BACKGROUND:There is large variation in case-fatality rates of breast cancer in young women across the world. The objective of this study was to estimate the ten-year overall survival of women diagnosed with breast cancer before age 40 in six countries, by clinical presentation and by treatments received. METHODS:Data were supplied by seven centers in six countries, including the USA, Canada, Poland, Iceland, Iran and Thailand, totaling 36,861 women diagnosed with breast cancer before age 40, from 1977 to 2020. American patients from the SEER registry were sub-divided into (Non-Hispanic) White and Black. The following factors were compared across countries: year of diagnosis, tumor size, lymph node status, estrogen receptor (ER) status, use of chemotherapy, use of tamoxifen and use of radiotherapy. The Kaplan-Meier method was used to estimate ten-year overall survival for patients in each center. Cross-center comparisons are provided. The Cox Proportional Hazards model was used to estimate the impacts of the various factors on death for each center separately and for all centers combined, for all patients and for patients with stage I breast cancer. For these comparisons, SEER white women were considered the reference group. RESULTS:The mean age of diagnosis was 35.4 years. The percentage of patients with node-positive breast cancer ranged from 48.5% in Poland to 53.4% in Iceland. Mean tumor size ranged from 2.1 cm in Poland to 3.5 cm in Iran. The percent of patients with ER-negative breast cancer ranged from 34.0% in USA White women to 47.4% in Canada. The use of chemotherapy ranged from 65.4% in Thailand to 78.8% in Poland. Ten-year survival rates ranged from 52.5% (95%CI: 50.4%-54.7%) in Thailand to 77.9% (95%CI: 75.5%-80.3%) in Poland. A two-fold variation in case-fatality across centers persisted after adjusting for year of diagnosis, stage, tumor features and treatment. The difference in case-fatality across countries was greatest for patients with stage I breast cancer (four-fold variation). CONCLUSIONS:There is a wide disparity around the world in the long-term survival of women diagnosed with breast cancer before age 40, which cannot be accounted for by differences in screening, tumor stage at presentation or other tumor features. It is possible that differences in survival are due to inherent ethnic differences and/or differences in cancer management, but more research is required.

BACKGROUND:TP53 mutations are among the most frequent genetic alterations in breast cancer and are strongly associated with aggressive tumor features and poor outcome. Although TP53 mutations occur across all major breast cancer subtypes, their prognostic significance appears to vary according to estrogen receptor (ER) status and remains incompletely defined. METHODS:Breast cancer-specific survival (BCSS) was analyzed in a population-based Icelandic cohort of 1201 patients diagnosed between 1970 and 2003. TP53 mutation status was determined using Sanger sequencing or next-generation sequencing and clinical data were collected from medical records. BCSS was analyzed using Kaplan-Meier methods and multivariable Cox regression models with follow-up through 2021. RESULTS:TP53 mutations were associated with significantly poorer BCSS, with the adverse prognostic effect confined to ER-positive disease. In multivariable analyses, ER-positive tumors harboring TP53 mutations showed a markedly increased risk of breast cancer-specific death (HR 2.68, 95% CI 1.77-4.06), whereas no independent association was observed in ER-negative tumors, with a corresponding estimate of 1.00 (95% CI 0.59 - 1.71). Among ER-positive tumors, TP53 mutation was independently associated with poorer BCSS in Luminal A disease (HR 4.99, 95% CI 1.64-15.17), while no significant association was observed in Luminal B tumors. CONCLUSION:TP53 mutation is a strong and independent predictor of poor BCSS in ER-positive cases especially in Luminal A tumors. These findings identify ER-positive tumors with TP53 mutations as a unique high-risk subgroup, highlighting the importance of TP53 status for prognostic stratification in breast cancer.

