Childhood injury after a parental cancer diagnosis

A parental cancer diagnosis is psychologically straining for the whole family. We investigated whether a parental cancer diagnosis is associated with a higher-than-expected risk of injury among children by using a Swedish nationwide register-based cohort study. Compared to children without parental cancer, children with parental cancer had a higher rate of hospital contact for injury during the first year after parental cancer diagnosis (hazard ratio [HR] = 1.27, 95% confidence interval [CI] = 1.22-1.33), especially when the parent had a comorbid psychiatric disorder after cancer diagnosis (HR = 1.41, 95% CI = 1.08-1.85). The rate increment declined during the second and third year after parental cancer diagnosis (HR = 1.10, 95% CI = 1.07-1.14) and became null afterwards (HR = 1.01, 95% CI = 0.99-1.03). Children with parental cancer also had a higher rate of repeated injuries than the other children (HR = 1.13, 95% CI = 1.12-1.15). Given the high rate of injury among children in the general population, our findings may have important public health implications

Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer.

Background:Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer. Methods:The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Rao's quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics. Results:A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P < .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI = 1.18 to 4.99). Conclusions:Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors

Mental health indicators in Sweden over a 12-month period during the COVID-19 pandemic – Baseline data of the Omtanke2020 Study

Funding Information: This study was funded with grants from NordForsk (CovidMent, 105668 ), Horizon 2020 (CoMorMent, 847776 ), and the Karolinska Institutet . Funding Information: The Omtanke2020 study is supported by NordForsk (project No. 105668 ) and Karolinska Institute (Strategic Research Area in Epidemiology and Senior Researcher Award). We acknowledge The Swedish Twin Registry for access to contact information to participating twins. The Swedish Twin Registry is managed by Karolinska Institutet and receives funding through the Swedish Research Council under the grant no 2017-00641. The Funding Sources had no direct or indirect impact on the analysis and interpretation of the results. Publisher Copyright: © 2022 The AuthorsBackground: The ongoing COVID-19 pandemic has had an unprecedented impact on the lives of people globally and is expected to have profound effects on mental health. Here we aim to describe the mental health burden experienced in Sweden using baseline data of the Omtanke2020 Study. Method: We analysed self-reported, cross-sectional baseline data collected over a 12-month period (June 9, 2020–June 8, 2021) from the Omtanke2020 Study including 27,950 adults in Sweden. Participants were volunteers or actively recruited through existing cohorts and, after providing informed consent, responded to online questionnaires on socio-demographics, mental and physical health, as well as COVID-19 infection and impact. Poisson regression was fitted to assess the relative risk of demonstrating high level symptoms of depression, anxiety, and COVID-19 related distress. Result: The proportion of persons with high level of symptoms was 15.6 %, 9.5 % and 24.5 % for depression, anxiety, and COVID-19 specific post-traumatic stress disorder (PTSD), respectively. Overall, 43.4 % of the participants had significant, clinically relevant symptoms for at least one of the three mental health outcomes and 7.3 % had significant symptoms for all three outcomes. We also observed differences in the prevalence of these outcomes across strata of sex, age, recruitment type, COVID-19 status, region, and seasonality. Conclusion: While the proportion of persons with high mental health burden remains higher than the ones reported in pre-pandemic publications, our estimates are lower than previously reported levels of depression, anxiety, and PTSD during the pandemic in Sweden and elsewhere.Peer reviewe

Is breast cancer prognosis inherited?

Introduction: A genetic component is well established in the etiology of breast cancer. It is not well known, however, whether genetic traits also influence prognostic features of the malignant phenotype. Methods: We carried out a population-based cohort study in Sweden based on the nationwide Multi-Generation Register. Among all women with breast cancer diagnosed from 1961 to 2001, 2,787 mother-daughter pairs and 831 sister pairs with breast cancer were identified; we achieved complete follow-up and classified 5-year breast cancer-specific prognosis among proband (mother or oldest sister) into tertiles as poor, intermediary, or good. We used Kaplan-Meier estimates of survival proportions and Cox models to calculate relative risks of dying from breast cancer within 5 years depending on the proband's outcome. Results: The 5-year survival proportion among daughters whose mothers died within 5 years was 87% compared to 91% if the mother was alive (p = 0.03). Among sisters, the corresponding proportions were 70% and 88%, respectively (p = 0.001). After adjustment for potential confounders, daughters and sisters of a proband with poor prognosis had a 60% higher 5-year breast cancer mortality compared to those of a proband with good prognosis (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.2 to 2.2; p for trend 0.002). This association was slightly stronger among sisters (HR, 1.8; 95% CI, 1.0 to 3.4) than among daughters (HR, 1.6; 95% CI, 1.1 to 2.3). Conclusion: Breast cancer prognosis of a woman predicts the survival in her first-degree relatives with breast cancer. Our novel findings suggest that breast cancer prognosis might be inherited

Background risk of breast cancer and the association between physical activity and mammographic density

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Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology

A genome-wide association scan on estrogen receptor-negative breast cancer

Introduction: Breast cancer is a heterogeneous disease and may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells. ER status of breast cancer is important clinically, and is used both as a prognostic indicator and treatment predictor. In this study, we focused on identifying genetic markers associated with ER-negative breast cancer risk.Methods: We conducted a genome-wide association analysis of 285,984 single nucleotide polymorphisms (SNPs) genotyped in 617 ER-negative breast cancer cases and 4,583 controls. We also conducted a genome-wide pathway analysis on the discovery dataset using permutation-based tests on pre-defined pathways. The extent of shared polygenic variation between ER-negative and ER-positive breast cancers was assessed by relating risk scores, derived using ER-positive breast cancer samples, to disease state in independent, ER-negative breast cancer cases.Results: Association with ER-negative breast cancer was not validated for any of the five most strongly associated SNPs followed up in independent studies (1,011 ER-negative breast cancer cases, 7,604 controls). However, an excess of small P-values for SNPs with known regulatory functions in cancer-related pathways was found (global P = 0.052). We found no evidence to suggest that ER-negative breast cancer share

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors