BJC reports最新文献

{"title":"Primary tumour location, molecular alterations, treatments, and outcome in a population-based metastatic colorectal cancer cohort.","authors":"Emerik Osterlund, Klara Hammarström, Luís Nunes, Lucy Mathot, Artur Mezheyeuski, Tobias Sjöblom, Bengt Glimelius","doi":"10.1038/s44276-025-00156-z","DOIUrl":"10.1038/s44276-025-00156-z","url":null,"abstract":"<p><strong>Background: </strong>Metastatic colorectal cancer (mCRC) patients in trials are selected. The aim was to study mCRC features population-based.</p><p><strong>Methods: </strong>All 765 mCRC patients in the Uppsala region, Sweden, 2010-2020 were identified and analysed for RAS (n = 356/708) and BRAF-V600E (n = 123/708) mutations (mt) and deficient mismatch repair (dMMR, n = 58/643).</p><p><strong>Results: </strong>Right colon primary tumours were associated with BRAF-V600Emt and dMMR and had worse median overall survival (mOS) than left colon or rectal mCRC. RAS&BRAF wildtype (wt) and proficient MMR were seen in 22%, 45%, and 31% of right colon, left colon, and rectum, respectively. Patients with right colon primaries received best supportive care only more often (34% vs 25% vs 24%) and metastasectomy less often (21% vs 31% vs 33%) than left colon and rectal primaries. In molecularly homogeneous subgroups (RAS&BRAFwt/RASmt/BRAF-V600Emt/dMMR) no difference in mOS were seen between right and left colon primaries, whereas rectal primaries had better mOS (26/15/8/9 vs 24/21/8/8 vs 32/23/6/NA months, respectively). This was also the case in homogenous treatment groups. Primary tumour location turned non-significant in multivariable OS analyses.</p><p><strong>Conclusions: </strong>The high variation of BRAF-V600Emt, RASmt, dMMR, and treatment allocation population-based per primary tumour location explain the poor outcome in right-sided cancers.</p>","PeriodicalId":519964,"journal":{"name":"BJC reports","volume":"3 1","pages":"38"},"PeriodicalIF":0.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12120107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"B cells and tertiary lymphoid structures in cancer therapy response.","authors":"Adèle Hegoburu, Mohammad Amer, Frank Frizelle, Rachel Purcell","doi":"10.1038/s44276-025-00146-1","DOIUrl":"10.1038/s44276-025-00146-1","url":null,"abstract":"<p><p>Recent advances in immuno-oncology research have revolutionised our understanding of the interplay between immune cells and the tumour microenvironment (TME), profoundly impacting patient responses to therapy. The TME, comprising tumour cells, immune cells, extracellular matrix, stromal cells, and co-existing microbes, orchestrates the immune phenotype of cancers, shaping disease progression and treatment outcomes. Immune-cell infiltration serves as a significant prognostic marker in various cancers, with higher rates correlating with improved prognosis. Recent discoveries have paved the way for immune checkpoint blockade therapies, which exhibit remarkable efficacy across multiple cancer types. However, understanding the nuanced contributions of different immune-cell populations to therapeutic responses remains a challenge. The majority of research has focussed on the role of T cells in the immune response to cancer therapies, with the potential importance of B cells only recently being recognised. Here, we review the diverse phenotypes of B cells within the TME, their structural organisation within tertiary lymphoid structures (TLS), and the role of both B cells and TLS in cancer prognosis and response to different therapies for cancer treatment.</p>","PeriodicalId":519964,"journal":{"name":"BJC reports","volume":"3 1","pages":"40"},"PeriodicalIF":0.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell analysis reveals tumour size as a key driver of immune cell profile alterations in primary breast tumours and corresponding lymph nodes.","authors":"Marit Otterlei Fjørtoft, Øystein Garred, Ole Christian Lingjærde, Karin Teien Lande, Lars Ottestad, Inger Riise Bergheim, Jon Lømo, Colin LaMont, June Helen Myklebust, Hege Russnes, Kanutte Huse, Inga Hansine Rye","doi":"10.1038/s44276-025-00152-3","DOIUrl":"https://doi.org/10.1038/s44276-025-00152-3","url":null,"abstract":"<p><strong>Background: </strong>At diagnosis, 30-40% of women with breast cancer have metastases in sentinel (SN) or axillary lymph nodes (ALN). Nodal status is a strong prognostic factor and guides treatment decisions. Immune checkpoint inhibition has shown some efficacy, which can increase in the neoadjuvant setting. A better understanding of how tumour cells in primary tumours and metastatic lymph nodes shape the local immune microenvironment may provide clues for more individualized therapeutic interventions.