BACKGROUND AND PURPOSE:Organised mammography screening reduces breast cancer mortality by 30-40% in women aged 50-69. Despite limited evidence for women aged 40-49, screening guidelines are trending toward younger ages. Iceland has offered biennial screening to women aged 40-69 since 1987. This study compares screening quality indicators and tumour characteristics between women aged 40-49 and 50-69 from 1990 to 2020. Patient/material and methods: Screening-related data were obtained from the Icelandic Breast Cancer Screening Program, and breast cancer diagnoses and tumour characteristics were sourced from the Icelandic Cancer Registry. RESULTS:In total, 84,677 women aged 40-69 years attended 455,532 organised screening sessions in Iceland over a 30-year period. Women aged 40-49 years demonstrated higher recall rates (4.9% vs. 3.5%) and lower participation rates (60.7% vs. 61.5%), lower breast cancer detection rates (2.1 vs. 6.0/1,000), and lower episode sensitivity (54.8% vs. 70.5%), compared to those aged 50-69 years. Among screen-detected cases, women aged 40-49 years exhibited a higher proportion of tumours larger than 20 mm (29.7% vs. 21.7%), more lymph node positivity (41.2% vs. 28.2%) and higher human epidermal growth factor receptor 2 (HER2) positivity (18.6% vs. 11.8%), compared to those aged 50-69 years. INTERPRETATION:The disparity in breast cancer screening performances between the age groups may reflect unmodifiable factors in younger women. The presence of advanced tumour characteristics among women aged 40-49 years who attended screening indicates the importance of early detection for improving prognosis.

INTRODUCTION:A large increase in new cancer cases is predicted worldwide, due to population growth, ageing and increased cancer risk. The age distribution of the Icelandic population is different from the other Nordic countries. The purpose of this study was to predict the number of new cancer cases in Iceland and other Nordic countries, and cancer survivors in Iceland, up to the year 2040. MATERIALS AND METHODS:Information on cancer diagnoses was retrieved from The Icelandic Cancer Registry and information on population projections from Statistics Iceland. Well known methods for population projection were used to predict the number of new cancer cases in 2040, but adjusted to consider Icelandic circumstances. It is also based on more recent data than is accessible elsewhere. Three different methods were used to estimate the number of survivors in 2040 and are presented here for the first time. RESULTS:In 2040 the predicted yearly average number of new cancer cases in Iceland will be up to 2,903 [95% CI 2.841-2.956], a 57% increase compared with 2022. The increase is higher in Iceland than in other Nordic countries (Norway 41%, Sweden 24%, Denmark 23%, Finland 21%). In 2022, the number of cancer survivors was around 17,500 and is predicted to be between 24,500 and 31,000 in 2040. CONCLUSION:The main reason for the predicted increase of cancer cases and survivors is population trends, especially the ageing of the population. This expected increase in the number of cancer patients and improved survival will increase the demand for healthcare.

Abstract Purpose Almost 200,000 tongue cancers were diagnosed worldwide in 2020. The aim of this study was to describe occupational risk variation in this malignancy. Methods The data are based on the Nordic Occupational Cancer (NOCCA) study containing 14.9 million people from the Nordic countries with 9020 tongue cancers diagnosed during 1961–2005. The standardized incidence ratio (SIR) of tongue cancer in each occupational category was calculated using national incidence rates as the reference. Results Among men, the incidence was statistically significantly elevated in waiters (SIR 4.36, 95% confidence interval (CI) 3.13-–5.92), beverage workers (SIR 3.42, 95% CI 2.02-5.40), cooks and stewards (SIR 2.55, 95% CI 1.82-3.48), seamen (SIR 1.66, 95% CI 1.36-2.00), journalists (SIR 1.85, 95% CI 1.18-2.75), artistic workers (SIR 2.05, 95% CI 1.54-2.66), hairdressers (SIR 2.17, 95% CI 1.39-3.22), and economically inactive persons (SIR 1.57, 95% CI 1.42-1.73). Among women, the SIR was statistically significantly elevated only in waitresses (SIR 1.39, 95% CI 1.05-1.81). Statistically significant SIRs ≤ 0.63 were observed in male farmers, gardeners, forestry workers and teachers, and in female launderers. Conclusions These findings may be related to consumption of alcohol and tobacco, but the effect of carcinogenic exposure from work cannot be excluded.

INTRODUCTION:The Icelandic Cancer Registry (ICR) was founded seventy years ago by the Icelandic Cancer Society. In 2007 the ICR became one of the health registers of the Directorate of Health. In this paper we present cancer incidence, mortality, and survival in Iceland over 70 years.MATERIAL AND METHODS:The ICR receives information on cancer diagnoses from histopathological laboratories, the Hospital Discharge Registry and the Cause of Death Registry. Iceland participates in the Nordic cancer database NORDCAN. Because of the small population size, random variation in numbers is very prominent. Therefore, data from ICR are published as five-year averages.RESULTS:For all malignancies combined, age-standardized incidence (ASI) in men rose steadily until around 15 years ago when a decline started. This is in line with prostate- and lung cancer incidence trends. In women, the ASI was lower than in men, but it is still on the rise despite declining lung cancer incidence. ASI for breast cancer, the most common cancer in women, is increasing. Simultaneously, cancer mortality for both sexes has declined in recent years and cancer survival is improving.CONCLUSIONS:Population-based cancer registration for over 70 years makes it possible to monitor the epidemiology of cancer in Iceland and compare with other countries. The changes in trends in ASI are in line with changes of cancer risk factors and diagnostic policy. The decline in cancer mortality and improvement in survival reflects advances in cancer treatment as well as effects of early detection and prevention.

