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Type 2 diabetes is associated with raised risk of several cancers, but for type 1 diabetes risk data are fewer and inconsistent We assembled a cohort of 23 473 UK patients with insulin‐treated diabetes diagnosed at ages <30, almost all of whom will have had type 1 diabetes, and for comparison 5058 diagnosed at ages 30 to 49, of whom we estimate two‐thirds will have had type 2, and followed them for an average of 30 years for cancer incidence and mortality compared with general population rates. Patients aged <30 at diabetes diagnosis had significantly raised risks only for ovarian (standardised incidence ratio = 1.58; 95% confidence interval 1.16‐2.11; P <.01) and vulval (3.55; 1.94‐5.96; P <.001) cancers, with greatest risk when diabetes was diagnosed at ages 10‐14. Risks of cancer overall (0.89; 0.84‐0.95; P <.001) and sites including lung and larynx were significantly diminished. Patients diagnosed with diabetes at ages 30 to 49 had significantly raised risks of liver (1.76;1.08‐2.72) and kidney (1.46;1.03‐2.00) cancers, and reduced risk of cancer overall (0.89; 0.84‐0.95). The raised ovarian and vulval cancer risks in patients with type 1 diabetes, especially with diabetes diagnosed around pubertal ages, suggest possible susceptibility of these organs at puberty to metabolic disruption at diabetes onset. Reduced risk of cancer overall, particularly smoking and alcohol‐related sites, might reflect adoption of a healthy lifestyle. [ABSTRACT FROM AUTHOR]

Background: External validation of risk models is critical for risk-stratified breast cancer prevention. We used the Individualized Coherent Absolute Risk Estimation (iCARE) as a flexible tool for risk model development and comparative model validation and to make projections for population risk stratification.Methods: Performance of two recently developed models, one based on the Breast and Prostate Cancer Cohort Consortium analysis (iCARE-BPC3) and another based on a literature review (iCARE-Lit), were compared with two established models (Breast Cancer Risk Assessment Tool and International Breast Cancer Intervention Study Model) based on classical risk factors in a UK-based cohort of 64 874 white non-Hispanic women (863 patients) age 35-74 years. Risk projections in a target population of US white non-Hispanic women age 50-70 years assessed potential improvements in risk stratification by adding mammographic breast density (MD) and polygenic risk score (PRS).Results: The best calibrated models were iCARE-Lit (expected to observed number of cases [E/O] = 0.98, 95% confidence interval [CI] = 0.87 to 1.11) for women younger than 50 years, and iCARE-BPC3 (E/O = 1.00, 95% CI = 0.93 to 1.09) for women 50 years or older. Risk projections using iCARE-BPC3 indicated classical risk factors can identify approximately 500 000 women at moderate to high risk (>3% 5-year risk) in the target population. Addition of MD and a 313-variant PRS is expected to increase this number to approximately 3.5 million women, and among them, approximately 153 000 are expected to develop invasive breast cancer within 5 years.Conclusions: iCARE models based on classical risk factors perform similarly to or better than BCRAT or IBIS in white non-Hispanic women. Addition of MD and PRS can lead to substantial improvements in risk stratification. However, these integrated models require independent prospective validation before broad clinical applications. [ABSTRACT FROM AUTHOR]

The constitutional t(11;22)(q23;q11) translocation is the only recurrent non‐Robertsonian translocation known in humans. Carriers are phenotypically normal and are usually referred for cytogenetic testing because of multiple miscarriages, infertility, or having aneuploidy in offspring. A breast cancer predisposition has been suggested, but previous studies have been small and had methodological shortcomings. We therefore conducted a long‐term prospective study of cancer and mortality risk in carriers. We followed 65 male and 101 female carriers of t(11;22)(q23;q11) diagnosed in cytogenetic laboratories in Britain during 1976–2005 for cancer and deaths for an average of 21.4 years per subject. Standardised mortality (SMR) and incidence (SIR) ratios were calculated comparing the numbers of observed events with those expected from national age‐, sex‐, country‐ and calendar‐period‐specific population rates. Cancer incidence was borderline significantly raised for cancer overall (SIR = 1.56, 95% CI: 0.98–2.36, n = 22), and significantly raised for invasive breast cancer (SIR = 2.74, 95% CI: 1.18–5.40, n = 8) and in situ breast cancer (SIR = 13.0, 95% CI: 3.55–33.4, n = 4). Breast cancer risks were particularly increased at ages <50 (SIR = 4.37, 95% CI: 1.42–10.2 for invasive, SIR = 22.8, 95% CI: 2.76–82.5 for in situ). Mortality was borderline significantly raised for breast cancer (SMR = 4.82, 95% CI: 0.99–14.1) but not significantly raised for other cancers or causes. Individuals diagnosed with t(11;22)(q23;q11) appear to be at several‐fold increased breast cancer risk, with the greatest risks at premenopausal ages. Further research is required to understand the genetic mechanism involving 11q23 and 22q11 and there may be a need for enhanced breast cancer surveillance among female carriers. What's new? The constitutional translocation between chromosome bands 11q23 and 22q11 is recurrent in human populations, with highly consistent breakpoints. A breast cancer predisposition among carriers has been suggested, but previous studies have been small and had methodological shortcomings. In this first long‐term follow‐up study of site‐specific cancer and mortality risks among carriers, an increased risk of breast cancer was observed compared to the general population, with greatest risks in younger women. The results suggest that carriers of t(11;22)(q23;q11) may require enhanced surveillance for breast cancer and point to the importance of the chromosomal regions 11q23 and 22q11 in breast cancer development. [ABSTRACT FROM AUTHOR]