</p><p><strong>Methods: </strong>We conducted deep immunophenotypic analysis of 29 primary breast tumours and 36 lymph nodes from 38 patients with primary operable breast cancer.</p><p><strong>Results: </strong>The immune profile of the primary tumour was not predictive of the lymph node immune profile or metastatic status. Primary tumours showed prominent CD8 T cell exhaustion and activated regulatory T cells, and the frequencies of these subsets were associated with tumour size. The immune cell profile in lymph nodes were different from the profile in primary tumours, except for the ALN+ nodes, which displayed a T-cell profile more similar to primary tumours. The frequencies of the T cell subsets in lymph nodeswere associated with metastatic size. Tumour cells from smaller metastases exhibited a distinct phenotype compared to those from larger tumour deposits, and the size of the tumour cell deposit impacted the local immune cell composition.</p><p><strong>Conclusion: </strong>The tumour size of primary tumours and metastatic size in lymph nodes are the main drivers of changes in immune cell composition.</p>","PeriodicalId":519964,"journal":{"name":"BJC reports","volume":"3 1","pages":"35"},"PeriodicalIF":0.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stereotactic ablative radiotherapy for patients with hepatocellular carcinoma: analysis of post-treatment radiology and explant histology.","authors":"Nekisa Zakeri, Ramanivas Sundareyan, Owen Cain, James Good, Tahir Shah, Shishir Shetty","doi":"10.1038/s44276-025-00136-3","DOIUrl":"10.1038/s44276-025-00136-3","url":null,"abstract":"<p><strong>Background: </strong>Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment modality for hepatocellular carcinoma (HCC). Evaluation of tumour responses following SABR are currently based on conventional radiological criteria used for locoregional therapies. Whether these criteria accurately reflect tumour responses following SABR remains unknown. In this study, we provide a direct comparison of post-SABR radiological evaluation and explant histology for patients with HCC who underwent bridging SABR prior to liver transplantation.</p><p><strong>Methods: </strong>Patients with HCC who received SABR as bridging therapy prior to liver transplantation (January 2016-December 2022) in a large UK liver transplant centre were included. Post-SABR imaging was reported by two specialist hepato-pancreato-biliary radiologists, and histological examination of the explanted liver was performed by experienced liver histopathologists.</p><p><strong>Results: </strong>Six patients with residual active HCC received SABR as bridging therapy prior to undergoing liver transplantation in our cohort. Of five patients with viable HCC detected on explant histology, recent radiological evaluation using LI-RADS treatment response criteria had suggested no evidence of residual active HCC for three patients, difficulty delineating residual disease from post-radiotherapy changes for one patient, and accurately identified viable tumour in one patient.</p><p><strong>Conclusion: </strong>In our case series conventional radiological criteria underestimated HCC tumour viability following SABR compared to explant histology. As the role for SABR expands in the management of HCC, caution is needed with radiological interpretation of HCC responses to radiotherapy using standard LI-RADS criteria. Prospective study in a larger cohort is required to identify radiological criteria capable of more conclusively evaluating HCC responses to SABR.</p>","PeriodicalId":519964,"journal":{"name":"BJC reports","volume":"3 1","pages":"36"},"PeriodicalIF":0.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Next-generation sequencing outperforms Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) in endometrial cancer molecular classification.","authors":"Takuma Yoshimura, Kohei Nakamura, Tatsuyuki Chiyoda, Reika Takamatsu, Ryutaro Kawano, Eriko Aimono, Miho Kawaida, Kensuke Sakai, Yohei Masugi, Hiroshi Nishihara, Wataru Yamagami","doi":"10.1038/s44276-025-00145-2","DOIUrl":"10.1038/s44276-025-00145-2","url":null,"abstract":"<p><strong>Background: </strong>We aimed to compare the values of next-generation sequencing (NGS) and Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) in redefining the molecular classification of endometrial cancer (EC).