our work describes a potential mechanism of tumorigenesis-epigenetic instability caused by deficient H2A.Z deposition-and suggests that ULs arise through an aberrant differentiation program driven by deranged chromatin, emanating from a small number of mutually exclusive driver mutations.

Sociodemographic features and patterns of non-participation in colorectal cancer screening in Finland.

BACKGROUND: Colorectal cancer (CRC) screening was run as a randomized health services programme in Finland between 2004 and 2016. This study evaluates sociodemographic features and patterns of non-participation among men and women invited to be screened. METHODS: The study population in this register-based study includes 233 211 men and women invited to guaiac faecal occult blood test screening on consecutive screening rounds (n = 708 621 invitations). A generalized estimating equation (GEE) was used to estimate incidence rate ratios (IRR) between sociodemographic features and non-participation. RESULTS: The overall proportion of non-participation was 31.6% and was higher in men (38.8%) than in women (24.6%). Birth cohort, education, marital status and country of birth were associated with non-participation. The birth cohort of 1950-54 was less likely to participate than the birth cohort of 1940-44. Men and women with primary education were more likely non-participants (IRR 1.26, CI 1.23-1.29 and IRR 1.22, CI 1.18-1.26, respectively) than men or women with tertiary education. Further, unmarried persons and immigrants had an increased risk of non-participation. Initial non-participation predicted subsequent behaviour, since, e.g. ∼80% of first-round non-participants also remained non-participants in the second round. CONCLUSION: Education, gender and marital status had a significant effect on non-participation in the CRC screening programme. As high and comprehensive participation is essential for a successful screening programme, attention should be paid in ensuring participation of all sociodemographic groups. Special efforts should be invested in those not participating in the first invitational round, since initial non-participation predicts non-participation to subsequent invitations.

Piloting gender-oriented colorectal cancer screening with a faecal immunochemical test: population-based registry study from Finland.

OBJECTIVE: To assess the feasibility and evaluate the performance of a relaunched colorectal cancer (CRC) screening programme with different cut-offs for men and women. DESIGN: Population-based registry study. SETTING: Nine municipalities in Finland which started CRC screening with faecal immunochemical test (FIT) in April 2019 with cut-off levels 70 µg Hg/g faeces for men and 25 µg Hg/g faeces for women. PARTICIPANTS: Men (n=13 059) and women (n=14 669) aged 60-66 years invited to screening during the first programme year. OUTCOME MEASURES: Participation rates, positivity rates, detection rates of CRC and advanced adenoma (AA), and positive predictive values (PPV) of FIT for CRC and AA. RESULTS: Altogether 21 993 invitees returned stool samples. The participation rate of women (83.4%; 95% CI 82.8 to 84.0) was significantly higher than that of men (74.7%; 95% CI 73.9 to 75.4). The positivity rates were 2.4% (2.2 to 2.7) and 2.8% (2.5 to 3.1), respectively. In total, 37 CRCs and 116 AAs were detected. The detection rates of CRC and AA per 1000 participants were 1.8 (1.1 to 2.9) and 7.2 (5.6 to 9.1) for men and 1.6 (0.9 to 2.4) and 3.8 (2.8 to 5.0) for women. The PPVs per 100 positive tests were 6.6 (4.0 to 10.3) and 25.7 (20.6 to 31.4) for men and 6.4 (3.9 to 9.8) and 15.5 (11.6 to 20.2) for women. CONCLUSIONS: The chosen FIT strategy narrowed the gap in the diagnostic performance between men and women especially in the detection of CRC. The participation rates were excellent. The levels of positivity and detection rates were moderate and need further action. The results indicate that gender-specific protocols can be introduced to organised CRC screening. It is yet to be seen whether they are more effective than a uniform screening protocol.

The effect of colorectal cancer screening on health status in a survey study.