A balanced robertsonian translocation (rob) results from fusion of 2 acrocentric chromosomes. Carriers are phenotypically normal and are often diagnosed because of recurrent miscarriages, infertility, or aneuploid offspring. Mortality and site-specific cancer risks in carriers have not been prospectively investigated. We followed 1,987 carriers diagnosed in Great Britain for deaths and cancer risk, over an average of 24.1 years. Standardized mortality and incidence ratios were calculated comparing the number of observed events against population rates. Overall mortality was higher for carriers diagnosed before age 15 years (standardized mortality ratio (SMR) = 2.00, 95% confidence interval (CI): 1.09, 3.35), similar for those diagnosed aged 15–44 years (SMR = 1.06, 95% CI: 0.86–1.28), and lower for those diagnosed aged 45–84 years (SMR = 0.81, 95% CI: 0.68, 0.95). Cancer incidence was higher for non-Hodgkin lymphoma (standardized incidence ratio (SIR) = 1.90, 95% CI: 1.01, 3.24) and childhood leukemia (SIR = 14.5, 95% CI: 1.75, 52.2), the latter particularly in rob(15;21) carriers (SIR = 447.8, 95% CI: 11.3, 2,495). Rob(13;14) carriers had a higher breast cancer risk (SIR = 1.58, 95% CI: 1.12, 2.15). Mortality risks relative to the population in diagnosed carriers depend on age at cytogenetic diagnosis, possibly reflecting age-specific cytogenetic referral reasons. Carriers might be at greater risk of childhood leukemia and non-Hodgkin lymphoma and those diagnosed with rob(13;14) of breast cancer. [ABSTRACT FROM AUTHOR]

There has been a worldwide epidemic of obesity in recent decades. In animal studies, there is convincing evidence that light exposure causes weight gain, even when calorie intake and physical activity are held constant. Disruption of sleep and circadian rhythms by exposure to light at night (LAN) might be one mechanism contributing to the rise in obesity, but it has not been well-investigated in humans. Using multinomial logistic regression, we examined the association between exposure to LAN and obesity in questionnaire data from over 100,000 women in the Breakthrough Generations Study, a cohort study of women aged 16 years or older who were living in the United Kingdom and recruited during 2003–2012. The odds of obesity, measured using body mass index, waist:hip ratio, waist:height ratio, and waist circumference, increased with increasing levels of LAN exposure (P < 0.001), even after adjustment for potential confounders such as sleep duration, alcohol intake, physical activity, and current smoking. We found a significant association between LAN exposure and obesity which was not explained by potential confounders we could measure. While the possibility of residual confounding cannot be excluded, the pattern is intriguing, accords with the results of animal experiments, and warrants further investigation. [ABSTRACT FROM PUBLISHER]

Prospective cohort studies examining sex hormones in relation to cancer risk have generally collected blood samples at 1 time point, with an assumption that hormone levels measured in these samples will be reliable markers of true levels at other times. In postmenopausal women, body fat is a major source of estradiol; therefore, changes in adiposity may affect the correlation of single measurements to more relevant long-term averages. To estimate the intraclass correlation coefficient (ICC) for estradiol and testosterone, we collected repeat blood samples from 119 postmenopausal women (average age = 59.4 (standard deviation, 4.7) years) from the United Kingdom during 2004–2005 and again during 2010–2011. The ICCs (adjusted for assay variation) were 0.73 (95% confidence interval: 0.63, 0.82) for total estradiol and 0.59 (95% confidence interval: 0.47, 0.72) for total testosterone. The ICCs were 3%–5% larger after adjustment for change in body mass index (weight (kg)/height (m)2) or leptin, which are 2 markers of change in adiposity. There was no increase in ICCs after adjustment for change in age, alcohol consumption, smoking, exercise, time between waking and blood collection, or season. The results suggest that other factors account for within-woman variation in these sex hormones. [ABSTRACT FROM PUBLISHER]