Age at menopause (AOM) has a substantial impact on fertility and disease risk. While many loci with variants that associate with AOM have been identified through genome-wide association studies (GWAS) under an additive model, other genetic models are rarely considered1. Here through GWAS meta-analysis under the recessive model of 174,329 postmenopausal women from Iceland, Denmark, the United Kingdom (UK; UK Biobank) and Norway, we study low-frequency variants with a large effect on AOM. We discovered that women homozygous for the stop-gain variant rs117316434 (A) in CCDC201 (p.(Arg162Ter), minor allele frequency ~1%) reached menopause 9 years earlier than other women (P = 1.3 × 10−15). The genotype is present in one in 10,000 northern European women and leads to primary ovarian insufficiency in close to half of them. Consequently, homozygotes have fewer children, and the age at last childbirth is 5 years earlier (P = 3.8 × 10−5). The CCDC201 gene was only found in humans in 2022 and is highly expressed in oocytes. Homozygosity for CCDC201 loss-of-function has a substantial impact on female reproductive health, and homozygotes would benefit from reproductive counseling and treatment for symptoms of early menopause. Genome-wide analysis of age at menopause under a recessive model identifies a stop-gain variant in CCDC201 associated with primary ovarian insufficiency. This homozygous genotype is present in 1 in 10,000 women of northern European ancestry.

Two-thirds of all human conceptions are lost, in most cases before clinical detection. The lack of detailed understanding of the causes of pregnancy losses constrains focused counseling for future pregnancies. We have previously shown that a missense variant in synaptonemal complex central element protein 2 ( SYCE2 ), in a key residue for the assembly of the synaptonemal complex backbone, associates with recombination traits. Here we show that it also increases risk of pregnancy loss in a genome-wide association analysis on 114,761 women with reported pregnancy loss. We further show that the variant associates with more random placement of crossovers and lower recombination rate in longer chromosomes but higher in the shorter ones. These results support the hypothesis that some pregnancy losses are due to failures in recombination. They further demonstrate that variants with a substantial effect on the quality of recombination can be maintained in the population.

Supplementary Tables 1-3. Supplemental Table 1. Prostate Cancer risk by combined recreational and occupational physical activity at baseline Supplemental Table 2. Prostate cancer risk by recreational physical activity (RPA), stratified by level of occupational physical activity (OPA) Supplemental table 3. Prostate cancer risk by current recreational physical activity, stratified by level of occupational physical activity

Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. Using whole-genome sequencing of 45,510 Icelandic and 130,709 UK Biobank participants combined with a mutational barcode method, we identified 16,306 people with CH. Prevalence approaches 50% in elderly participants. Smoking demonstrates a dosage-dependent impact on risk of CH. CH associates with several smoking-related diseases. Contrary to published claims, we find no evidence that CH is associated with cardiovascular disease. We provide evidence that CH is driven by genes that are commonly mutated in myeloid neoplasia and implicate several new driver genes. The presence and nature of a driver mutation alters the risk profile for hematological disorders. Nevertheless, most CH cases have no known driver mutations. A CH genome-wide association study identified 25 loci, including 19 not implicated previously in CH. Splicing, protein and expression quantitative trait loci were identified for CD164 and TCL1A .

Estrogen receptor-positive (ER+) breast cancer generally confers a more favorable prognosis than ER-negative cancer, however, a different picture is emerging for BRCA2 mutation carriers and young patients. We used nationwide data from population-based registries to study prognostic effects in those two groups. Of all 2817 eligible women diagnosed with breast cancer in Iceland during 1980-2004, 85% had been tested for the Icelandic 999del5 BRCA2 (c.771_775delTCAAA) founder pathogenic variant. We compared breast cancer-specific survival, effects of ER status, other clinical parameters, and treatment, between three mutually exclusive groups: BRCA2-carriers, non-carriers diagnosed 40 years or younger, and older non-carriers. Prevalence of the BRCA2 mutation among tested patients <=40 years of age was 21.0%, but it was 5.4% among women diagnosed >40 years of age. For ER+ cancer, breast cancer-specific 15-year survival was 49.7%, 55.2%, and 74.7%, among BRCA2-carriers, young and older non-carriers, respectively, whereas for ER-negative cancer, survival was similar (64.0-69.3%) for all three groups. Neither BRCA2 carriers nor young non-carriers did tumor grade 3 predict worse survival than did tumor grade 1. The adverse outcome for the young cases cannot be explained by BRCA2 mutations, as carriers were excluded from the group. Those two clinically important patient groups need special attention with respect to treatment choices, in particular, if diagnosed with ER+ tumors. It is thus advisable to have knowledge of BRCA2 status when treatment decisions are made. Finally, it is important to understand the biological basis for the specific nature of ER+ tumors in young women and BRCA2 carriers.

INTRODUCTION:Worldwide, the health-promoting effects of breastfeeding on children and their mothers are indisputable. The frequency and duration of breastfeeding varies greatly internationally but studies on prevalence and influencing factors of breastfeeding in Iceland are scanty and the published ones deal with small groups. The aim of this research is to describe the epidemiology of breastfeeding duration and its influencing factors in Iceland among a large cohort in a whole population over almost one century.MATERIAL AND METHODS:This is a historical cohort study, using data from The Cancer Detection Clinic Cohort of The Icelandic Cancer Society, collected retrospectively by questionnaires during the years 1964-2008. The data consisted of mothers´ reported information on breastfeeding of their 81,889 children, 36,537 first-borns and 45,352 younger siblings. The frequency and duration of breastfeeding was calculated and the effects of the following exposure variables were assessed: Maternal age, BMI (N=4950, data collected 1979-2008) and smoking (N=32.087, data collected 1995-2008), the child's year of birth and its order in the sibling group.RESULTS:The children were born in the period of 1917-2008. In the late 1970s, the average duration of breastfeeding began to increase, in all age groups of mothers, increasing rapidly from 3 months to 7-8 months. At about the same time, the breastfeeding duration increased depending on the birth order of the children, younger children were breastfed for longer than their older siblings. Women with normal weight (BMI 18.5 to 24.9) breastfed their babies the longest, while obese women breastfed the shortest. Women with any history of smoking reported shorter duration of breastfeeding than women who had never smoked.CONCLUSION:The increase in the average duration of breastfeeding in Iceland a few decades ago is in accordance with the information in the World Health Organization's database from European countries 1975-2000, where the Nordic countries and most Northern European countries promoted breastfeeding at a similar time. High BMI and maternal smoking are important variables when studying breastfeeding and this study indicates their negative association with the duration of breastfeeding.

Supplementary Methods, Supplementary Tables 1-18 and Supplementary Figures 1-5.

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.

INTRODUCTION In the coming years, an increase in the number of cancer cases can be expected in Iceland. It is important to gain more insight into the experiences of the diagnostic- and treatment phase among those diagnosed with cancer to improve quality of life and life expectancy. METHODS The study included 4575 individuals diagnosed with cancer between 2015 and 2019 in Iceland, 18 years or older at the time. Participants answered an on-line questionnaire once between 2020 and 2021. RESULTS A total of 1672 (37%) individuals responded to the questionnaire. The mean age at diagnosis was 59 years (±12). The majority of participants were informed on their cancer diagnosis during a doctor's appointment (67%), but a quarter (25%) received the information by telephone. A total of 77% of participants were satisfied with the diagnostic process, thereof relatively fewer women than men (73% vs. 83%) (p<0,001). Fewer of those who received the cancer diagnosis by telephone were pleased with the diagnostic process (62%) compared with those receiving information during a doctor's appointment (85%) (p<0,001). More women (58%) than men (33%) expressed the need for support regarding mental well-being from healthcare professionals during the diagnostic process (p<0.001). In 2015, 36% of participants started treatment more than month after diagnosis, compared with 51% in 2019. The need for various specific resources during treatment, e.g. physiotherapy, psychological services or nutritional counseling were regularly assessed among 20-30% of participants. CONCLUSION A quarter of respondents diagnosed with cancer received information about the diagnosis over the phone instead of an interview. There is a suggestion that the time from diagnosis to the start of cancer treatment is increasing. It is necessary to assess whether it is possible to support individuals with cancer better during the diagnostic- and treatment phase based on their individual needs.