BACKGROUND: Colorectal cancer (CRC) screening has been found to reduce mortality from CRC but it may have adverse effects on other aspects of health. Our aim was to evaluate the effect of CRC screening on overall health status among men and women within a randomized health-services study in Finland. MATERIAL AND METHODS: A random sample of 10,648 men and women born in 1951 received a questionnaire on health and lifestyle. They were randomized for CRC screening or controls (1:1) in 2011 (N = 10,271). The current study population consisted of those who responded to the questionnaire both before and after screening (n = 4895). Self-rated health (SRH), perceived healthiness of diet and perceived physical fitness were used to determine health status, and assessed with logistic and ordered logistic models using calendar time (2010, 2012), screening randomization and demographic characteristics as covariates. RESULTS: SRH, healthiness of diet and physical fitness improved over time (OR 1.32, CI 1.17-1.48, OR 1.23, CI 1.08-1.41 and OR 1.44, CI 1.28-1.60, respectively). Compared to non-invited controls, CRC screening invitation had no effect on these measures (OR 0.91, CI 0.74-1.12, OR 0.95, CI 0.75-1.20, and OR 1.09, CI 0.87-1.37, respectively). Women reported better health status than men. However, among those who attended screening, women reported weaker, and men better health status than the respective controls. CONCLUSIONS: CRC screening did not have any effect on health status measured using self-rated health, healthiness of diet, and physical fitness. Thus, screening for colorectal cancer can be recommended as a health policy.

Respondent selection in a repeated survey on lifestyle within the randomized colorectal cancer screening programme.

Screening for colorectal cancer (CRC) has been shown to decrease colorectal cancer mortality in randomized-controlled trials. However, screening may have an adverse impact on an individual's lifestyle. We describe here the design of a repeated survey study on lifestyle and assess response in the survey target population by randomization to CRC screening and demographic factors. The survey study population (n=10271) included Finnish men and women born in 1951 who were randomized for the CRC screening programme in 2011 and received a questionnaire on lifestyle in 2010 and 2012. We assessed responding by randomization to CRC screening, calendar time and demographic factors using the population-averaged Poisson model. Responding to survey was overall similar in 2010 and 2012. Those invited for CRC screening increased responding in time [incidence rate ratio (IRR) 1.06, confidence interval (CI) 1.03-1.09], whereas controls decreased their responding (IRR 0.97, CI 0.94-1.00). Women were more likely to respond than men (IRR 1.17, CI 1.12-1.23). Also, secondary (IRR 1.20, CI 1.13-1.27) and tertiary (IRR 1.31, CI 1.23-1.40) level education increased the response proportion compared with primary-level education. We could reliably assess the effect of CRC screening invitation and demographic factors on survey response. Although invitation to CRC screening increased responding, the self-selection was similar on both survey rounds. Self-selection should be taken into account when generalizing results from survey studies to their target population.

Design and respondent selection of a population-based study on associations between breast cancer screening, lifestyle and quality of life.

BACKGROUND: Only few studies have integrated breast cancer screening, lifestyle, and quality of life. Potential bias due to selective non-response may disrupt associations being investigated. We describe the design of a Finnish population-based study on associations between breast cancer screening and various indicators for lifestyle and quality of life, and evaluate the level of bias among the respondents from the first study rounds over 2 years. METHODS: The study target population of 10,000, 49-year-old women was randomly drawn from the Finnish National Population Registry. The data included birth year, marital status, municipality, and primary language. Data on education were retrieved from Statistics Finland. Questionnaires focusing on lifestyle-related risk factors and quality of life were sent to the target population in 2012-13, 1 year before the first invitation to organized breast cancer screening. We evaluated associations between willingness to respond and demographic characteristics in the eligible study population. Additionally, we examined associations between the demographic characteristics and the Satisfaction With Life Scale (SWLS), and evaluated the impact of non-response using inverse probability weighting and multiple imputation. RESULTS: The questionnaire response proportion was 52.4%. Compared to non-respondents, respondents were more often married, academically educated, and native speakers of Finnish or Swedish. Nevertheless, the estimates of the SWLS among the respondents were in line with those corrected by non-response in the eligible study population. CONCLUSIONS: Based on the SWLS, the respondents are representative of women in the entire eligible study population.