The authors examined the effect of women’s lifestyles on the timing of natural menopause using data from a cross-sectional questionnaire used in the United Kingdom-based Breakthrough Generations Study in 2003–2011. The analyses included 50,678 women (21,511 who had experienced a natural menopause) who were 40–98 years of age at study entry and did not have a history of breast cancer. Cox competing risks proportional hazards models were fitted to examine the relation of age at natural menopause to lifestyle and anthropometric factors. Results were adjusted for age at reporting, smoking status at menopause, parity, and body mass index at age 40 years, as appropriate. All P values were 2-sided. High adult weight (Ptrend < 0.001), high body mass index (Ptrend < 0.001), weight gain between the ages of 20 and 40 years (Ptrend = 0.01), not smoking (P < 0.001), increased alcohol consumption (Ptrend < 0.001), regular strenuous exercise (P < 0.01), and not being a vegetarian (P < 0.001) were associated with older age at menopause. Neither height nor history of an eating disorder was associated with menopausal age. These findings show the importance of lifestyle factors in determining menopausal age. [ABSTRACT FROM PUBLISHER]

Menarcheal age decreased over time in Western countries until cohorts born in the mid-20th century. It then stabilised, but limited data are available for recent cohorts. Menarche data were collected retrospectively by questionnaire in 2003-10 from 94,170 women who were participating in the Breakthrough Generations Study, aged 16-98 years, born 1908-93 and resident in the UK. Average menarcheal age declined from women born in 1908-19 (mean=13.5 years) to those born in 1945-49 (mean=12.6 years). It was then stable for several birth cohorts, but resumed its downward trend in recent cohorts (mean=12.3 years in 1990-93 cohort). Trends differed between socio-economic groups, but the recent decline was present in each group. In conclusion, menarcheal age appears to have decreased again in recent cohorts after a period of stabilisation. [ABSTRACT FROM AUTHOR]

Age at menarche is correlated within families, but estimates of the heritability of menarcheal age have a wide range (0.45-0.95). We examined the familial resemblance for age at menarche and the extent to which this is due to genetic and shared environmental factors. Between 2003 and 2010 data were retrospectively collected by questionnaire from participants within the UK-based Breakthrough Generations Study. These analyses included 25,970 female participants aged 16-98 with at least one female relative who was also a study participant. A woman's menarche was significantly delayed for each yearly increase in the menarcheal age of her monozygotic twin (average increase = 7.2 months, P < 0.001), dizygotic twin (average increase = 3.0 months, P = 0.03), older sister (average increase = 3.3 months, P < 0.001), mother (average increase = 3.4 months, P < 0.001), maternal grandmother (average increase = 1.5 months, P = 0.04), maternal aunt (average increase = 1.4 months, P < 0.001) and paternal aunt (average increase = 3.0 months, P < 0.001). There was not a significant association between the menarcheal ages of half-sister pairs or of paternal grandmother-granddaughter pairs, based on small numbers. Heritability was estimated as 0.57 [95% confidence interval 0.53, 0.61]. Shared environmental factors did not have an effect in the model. In conclusion, approximately half of the variation in age at menarche was attributable to additive genetic effects with the remainder attributable to non-shared environmental effects. [ABSTRACT FROM AUTHOR]

The article presents an obituary for British general practice physician Edward Somerset Short.

