British Journal of Cancer最新文献

{"title":"A novel AI-based score for assessing the prognostic value of intra-epithelial lymphocytes in oral epithelial dysplasia","authors":"Adam J. Shephard, Hanya Mahmood, Shan E. Ahmed Raza, Syed Ali Khurram, Nasir M. Rajpoot","doi":"10.1038/s41416-024-02916-z","DOIUrl":"10.1038/s41416-024-02916-z","url":null,"abstract":"Oral epithelial dysplasia (OED) poses a significant clinical challenge due to its potential for malignant transformation and the lack of reliable prognostic markers. Current OED grading systems do not reliably predict transformation and suffer from considerable observer variability. Recent studies have highlighted that peri-epithelial lymphocytes may play an important role in OED malignant transformation, with indication that intra-epithelial lymphocytes (IELs) may also be important. We propose a novel artificial intelligence (AI) based IEL score from Haematoxylin and Eosin (H&E) stained Whole Slide Images (WSIs) of OED tissue slides. We determine the prognostic value of our IEL score on a digital dataset of 219 OED WSIs (acquired using three different scanners), compared to pathologist-led clinical grading. Our IEL scores demonstrated significant prognostic value (C-index = 0.67, p < 0.001) and were shown to improve both the binary/WHO grading systems in multivariate analyses (p < 0.001). Nuclear analyses confirmed the positive association between higher IEL scores, more severe OED and malignant transformation (p < 0.05). This underscores the potential importance of IELs, and by extension our IEL score, as prognostic indicators in OED. Further validation through prospective multi-centric studies is warranted to confirm the clinical utility of IELs.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 2","pages":"168-179"},"PeriodicalIF":6.4,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02916-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor budding and lymphovascular invasion as prognostic factors in p16-positive oropharyngeal squamous cell carcinomas","authors":"Fabian Stögbauer, Markus Wirth, Maren Lauterbach, Barbara Wollenberg, Benedikt Schmidl, Cosima C. Hoch, Iordanis Ourailidis, Jochen Hess, Markus Eckstein, Arndt Hartmann, Heinrich Iro, Antoniu-Oreste Gostian, Matthias Balk, Moritz Jesinghaus, Julika Ribbat-Idel, Verena-Wilbeth Sailer, Sven Perner, Karl-Ludwig Bruchhage, Markus Hoffmann, Lukas Lükewille, Christiane Maria Stuhlmann-Laeisz, Christoph Röcken, Carolin Mogler, Jan Budczies, Melanie Boxberg","doi":"10.1038/s41416-024-02912-3","DOIUrl":"10.1038/s41416-024-02912-3","url":null,"abstract":"We aimed to validate the prognostic significance of tumor budding (TB) in p16-positive oropharyngeal squamous cell carcinomas (OPSCC). We analyzed digitized H&E-stained slides from a multicenter cohort of five large university centers consisting of n = 275 cases of p16-positive OPSCC. We evaluated TB along with other histological parameters (morphology, tumor-stroma-ratio, lymphovascular invasion (LVI), perineural invasion) and calculated survival outcomes using both univariate and multivariate analyses. TB was identified as an independent prognostic parameter, with TB-high cases showing inferior outcomes in univariate (HR: 3.08, 95%-CI: 1.71–5.54) and multivariate analyses (HR: 4.03, 95%-CI: 1.65–9.83). Similarly, LVI remained an independent prognostic factor (HR: 3.00, 95%-CI: 1.22–7.38). A combined classification including TB and LVI stratified cases into low-, intermediate- and high-risk categories. We could not detect correlations between TB and the number of lymph node metastases or between TB and an extracapsular extension of lymph node metastases. In addition to LVI, we could identify TB as an independent prognostic factor in p16-positive OPSCC in this multicenter study cohort. Thus, evaluating TB along with LVI in a combined scheme for prognostication might help to establish a more personalized treatment regimen for patients with p16-positive OPSCC.