Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
- MeSH
- Asijci * genetika MeSH
- běloši * genetika MeSH
- celogenomová asociační studie * MeSH
- genetická predispozice k nemoci * MeSH
- jednonukleotidový polymorfismus * MeSH
- kolorektální nádory * genetika MeSH
- lidé MeSH
- lokus kvantitativního znaku * MeSH
- mapování chromozomů MeSH
- sekvenování exomu MeSH
- studie případů a kontrol MeSH
- transkriptom MeSH
- východní Asiaté MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.
Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
- MeSH
- celogenomová asociační studie MeSH
- Evropané * genetika MeSH
- genetická predispozice k nemoci MeSH
- jednonukleotidový polymorfismus genetika MeSH
- kolorektální nádory * genetika MeSH
- lidé MeSH
- multiomika MeSH
- východní Asiaté * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Cancer research is a crucial pillar for countries to deliver more affordable, higher quality, and more equitable cancer care. Patients treated in research-active hospitals have better outcomes than patients who are not treated in these settings. However, cancer in Europe is at a crossroads. Cancer was already a leading cause of premature death before the COVID-19 pandemic, and the disastrous effects of the pandemic on early diagnosis and treatment will probably set back cancer outcomes in Europe by almost a decade. Recognising the pivotal importance of research not just to mitigate the pandemic today, but to build better European cancer services and systems for patients tomorrow, the Lancet Oncology European Groundshot Commission on cancer research brings together a wide range of experts, together with detailed new data on cancer research activity across Europe during the past 12 years. We have deployed this knowledge to help inform Europe's Beating Cancer Plan and the EU Cancer Mission, and to set out an evidence-driven, patient-centred cancer research roadmap for Europe. The high-resolution cancer research data we have generated show current activities, captured through different metrics, including by region, disease burden, research domain, and effect on outcomes. We have also included granular data on research collaboration, gender of researchers, and research funding. The inclusion of granular data has facilitated the identification of areas that are perhaps overemphasised in current cancer research in Europe, while also highlighting domains that are underserved. Our detailed data emphasise the need for more information-driven and data-driven cancer research strategies and planning going forward. A particular focus must be on central and eastern Europe, because our findings emphasise the widening gap in cancer research activity, and capacity and outcomes, compared with the rest of Europe. Citizens and patients, no matter where they are, must benefit from advances in cancer research. This Commission also highlights that the narrow focus on discovery science and biopharmaceutical research in Europe needs to be widened to include such areas as prevention and early diagnosis; treatment modalities such as radiotherapy and surgery; and a larger concentration on developing a research and innovation strategy for the 20 million Europeans living beyond a cancer diagnosis. Our data highlight the important role of comprehensive cancer centres in driving the European cancer research agenda. Crucial to a functioning cancer research strategy and its translation into patient benefit is the need for a greater emphasis on health policy and systems research, including implementation science, so that the innovative technological outputs from cancer research have a clear pathway to delivery. This European cancer research Commission has identified 12 key recommendations within a call to action to reimagine cancer research and its implementation in Europe. We hope this call to action will help to achieve our ambitious 70:35 target: 70% average 10-year survival for all European cancer patients by 2035.
- MeSH
- COVID-19 * epidemiologie MeSH
- lidé MeSH
- nádory * diagnóza epidemiologie terapie MeSH
- pandemie MeSH
- výzkum zdravotnických služeb MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Geografické názvy
- Evropa MeSH
- východní Evropa MeSH
CONTEXT: The chemo-free immunotherapy tafasitamab + lenalidomide (LEN), has received accelerated approval in the United States (2020) and conditional marketing authorization in Europe and Canada (2021) for treatment of relapsed/refractory diffuse large cell lymphoma (DLBCL), in patients ineligible for autologous stem cell transplant. The primary analysis of First-MIND (NCT04134936) demonstrated that adding tafasitamab + LEN does not impair dosing and scheduling of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), and toxicities were similar to those expected with R-CHOP alone (ASH 2021; #3556). OBJECTIVE: frontMIND (NCT04824092) will investigate the efficacy and safety of R-CHOP + tafasitamab + LEN versus R-CHOP alone in previously untreated patients with high-intermediate and high-risk DLBCL. DESIGN: A Phase III, multicenter, randomized, double-blind, placebo-controlled study. SETTING: Approximately 350 centers from the Americas, Europe, and the Asia-Pacific region. PATIENTS: Eligible patients (n=880) will be aged 18-80 years with previously untreated local biopsy-proven, CD20-positive DLBCL, International Prognostic Index (IPI) score 3-5 (age-adjusted IPI 2-3 if ≤60 years), and ECOG performance score 0-2. Patients with transformed lymphoma are excluded. INTERVENTIONS: Patients will be randomized 1:1 to receive six 21-day cycles of either R-CHOP + tafasitamab (12 mg/kg intravenously, Days 1, 8, and 15) + LEN (25 mg orally, Days 1-10) or R-CHOP + tafasitamab + LEN placebos. MAIN OUTCOME MEASURES: The primary endpoint is investigator-assessed progression-free survival; secondary endpoints include event-free survival, overall survival, and safety. Minimal residual disease parameters will also be investigated. RESULTS: Results for this study are not yet available. CONCLUSIONS: There remains a high unmet need to improve treatment options for newly diagnosed patients with high-intermediate and high-risk DLBCL. The combination of tafasitamab + LEN + R-CHOP may have synergistic potential. Preliminary data from the First-MIND study suggest that tafasitamab ± LEN + R-CHOP may be tolerable in patients with treatment-naïve DLBCL. frontMIND will provide further evaluation of clinical benefits and safety in patients with newly diagnosed high-intermediate and high-risk DLBCL. The study is funded by MorphoSys AG and conducted with the scientific support of members of the Fondazione Italiana Linfomi and the German Lymphoma Alliance.
