Prognostic genome and transcriptome signatures in colorectal cancers.

Colorectal cancer is caused by a sequence of somatic genomic alterations affecting driver genes in core cancer pathways1. Here, to understand the functional and prognostic impact of cancer-causing somatic mutations, we analysed the whole genomes and transcriptomes of 1,063 primary colorectal cancers in a population-based cohort with long-term follow-up. From the 96 mutated driver genes, 9 were not previously implicated in colorectal cancer and 24 had not been linked to any cancer. Two distinct patterns of pathway co-mutations were observed, timing analyses identified nine early and three late driver gene mutations, and several signatures of colorectal-cancer-specific mutational processes were identified. Mutations in WNT, EGFR and TGFß pathway genes, the mitochondrial CYB gene and 3 regulatory elements along with 21 copy-number variations and the COSMIC SBS44 signature correlated with survival. Gene expression classification yielded five prognostic subtypes with distinct molecular features, in part explained by underlying genomic alterations. Microsatellite-instable tumours divided into two classes with different levels of hypoxia and infiltration of immune and stromal cells. To our knowledge, this study constitutes the largest integrated genome and transcriptome analysis of colorectal cancer, and interlinks mutations, gene expression and patient outcomes. The identification of prognostic mutations and expression subtypes can guide future efforts to individualize colorectal cancer therapy.

Risk of Esophageal Adenocarcinoma After Helicobacter pylori Eradication Treatment in a Population-Based Multinational Cohort Study.

BACKGROUND & AIMS: Helicobacter pylori infection is associated with a decreased risk of esophageal adenocarcinoma, and the decreasing prevalence of such infection might contribute to the increasing incidence of this tumor. We examined the hypothesis that eradication treatment of H pylori increases the risk of esophageal adenocarcinoma. METHODS: This population-based multinational cohort, entitled "Nordic Helicobacter Pylori Eradication Project (NordHePEP)," included all adults (≥18 years) receiving H pylori eradication treatment from 1995-2018 in any of the 5 Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) with follow-up throughout 2019. Data came from national registers. We calculated standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) by dividing the cancer incidence in the exposed cohort by that of the entire Nordic background populations of the corresponding age, sex, calendar period, and country. Analyses were stratified by factors associated with esophageal adenocarcinoma (ie, education, comorbidity, gastroesophageal reflux, and certain medications). RESULTS: Among 661,987 participants who contributed 5,495,552 person-years after eradication treatment (median follow-up, 7.8 years; range, 1-24 years), 550 cases of esophageal adenocarcinoma developed. The overall SIR of esophageal adenocarcinoma was not increased (SIR = 0.89; 95% CI, 0.82-0.97). The SIR did not increase over time after eradication treatment, but rather decreased and was 0.73 (95% CI, 0.61-0.86) at 11-24 years after treatment. There were no major differences in the stratified analyses. The overall SIR of esophageal squamous cell carcinoma, calculated for comparison, showed no association (SIR = 0.99; 95% CI, 0.89-1.11). CONCLUSIONS: This absence on an increased risk of esophageal adenocarcinoma after eradication treatment of H pylori suggests eradication is safe from a cancer perspective.

Noninvasive detection of any-stage cancer using free glycosaminoglycans.

Cancer mortality is exacerbated by late-stage diagnosis. Liquid biopsies based on genomic biomarkers can noninvasively diagnose cancers. However, validation studies have reported ~10% sensitivity to detect stage I cancer in a screening population and specific types, such as brain or genitourinary tumors, remain undetectable. We investigated urine and plasma free glycosaminoglycan profiles (GAGomes) as tumor metabolism biomarkers for multi-cancer early detection (MCED) of 14 cancer types using 2,064 samples from 1,260 cancer or healthy subjects. We observed widespread cancer-specific changes in biofluidic GAGomes recapitulated in an in vivo cancer progression model. We developed three machine learning models based on urine (Nurine = 220 cancer vs. 360 healthy) and plasma (Nplasma = 517 vs. 425) GAGomes that can detect any cancer with an area under the receiver operating characteristic curve of 0.83-0.93 with up to 62% sensitivity to stage I disease at 95% specificity. Undetected patients had a 39 to 50% lower risk of death. GAGomes predicted the putative cancer location with 89% accuracy. In a validation study on a screening-like population requiring ≥ 99% specificity, combined GAGomes predicted any cancer type with poor prognosis within 18 months with 43% sensitivity (21% in stage I; N = 121 and 49 cases). Overall, GAGomes appeared to be powerful MCED metabolic biomarkers, potentially doubling the number of stage I cancers detectable using genomic biomarkers.