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 2","pages":"212-221"},"PeriodicalIF":6.4,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02912-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATR inhibition potentiates FOLFIRINOX cytotoxic effect in models of pancreatic ductal adenocarcinoma by remodelling the tumour microenvironment","authors":"Marine Bruciamacchie, Véronique Garambois, Nadia Vie, Thomas Bessede, Henri-Alexandre Michaud, Laure-Agnès Chepeaux, Laurent Gros, Nathalie Bonnefoy, Mathilde Robin, Dorian Brager, Kevin Bigot, Alexandre Evrard, Philippe Pourquier, Jacques Colinge, Muriel Mathonnet, Ismahane Belhabib, Christine Jean, Corinne Bousquet, Pierre-Emmanuel Colombo, Marta Jarlier, Diégo Tosi, Céline Gongora, Christel Larbouret","doi":"10.1038/s41416-024-02904-3","DOIUrl":"10.1038/s41416-024-02904-3","url":null,"abstract":"In pancreatic ductal adenocarcinoma (PDAC), the dense stroma rich in cancer-associated fibroblasts (CAFs) and the immunosuppressive microenvironment confer resistance to treatments. To overcome such resistance, we tested the combination of FOLFIRINOX (DNA damage-inducing chemotherapy drugs) with VE-822 (an ataxia-telangiectasia and RAD3-related inhibitor that targets DNA damage repair). PDAC spheroid models and organoids were used to assess the combination effects. Tumour growth and the immune and fibrotic microenvironment were evaluated by immunohistochemistry, single-cell analysis and spatial proteomics in patient-derived xenograft (PDX) and orthotopic immunocompetent KPC mouse models. The FOLFIRINOX and VE-822 combination had a strong synergistic effect in several PDAC cell lines, whatever their BRCA1, BRCA2 and ATM mutation status and resistance to standard chemotherapy agents. This was associated with high DNA damage and inhibition of DNA repair signalling pathways, leading to increased apoptosis. In immunocompetent and PDX mouse models of PDAC, the combination inhibited tumour growth more effectively than FOLFIRINOX alone. This was associated with tumour microenvironment remodelling, particularly decreased proportion of fibroblast activated protein-positive CAFs and increased anti-tumorigenic immune cell infiltration and interaction. The FOLFIRINOX and VE-822 combination is a promising strategy to improve FOLFIRINOX efficacy and overcome drug resistance in PDAC.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 2","pages":"222-235"},"PeriodicalIF":6.4,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Normal weight obesity, circulating biomarkers and risk of breast cancer: a prospective cohort study and meta-analysis","authors":"Wenjie Wang, Xiaoyan Wang, Ying Jiang, Yingying Guo, Peifen Fu, Wei He, Xiaohua Fu","doi":"10.1038/s41416-024-02906-1","DOIUrl":"10.1038/s41416-024-02906-1","url":null,"abstract":"Individuals with normal weight obesity (NWO) often escape the attention of healthcare providers who may assume that a normal body mass index (BMI) correlates with low health risks. However, it remains unknown whether NWO increases the risk of breast cancer. This study included 22,257 and 52,506 pre- and postmenopausal females with normal BMI in the UK Biobank. NWO was defined as participants with a normal BMI (18.5–24.9 kg/m2) and an excess percent body fat (PBF > 33.3%). Cox proportional hazard models were used to investigate the associations of NWO and NWO-related biomarkers with incident breast cancer. NWO was not associated with premenopausal breast cancer, whereas it was associated with a higher risk of postmenopausal breast cancer (hazard ratio = 1.19, 95% CI: 1.08–1.31). In our meta-analysis, per 5-unit increment in percent body fat level was linked to a 15% (95% CI: 10–19%) elevated risk of postmenopausal breast cancer in females with normal BMI. Stratified analyses showed a stronger positive association in females with higher genetic risk. In our NWO-biomarkers analyses, NWO was linked to 34 identified biomarkers, of which three inflammation markers (monocyte count, neutrophil count, and C-reactive protein), and one ketone body metabolite (β-Hydroxybutyrate) also indicated a positive association with postmenopausal breast cancer. NWO is associated with an increased risk of postmenopausal breast cancer, indicating that relying solely on BMI neglects the higher risk faced by non-obese postmenopausal women.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 2","pages":"203-211"},"PeriodicalIF":6.