- MeSH
- cyklofosfamid farmakologie terapeutické užití MeSH
- difúzní velkobuněčný B-lymfom * diagnóza farmakoterapie MeSH
- doxorubicin škodlivé účinky MeSH
- dvojitá slepá metoda MeSH
- humanizované monoklonální protilátky MeSH
- lenalidomid farmakologie terapeutické užití MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- myší monoklonální protilátky terapeutické užití MeSH
- nehodgkinský lymfom * farmakoterapie MeSH
- prednison farmakologie terapeutické užití MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky MeSH
- rituximab farmakologie terapeutické užití MeSH
- vinkristin škodlivé účinky MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
This study's focus is the association of end-of-therapy (EOT) PET results with progression-free (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma receiving first-line chemoimmunotherapy. We develop a Bayesian hierarchical model for predicting PFS and OS from EOT PET-complete response (PET-CR) using a literature-based meta-analysis of 20 treatment arms and a substudy of 4 treatment arms in 3 clinical trials for which we have patient-level data. The PET-CR rate in our substudy was 72%. The modeled estimates for hazard ratio (PET-CR/non-PET-CR) were 0.13 for PFS (95% CI 0.10, 0.16) and 0.10 for OS (CI 0.07, 0.12). Hazard ratios varied little by patient subtype and were confirmed by the overall meta-analysis. We link these findings to designing future clinical trials and show how our model can be used in adapting the sample size of a trial to accumulating results regarding treatment benefits on PET-CR and a survival endpoint.
- MeSH
- Bayesova věta MeSH
- biologické markery analýza MeSH
- difúzní velkobuněčný B-lymfom * diagnostické zobrazování farmakoterapie MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- přežití po terapii bez příznaků nemoci MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
PURPOSE: Triple-negative breast cancer (TNBC) is considered aggressive, and therefore, virtually all young patients with TNBC receive (neo)adjuvant chemotherapy. Increased stromal tumor-infiltrating lymphocytes (sTILs) have been associated with a favorable prognosis in TNBC. However, whether this association holds for patients who are node-negative (N0), young (< 40 years), and chemotherapy-naïve, and thus can be used for chemotherapy de-escalation strategies, is unknown. METHODS: We selected all patients with N0 TNBC diagnosed between 1989 and 2000 from a Dutch population-based registry. Patients were age < 40 years at diagnosis and had not received (neo)adjuvant systemic therapy, as was standard practice at the time. Formalin-fixed paraffin-embedded blocks were retrieved (PALGA: Dutch Pathology Registry), and a pathology review including sTILs was performed. Patients were categorized according to sTILs (< 30%, 30%-75%, and ≥ 75%). Multivariable Cox regression was performed for overall survival, with or without sTILs as a covariate. Cumulative incidence of distant metastasis or death was analyzed in a competing risk model, with second primary tumors as competing risk. RESULTS: sTILs were scored for 441 patients. High sTILs (≥ 75%; 21%) translated into an excellent prognosis with a 15-year cumulative incidence of a distant metastasis or death of only 2.1% (95% CI, 0 to 5.0), whereas low sTILs (< 30%; 52%) had an unfavorable prognosis with a 15-year cumulative incidence of a distant metastasis or death of 38.4% (32.1 to 44.6). In addition, every 10% increment of sTILs decreased the risk of death by 19% (adjusted hazard ratio: 0.81; 95% CI, 0.76 to 0.87), which are an independent predictor adding prognostic information to standard clinicopathologic variables (χ2 = 46.7, P < .001). CONCLUSION: Chemotherapy-naïve, young patients with N0 TNBC with high sTILs (≥ 75%) have an excellent long-term prognosis. Therefore, sTILs should be considered for prospective clinical trials investigating (neo)adjuvant chemotherapy de-escalation strategies.
- MeSH
- adjuvantní chemoterapie MeSH
- dospělí MeSH
- lidé MeSH
- nádorové biomarkery MeSH
- neoadjuvantní terapie MeSH
- prognóza MeSH
- prospektivní studie MeSH
- triple-negativní karcinom prsu * farmakoterapie MeSH
- tumor infiltrující lymfocyty MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