Omental metastases in patients with pseudomyxoma peritonei or colorectal peritoneal metastases - is routine omentectomy justified?

BACKGROUND: The greater omentum is routinely resected during cytoreductive surgery (CRS), but few studies have analyzed the rationale behind this. This study aimed to assess the prevalence of omental metastases (OM) and the correlation between macroscopically suspected and microscopically confirmed OM, in patients with pseudomyxoma peritonei (PMP) or colorectal peritoneal metastases (PM). METHOD: All patients without previous omentectomy, treated with initial CRS and hyperthermic intraperitoneal chemotherapy for PMP or colorectal PM, at Uppsala University Hospital in 2013-2021, were included. Macroscopic OM in surgical reports was compared with histopathological analyses. RESULTS: In all, 276 patients were included. In those with PMP, 112 (98%) underwent omentectomy and 67 (59%) had macroscopic suspicion of OM. In 5 (4%) patients, the surgeon was uncertain. Histopathology confirmed OM in 81 (72%). In patients with macroscopic suspicion, 96% had confirmed OM (positive predictive value, PPV). In patients with no suspicion, 24% had occult OM (negative predictive value, NPV = 76%). In patients with colorectal PM, 156 (96%) underwent omentectomy and 97 (60%) had macroscopic suspicion. For 5 (3%) patients, the surgeon was uncertain. OM was microscopically confirmed in 90 (58%). PPV was 85% and NPV was 89%. The presence of OM was a univariate risk factor for death in PMP (HR 3.62, 95%CI 1.08-12.1) and colorectal PM (HR 1.67, 95%CI 1.07-2.60), but not in multivariate analyses. CONCLUSION: OM was common and there was a high risk of missing occult OM in both PMP and colorectal PM. These results support the practice of routine omentectomy during CRS.

[Cancer registration in Iceland for 70 years - incidence, mortality and survival].

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.

[Prediction of cancer incidence and prevalence in Iceland up to the year 2040 - Icelandic Cancer Registry and Research Center].

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.

Cohort profile: Nordic Helicobacter Pylori eradication project (NordHePEP).

PURPOSE: This cohort description presents the Nordic Helicobacter Pylori Eradication Project (NordHePEP), a population-based cohort of patients having received eradication treatment for Helicobacter pylori (HP). The cohort is created with the main purpose of examining whether and to what extent HP eradication treatment influences the risk of gastrointestinal cancer. PARTICIPANTS: NordHePEP includes all adults (aged ≥18 years) having been prescribed and dispensed HP eradication treatment according to the nationwide complete drug registries in any of the five Nordic countries (Denmark, Finland, Iceland, Norway, or Sweden) between 1994 and 2020 (start and end year varies between countries). We have retrieved and merged individual-level data from multiple national registries, including drug, patient, cancer, population, and death registries. FINDINGS: The cohort includes 674,771 patients having received HP eradication treatment. During up to 23 years of follow-up, 59,292 (8.8%) participants were diagnosed with cancer (non-melanoma skin cancer excluded), whereof 15,496 (2.3%) in the gastrointestinal tract. FUTURE PLANS: We will analyse HP eradication treatment in relation to gastrointestinal cancer risk. Standardised incidence ratios will be calculated as the observed cancer incidence in the cohort divided by the expected cancer incidence, derived from the background population of the corresponding age, sex, and calendar year.

The impact of the COVID-19 pandemic on cancer diagnosis based on pathology notifications: A comparison across the Nordic countries during 2020.

The severity of the COVID-19 pandemic and subsequent mitigation strategies have varied across the Nordic countries. In a joint Nordic population-based effort, we compared patterns of new cancer cases and notifications between the Nordic countries during 2020. We used pathology notifications to cancer registries in Denmark, the Faroe Islands, Finland, Iceland, Norway and Sweden to determine monthly numbers of pathology notifications of malignant and in situ tumours from January to December 2020 compared to 2019 (2017-2019 for Iceland and the Faroe Islands). We compared new cancer cases per month based on unique individuals with pathology notifications. In April and May 2020, the numbers of new malignant cases declined in all Nordic countries, except the Faroe Islands, compared to previous year(s). The largest reduction was observed in Sweden (May: -31.2%, 95% CI -33.9, -28.3), followed by significant declines in Finland, Denmark and Norway, and a nonsignificant decline in Iceland. In Denmark, Norway, Sweden and Finland the reporting rates during the second half of 2020 rose to almost the same level as in 2019. However, in Sweden and Finland, the increase did not compensate for the spring decline (annual reduction -6.2% and -3.6%, respectively). Overall, similar patterns were observed for in situ tumours. The COVID-19 pandemic led to a decline in rates of new cancer cases in Sweden, Finland, Denmark and Norway, with the most pronounced reduction in Sweden. Possible explanations include the severity of the pandemic, temporary halting of screening activities and changes in healthcare seeking behaviour.

Age-specific survival trends and life-years lost in women with breast cancer 1990-2016: the NORDCAN survival studies.

BACKGROUND: A recent overview of cancer survival trends 1990-2016 in the Nordic countries reported continued improvements in age-standardized breast cancer survival among women. The aim was to estimate age-specific survival trends over calendar time, including life-years lost, to evaluate if improvements have benefited patients across all ages in the Nordic countries. METHODS: Data on breast cancers diagnosed 1990-2016 in Denmark, Finland, Iceland, Norway, and Sweden were obtained from the NORDCAN database. Age-standardized and age-specific relative survival (RS) was estimated using flexible parametric models, as was reference-adjusted crude probabilities of death and life-years lost. RESULTS: Age-standardized period estimates of 5-year RS in women diagnosed with breast cancer ranged from 87% to 90% and 10-year RS from 74% to 85%. Ten-year RS increased with 15-18 percentage points from 1990 to 2016, except in Sweden (+9 percentage points) which had the highest survival in 1990. The largest improvements were observed in Denmark, where a previous survival disadvantage diminished. Most recent 5-year crude probabilities of cancer death ranged from 9% (Finland, Sweden) to 12% (Denmark, Iceland), and life-years lost from 3.3 years (Finland) to 4.6 years (Denmark). Although survival improvements were consistent across different ages, women aged ≥70 years had the lowest RS in all countries. Period estimates of 5-year RS were 94-95% in age 55 years and 84-89% in age 75 years, while 10-year RS were 88-91% in age 55 years and 69-84% in age 75 years. Women aged 40 years lost on average 11.0-13.8 years, while women lost 3.8-6.0 years if aged 55 and 1.9-3.5 years if aged 75 years. CONCLUSIONS: Survival for Nordic women with breast cancer improved from 1990 to 2016 in all age groups, albeit with larger country variation among older women where survival was also lower. Women over 70 years of age have not had the same survival improvement as women of younger age.

[Liver surgeries in Iceland 2013-2017 - Comparison with Sweden in terms of quality registration].

INTRODUCTION: Cancers in the liver, bile duct system, gallbladder as well as metastases of the liver, have poor prognosis. Their treatment is comparable, with surgery being the most widespread, available curative treatment. Surgical treatment is anatomical or non-anatomical resection of the liver where the tumor and the adjacent liver tissue are removed. MATERIALS/METHODS: A list of patients diagnosed with cancer in the liver, bile duct system, gallbladder or metastases of the liver, during the time period 2013-2017, was obtained from the Icelandic Cancer Registry. Additional information was retrieved from medical records and entered into the electronic quality registration forms of Landspítalinn. A comparison was made between Sweden and Iceland. RESULTS: In total 108 patients were diagnosed with primary cancer of the liver, of which 24 (22%) underwent liver surgery. Of 264 diagnosed with liver metastases 38 (14%) underwent surgical treatment. A total of 63% of all reported cases were discussed at a multidisciplinary team meeting in Iceland but 93% in Sweden (p<0.0001). A sum of 29 patients (43%) developed complications within 30 days of surgery. Number of partial liver resections per 100.000 inhabitants were 2-8 in Iceland versus 4-13 in Sweden. The difference was even more apparent in patients with liver metastases. CONCLUSION: Liver surgeries performed in Iceland seem to be comparable to Sweden in terms of complications and post operative mortality. In Iceland, considerably fewer operations are performed per capita, especially on liver metastases which could be explained by the fact that fewer patients are discussed at multidisciplinary team meetings.