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02906-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early onset metastatic colorectal cancer patients as a distinctive clinical and molecular phenomenon","authors":"Andrea Pretta, Pina Ziranu, Eleonora Perissinotto, Filippo Ghelardi, Federica Marmorino, Riccardo Giampieri, Mariangela Puci, Maria Caterina De Grandis, Eleonora Lai, Vincenzo Nasca, Paolo Ciraci, Marco Puzzoni, Krisida Cerma, Carolina Sciortino, Ada Taravella, Gianluca Pretta, Lorenzo Giuliani, Camilla Damonte, Valeria Pusceddu, Giovanni Sotgiu, Rossana Berardi, Sara Lonardi, Francesca Bergamo, Filippo Pietrantonio, Chiara Cremolini, Mario Scartozzi","doi":"10.1038/s41416-024-02902-5","DOIUrl":"10.1038/s41416-024-02902-5","url":null,"abstract":"Despite a reduction of both incidence and mortality from CRC, recent studies have shown an increase in the incidence of early-onset CRC (EO-CRC). Data on this setting are limited. The aim of our study was to evaluate the clinical and molecular profiles of metastatic EO-CRC patients in order to identify differences compared to a late-onset CRC (LO-CRC) control group. We retrospectively collected data from 1272 metastatic colorectal cancers from 5 different Italian Institutions. The main objective was to the evaluate clinical outcome for EO-CRC patients in comparison to patients included in the control group. In the overall population, mOS was 34,7 in EO-CRC pts vs 43,0 months (mo) (p < 0,0001). In the RAS/BRAF mutated subgroup mOS in EO-CRC pts was 30,3 vs 34,0 mo (p = 0,0156). In RAS/BRAF wild-type EO-CRC mOS was 43,0 vs 50,0 mo (p = 0,0290). mPFS was 11,0 in EO-CRC pts vs 14,0 mo (p < 0,0001). Findings indicate a general worse prognosis for patients with early-onset colorectal cancer compared to late-onset patients. Interestingly this seems to occur regardless of the molecular status. These observations might have a considerable impact on clinical practice and research.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 2","pages":"188-194"},"PeriodicalIF":6.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-10RA governor the expression of IDO in the instruction of lymphocyte immunity","authors":"Tzong-Shyuan Tai, Duen-Wei Hsu, Yu-Shao Yang, Ching-Yen Tsai, Jai-Wen Shi, Chien-Hui Wu, Shu-Ching Hsu","doi":"10.1038/s41416-024-02893-3","DOIUrl":"10.1038/s41416-024-02893-3","url":null,"abstract":"Indoleamine 2,3-dioxygenase (IDO) impairs anti-pathogen and anti-tumour immunity. Mesenchymal stem cells (MSCs) modulate immunity via IDO but also suppress IFN-γ. While MSC IDO induction by IFN-γ is established, other drivers in this immunosuppressive setting remain unknown. Human bone marrow mesenchymal stem cells (MSCs) with IDO or IL-10RA knockdown were co-cultured with healthy donor T cells to assess immunosuppression. PDAC organoid anticancer activity was also tested in these co-cultures. Co-culturing MSCs with T cells in an IL-10RA-enriched environment enhances IDO expression, resulting in T cell suppression. Moreover, IL-10RA-positive MSCs collected from co-cultures with IL-10 supplementation show increased IDO expression. Conversely, MSCs with IL-10RA knockdown exhibit a significant reduction in IDO RNA and protein expression, as well as STAT3 phosphorylation status, which is a known upstream signalling pathway in IDO gene regulation, in T cell co-cultures. Down-regulation of IL-10RA also inhibits IDO activity in MSCs, resulting in reduced T cell suppression, and enabling the co-cultured T cells to kill PDAC organoids. Our research reveals IL-10RA as a pharmacological target in stromal cells for enhancing T cell-mediated PDAC eradication by downregulating IDO via blocked IL-10/IL-10RA signalling in MSCs. This advances IL-10RA interference in the tumour microenvironment (TME) to restore T cell cytotoxicity against cancers.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 1","pages":"126-136"},"PeriodicalIF":6.