It is proposed that, through restriction to individuals delineated as high risk, polygenic risk scores (PRSs) might enable more efficient targeting of existing cancer screening programmes and enable extension into new age ranges and disease types. To address this proposition, we present an overview of the performance of PRS tools (ie, models and sets of single nucleotide polymorphisms) alongside harms and benefits of PRS-stratified cancer screening for eight example cancers (breast, prostate, colorectal, pancreas, ovary, kidney, lung, and testicular cancer). For this modelling analysis, we used age-stratified cancer incidences for the UK population from the National Cancer Registration Dataset (2016–18) and published estimates of the area under the receiver operating characteristic curve for current, future, and optimised PRS for each of the eight cancer types. For each of five PRS-defined high-risk quantiles (ie, the top 50%, 20%, 10%, 5%, and 1%) and according to each of the three PRS tools (ie, current, future, and optimised) for the eight cancers, we calculated the relative proportion of cancers arising, the odds ratios of a cancer arising compared with the UK population average, and the lifetime cancer risk. We examined maximal attainable rates of cancer detection by age stratum from combining PRS-based stratification with cancer screening tools and modelled the maximal impact on cancer-specific survival of hypothetical new UK programmes of PRS-stratified screening. The PRS-defined high-risk quintile (20%) of the population was estimated to capture 37% of breast cancer cases, 46% of prostate cancer cases, 34% of colorectal cancer cases, 29% of pancreatic cancer cases, 26% of ovarian cancer cases, 22% of renal cancer cases, 26% of lung cancer cases, and 47% of testicular cancer cases. Extending UK screening programmes to a PRS-defined high-risk quintile including people aged 40–49 years for breast cancer, 50–59 years for colorectal cancer, and 60–69 years for prostate cancer has the potential to avert, respectively, a maximum of 102, 188, and 158 deaths annually. Unstratified screening of the full population aged 48–49 years for breast cancer, 58–59 years for colorectal cancer, and 68–69 years for prostate cancer would use equivalent resources and avert, respectively, an estimated maximum of 80, 155, and 95 deaths annually. These maximal modelled numbers will be substantially attenuated by incomplete population uptake of PRS profiling and cancer screening, interval cancers, non-European ancestry, and other factors. Under favourable assumptions, our modelling suggests modest potential efficiency gain in cancer case detection and deaths averted for hypothetical new PRS-stratified screening programmes for breast, prostate, and colorectal cancer. Restriction of screening to high-risk quantiles means many or most incident cancers will arise in those assigned as being low-risk. To quantify real-world clinical impact, costs, and harms, UK-specific cluster-randomised trials are required. The Wellcome Trust. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic., Design: We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2-6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19-related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008-2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval., Results: Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk-benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%., Conclusions: Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the appreciable false-negative rate of FIT in symptomatic patients means most colonoscopies will still be required., Competing Interests: Competing interests: ML has received honoraria from Pfizer, EMD Merck Serono and Roche for speaking honoraria unrelated to this work. ML has received an unrestricted educational grant from Pfizer for research unrelated to this work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Preeclampsia and hyperemesis gravidarum are pregnancy complications associated with altered sex hormone levels. Previous studies suggest preeclampsia may be associated with a decreased risk of subsequent breast cancer and hyperemesis with an increased risk, but the evidence remains unclear. We used data from the Generations Study, a large prospective study of women in the United Kingdom, to estimate relative risks of breast cancer in relation to a history of preeclampsia and hyperemesis using Cox regression adjusting for known breast cancer risk factors. During 7.5 years average follow-up of 82,053 parous women, 1,969 were diagnosed with invasive or in situ breast cancer. Women who had experienced preeclampsia during pregnancy had a significantly decreased risk of premenopausal breast cancer (hazard ratio (HR) =0.67, 95% confidence interval (CI): 0.49-0.90) and of HER2-enriched tumours (HR = 0.33, 95% CI: 0.12-0.91), but there was no association with overall (HR = 0.90, 95% CI: 0.80-1.02) or postmenopausal (HR = 0.97, 95% CI: 0.85-1.12) breast cancer risk. Risk reductions among premenopausal women were strongest within 20 years since the last pregnancy with preeclampsia. Hyperemesis was associated with a significantly increased risk of HER2-enriched tumours (HR = 1.76, 95% CI: 1.07-2.87), but not with other intrinsic subtypes or breast cancer risk overall. These results provide evidence that preeclampsia is associated with a decreased risk of premenopausal and HER2-enriched breast cancer and that hyperemesis, although not associated with breast cancer risk overall, may be associated with raised risk of HER2-enriched tumours., (© 2018 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Circadian disruption caused by exposure to light at night (LAN) has been proposed as a risk factor for breast cancer and a reason for secular increases in incidence. Studies to date have largely been ecological or case-control in design and findings have been mixed., Methods: We investigated the relationship between LAN and breast cancer risk in the UK Generations Study. Bedroom light levels and sleeping patterns at age 20 and at study recruitment were obtained by questionnaire. Analyses were conducted on 105 866 participants with no prior history of breast cancer. During an average of 6.1 years of follow-up, 1775 cases of breast cancer were diagnosed. Cox proportional hazard models were used to calculate hazard ratios (HRs), adjusting for potential confounding factors., Results: There was no association between LAN level and breast cancer risk overall (highest compared with lowest LAN level at recruitment: HR=1.01, 95% confidence interval (CI): 0.88-1.15), or for invasive (HR=0.98, 95% CI: 0.85-1.13) or in situ (HR=0.96, 95% CI: 0.83-1.11) breast cancer, or oestrogen-receptor (ER) positive (HR=0.98, 95% CI: 0.84-1.14); or negative (HR=1.16, 95% CI: 0.82-1.65) tumours separately. The findings did not differ by menopausal status. Adjusting for sleep duration, sleeping at unusual times (non-peak sleep) and history of night work did not affect the results. Night waking with exposure to light, occurring around age 20, was associated with a reduced risk of premenopausal breast cancer (HR for breast cancer overall=0.74, 95% CI: 0.55-0.99; HR for ER-positive breast cancer=0.69, 95% CI: 0.49-0.97)., Conclusions: In this prospective cohort analysis of LAN, there was no evidence that LAN exposure increased the risk of subsequent breast cancer, although the suggestion of a lower breast cancer risk in pre-menopausal women with a history of night waking in their twenties may warrant further investigation.