To study whether dietary patterns in adolescence are associated with risk of colorectal cancer (CRC). Food frequency data were obtained from the AGES-Reykjavik study, conducted between 2002 and 2006, which included 5,078 (58% women) participants with mean age of 77 (± 5.8) years. Principal component analysis was used to identify dietary patterns. Participants were followed through linkage to the Icelandic Cancer Registry. Multivariable Cox models were used to calculate hazard ratios (HR) of CRC and 95% confidence interval (CI) by dietary patterns. During the follow-up period (mean 8.2 years), 136 participants (75 women and 61 men) were diagnosed with CRC. The main dietary pattern in adolescence was characterized by high intake of traditional food items consumed in the earlier half of the twentieth century, namely, salted or smoked meat and fish, milk, offal, rye bread, and oatmeal. Compared to the lowest tertile, the middle tertile of this pattern was associated with increased risk of CRC (HR 1.63, 95% CI 1.04–2.57), while the highest tertile was not statistically associated with CRC (HR 1.48, 95% CI 0.93–2.37), except among women (HR 2.06, 95% CI 1.11–3.84). These data suggest that strong adherence to a traditional Icelandic diet in adolescence might increase the risk of CRC, particularly among women. More research is need on the association between food items and dietary patterns of relevance to CRC at different points in the life cycle.

Brief Summary: This population-based study retrospectively compared hospital admissions for skeletal issues in a group of 26,334 cancer survivors (CCS) diagnosed before 20 years of age and 127,531 matched controls. 1,987 CCS vs 8,986 controls had at least one skeletal adverse event. Total hospitalization rate ratio (RR) for skeletal adverse events was higher in CCS than controls (RR 1.35).

Supplemental Digital Content is available in the text Objective: To identify risk factors for suicide after bariatric surgery. Summary background data: Bariatric surgery reduces obesity-related mortality. However, it is for unclear reasons is associated with an increased risk of suicide. Methods: This population-based cohort study included patients having undergone bariatric surgery in 1982 to 2012 in any of the 5 Nordic countries, with follow-up through 2012. Eleven potential risk factors of suicide (sex, age, comorbidity, surgery type, surgical approach, calendar year of surgery, history of depression or anxiety, psychosis, schizophrenia, mania, or bipolar disorder, personality disorder, substance use, and number of previously documented psychiatric diagnoses) were analyzed using Cox regression. Results: Of 49,977 bariatric surgery patients, 98 (0.2%) committed suicide during follow-up. Women had a decreased risk of suicide compared to men (hazard ratio [HR] = 0.48, 95% confidence interval [CI] 0.33–0.77), although age and comorbidity did not influence this risk. Compared to gastric bypass, other types of bariatric surgery had lower risk of suicide (HR = 0.44, 95%CI 0.27–0.99). There was no difference in suicide risk between laparoscopic and open surgical approach. A history of depression or anxiety (HR = 6.87, 95%CI 3.97–11.90); mania, bipolar disorder, psychosis, or schizophrenia (HR = 2.70, 95%CI 1.14–6.37); and substance use (HR = 2.28, 95%CI 1.08–4.80), increased the risk of suicide. More of the above psychiatric diagnoses increased the risk of suicide (HR = 22.59, 95%CI 12.96–39.38 for ≥2 compared to 0 diagnoses). Conclusions: Although the risk of suicide is low, psychiatric disorders, male sex, and gastric bypass procedure seem to increase the risk of suicide after bariatric surgery, indicating a role for tailored preoperative psychiatric evaluation and postoperative surveillance.

Growth rate is regulated by hormonal pathways that might affect early cancer development. We explored the association between rate of growth in height from ages 8 to 13 years (childhood) and from age 13 to attainment of adult height (adolescence), as measured at study entry, and the risk of breast or prostate cancer. Participants were 2,037 Icelanders born during 1915-1935, who took part in the Reykjavik Study, established in 1967. Height measurements were obtained from school records and at study entry. We used multivariable Cox regression models to calculate hazard ratios with 95% confidence intervals of breast and prostate cancer by rates of growth in tertiles. During a mean follow-up of 66 years (women) and 64 years (men), 117 women were diagnosed with breast cancer and 118 men with prostate cancer (45 with advanced disease). Women in the highest growth-rate tertile in adolescence had a higher risk of breast cancer (hazard ratio = 2.4, 95% confidence interval: 1.3, 4.3) compared with women in the lowest tertile. A suggestive inverse association was observed for highest adolescent growth rate in men and advanced prostate cancer: hazard ratio = 0.4, 95% confidence interval: 0.2, 1.0. Rapid growth, particularly in adolescence may affect cancer risk later in life.