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02893-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pregabalin for chronic cough due to lung cancer: randomized, double-blind, placebo-controlled trial","authors":"Vanita Noronha, Nandini Menon, Vijay M. Patil, Minit Shah, Amit Joshi, Srushti Shah, Kavita Nawale, Rohan Surve, Gunj Bafna, Shweta Jogdhankar, Priyanka Shelar, Ankush Shetake, Ashish Singh, Sushmita Salian, Pundlik Jadhav, Hetakshi Shah, Neha Mer, Ananya Vohra, Swaratika Majumdar, Shripad Banavali, Rajendra Badwe, Kumar Prabhash","doi":"10.1038/s41416-024-02913-2","DOIUrl":"10.1038/s41416-024-02913-2","url":null,"abstract":"Developing effective therapies for cough in lung cancer is an unmet need Neuromodulators like pregabalin may act centrally as cough suppressants. Randomized double-blind placebo-controlled study in patients with locally advanced/metastatic lung cancer and at least 2 weeks of moderate or severe cough. Randomization was 1:1 to pregabalin 300 mg orally daily or matching placebo, both administered for 9 weeks. Primary endpoint was the change in cough severity as measured by the difference in VAS scores. Between Jul 2022 and Dec 2023, we enrolled 166 patients: 83 to each arm. Baseline cough severity was grade 2 in 128 (77.1%) and grade 3 in 38 (22.9%) patients; median cough duration was 12 weeks (IQR, 6–20). Systemic cancer-directed therapy was started in 78 (94.0%) and 72 (86.7%) patients in the pregabalin and placebo arms, respectively; P = 0.187. The mean (SD) VAS score (in mm) decreased from 71.58 (14.99) at baseline, to 45.54 (26.60) on day 7, and 22.27 (24.20) by week 9 in the pregabalin arm; and 71.75 (17.58), 46.35 (25.00), and 23.08 (22.42), respectively in the placebo arm; P = 0.877. Pregabalin does not significantly decrease cough in patients with lung cancer. Systemic cancer-directed therapy is the most effective antitussive. Name of the registry: Clinical Trials Registry India Registration number: CTRI/2020/11/029275 Website: www.ctri.nic.in","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 1","pages":"58-68"},"PeriodicalIF":6.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02913-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of tamoxifen on cognitive function in patients with primary breast cancer","authors":"Maryse J. Luijendijk, Sanne M. Buijs, Agnes Jager, Stijn L. W. Koolen, Elsken van der Wall, Sanne B. Schagen, Ron H. J. Mathijssen","doi":"10.1038/s41416-024-02914-1","DOIUrl":"10.1038/s41416-024-02914-1","url":null,"abstract":"Tamoxifen may adversely affect cognitive function by interfering with estrogen action in the brain. Despite growing evidence for a relationship between tamoxifen and cognitive problems, findings remain inconclusive. While some tamoxifen-related side effects seem exposure-dependent with concentrations of tamoxifen or its main metabolite, endoxifen, this has never been investigated for cognitive function. We investigated cognitive function after two years of tamoxifen and its association with tamoxifen and endoxifen exposure. 135 women with breast cancer completed the Amsterdam Cognition Scan (ACS), an online neuropsychological test battery, after two years of tamoxifen. Test scores were converted to standardized Z-scores based on a matched ‘no-cancer’ control group. Tamoxifen and endoxifen concentrations and tamoxifen dose were regressed separately on cognitive functioning. Patients reported mild cognitive complaints and had worse verbal learning, processing speed, executive functioning, and motor functioning compared to matched controls. After correcting for age, mean tamoxifen and endoxifen levels, as well as tamoxifen dose, were associated with worse performance on several cognitive domains. Tamoxifen is adversely associated with objective as well as self-reported cognitive function, which may depend on the level of exposure to tamoxifen and endoxifen. Further research is warranted to confirm this hypothesis.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 2","pages":"180-187"},"PeriodicalIF":6.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SKP2 inhibition activates tumor cell-intrinsic immunity by inducing DNA replication stress and genomic instability","authors":"Yuchong Peng, Xuli Qi, Liuyang Ding, Jingjing Huang, Youhong Liu, Rirong Zheng, Yongming Fu, Linglong Yin, Tanggang Deng, Yubing Ye, Size Chen, Xiong Li","doi":"10.1038/s41416-024-02909-y","DOIUrl":"10.1038/s41416-024-02909-y","url":null,"abstract":"S-phase kinase-associated protein 2 (SKP2) is a typical oncogene aberrantly overexpressing in a variety of cancer types, but it remains elusive whether SKP2 regulates the antitumor immunity of triple-negative breast cancer. The efficacy of anti-PD-1 was evaluated in the orthotopic xenografts of immunocompetent mice models. The infiltration of cytotoxic T cells in tumor microenvironment(TME) were assessed by immunofluorescence staining. The levels of pro-inflammatory chemokines were analyzed by ELISA. The protein interaction was analyzed by co-immunoprecipitation and GST pull-down. The genomic instability was analyzed by fluorescent microscopy. SKP2 inhibition significantly improved the antitumor efficacy of immune checkpoint blockade (ICB). Furthermore, SKP2 inhibition activated the cGAS/STING signal pathway and induced the secretion of pro-inflammatory chemokines, thereby promoting cytotoxic T cell infiltration. Additionally, we identified CDC6, a DNA replication licensing factor as a novel substrate of SKP2 in addition to CDT1. SKP2 induced protein degradation of CDC6 and CDT1 through the ubiquitin-proteasome pathway. Conversely, SKP2 inhibition elevated CDC6 and CDT1 protein levels, which caused DNA aberrant replication, DNA damage and genomic instability, thereby resulting in the accumulation of cytosolic DNA, activating cGAS/STING signaling pathway and improving antitumor immunity. SKP2 may be used as an effective therapeutic target to enable ICB antitumor immunotherapy. Peng et al. found that SKP2 inhibition improved the antitumor immunotherapy by activating tumor cell-intrinsic immunity, thereby providing evidences that SKP2 may be used as an effective therapeutic target to enable ICB antitumor immunotherapy.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 1","pages":"81-92"},"PeriodicalIF":6.4,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of blood lipids and LDL cholesterol lowering drug-targets with colorectal cancer risk: a Mendelian randomisation study","authors":"Wing Ching Chan, Lili Liu, Emmanouil Bouras, Verena Zuber, Wanqing Wen, Jirong Long, Dipender Gill, Neil Murphy, Marc J. Gunter, Themistocles L. Assimes, Luis Bujanda, Stephen B. Gruber, Sébastien Küry, Brigid M. Lynch, Conghui Qu, Minta Thomas, Emily White, Michael O. Woods, Ulrike Peters, Christopher I. Li, Andrew T. Chan, Hermann Brenner, Konstantinos K. Tsilidis, Wei Zheng","doi":"10.1038/s41416-024-02900-7","DOIUrl":"10.1038/s41416-024-02900-7","url":null,"abstract":"Whether blood lipids are causally associated with colorectal cancer (CRC) risk remains unclear. Using two-sample Mendelian randomisation (MR), our study examined the associations of genetically-predicted blood concentrations of lipids and lipoproteins (primary: LDL-C, HDL-C, triglycerides, and total cholesterol), and genetically-proxied inhibition of HMGCR, NPC1L1, and PCSK9 (which mimic therapeutic effects of LDL-lowering drugs), with risks of CRC and its subsites. Genetic associations with lipids were obtained from the Global Lipids Genetics Consortium (n = 1,320,016), while genetic associations with CRC were obtained from the largest existing CRC consortium (n = 58,221 cases and 67,694 controls). Our main analysis was a multivariable MR (MVMR) with mutual adjustments for LDL-C, HDL-C, and triglycerides. Secondary analyses, including MVMR additionally-adjusting for BMI or diabetes, were also performed. Genetically-predicted LDL-C was positively associated with CRC risk in the MVMR adjusted for HDL-C and triglycerides (OR = 1.09; 95%CI 1.02–1.16 per SD increase) and additionally-adjusted for BMI (OR = 1.12; 95%CI 1.05–1.21) or diabetes (OR = 1.09; 95%CI 1.02–1.17). Associations were generally consistent across anatomical subsites. No clear evidence of association was found for other lipids, lipoproteins, or LDL-lowering drug-targets. We found evidence of a weak positive association between LDL-C and CRC that did not appear to be explained by potential pleiotropic pathways such as via HDL-C, triglycerides, BMI, or diabetes.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 1","pages":"103-110"},"PeriodicalIF":6.4,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-024-02900-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}