</p><p><strong>Methods: </strong>We investigated the relationship between clinical outcomes and molecular subtypes of POLE, microsatellite instability-high (MSI-H), copy number low (CN-L), and copy number high (CN-H) classified by cancer gene panel testing for 145 cancer-related genes, as well as the immunohistochemical status of p53 and mismatch repair genes, in 200 cases of EC.</p><p><strong>Results: </strong>The NGS-based classification identified CN-L subtype as the most prevalent (104/200, 52.0%), followed by MSI-H (38/200, 19.0%), POLE (33/200, 16.5%), and CN-H (25/200, 12.5%). Overall survival differed significantly for the four subtypes based on the NGS (p = 0.006) but not on the ProMisE (p = 0.117) classification. Additional mutations were identified for some POLE subtypes beyond the known hotspots, with 18.2% (6 of 33) showing concurrent MSI-H. Immunohistochemistry showed a p53 wild-type pattern for 12 (48%) CN-H cases, and there was no significant difference in prognosis depending on the p53 status in the CN-H subtype.</p><p><strong>Conclusions: </strong>NGS surpassed ProMisE in EC molecular classification, offering precise stratification and prognostication. Our NGS platform has the potential to contribute to personalized treatment in EC.</p>","PeriodicalId":519964,"journal":{"name":"BJC reports","volume":"3 1","pages":"37"},"PeriodicalIF":0.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep learning-based interpretable prediction of recurrence of diffuse large B-cell lymphoma.","authors":"Hussein Naji, Paul Hahn, Juan I Pisula, Stefano Ugliano, Adrian Simon, Reinhard Büttner, Katarzyna Bozek","doi":"10.1038/s44276-025-00147-0","DOIUrl":"10.1038/s44276-025-00147-0","url":null,"abstract":"<p><strong>Background: </strong>The heterogeneous and aggressive nature of diffuse large B-cell lymphoma (DLBCL) presents significant treatment challenges as up to 50% of patients experience recurrence of disease after chemotherapy. Upfront detection of recurring patients could offer alternative treatments. Deep learning has shown potential in predicting recurrence of various cancer types but suffers from lack of interpretability. Particularly in prediction of recurrence, an understanding of the model's decision could eventually result in novel treatments.</p><p><strong>Methods: </strong>We developed a deep learning-based pipeline to predict recurrence of DLBCL based on histological images of a publicly available cohort. We utilized attention-based classification to highlight areas within the images that were of high relevance for the model's classification. Subsequently, we segmented the nuclei within these areas, calculated morphological features, and statistically analyzed them to find differences between recurred and non-recurred patients.</p><p><strong>Results: </strong>We achieved an f1 score of 0.88 indicating that our model can distinguish non-recurred from recurred patients. Additionally, we found that features that are the most predictive of recurrence include large and irregularly shaped tumor cell nuclei.</p><p><strong>Discussion: </strong>Our work underlines the value of histological images in predicting treatment outcomes and enhances our understanding of complex biological processes in aggressive, heterogeneous cancers like DLBCL.</p>","PeriodicalId":519964,"journal":{"name":"BJC reports","volume":"3 1","pages":"34"},"PeriodicalIF":0.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the risk of second primary lung cancer in women after previous breast cancer.","authors":"Yuanhui Huang, Jenny J Lin, Juan P Wisnivesky, Chung Yin Kong, Keith Sigel","doi":"10.1038/s44276-025-00151-4","DOIUrl":"10.1038/s44276-025-00151-4","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer (BC) survivors may be at increased risk of developing second cancers compared to those without BC diagnosis due to shared risk factors and potential carcinogenic effects of cancer therapy. Lung cancer (LC) is the most common second primary cancer among BC survivors. This study aimed to evaluate the association between BC and the subsequent incidence of LC.</p><p><strong>Methods: </strong>Women aged 55-74 were identified from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. The risk of incident LC was compared by BC status using a multivariable Cox regression model with BC and smoking exposures incorporated as time-updated variables.</p><p><strong>Results: </strong>75,951 females from the PLCO trial were identified, with 5808 diagnosed with BC after enrollment. The unadjusted incidence rate (IR) of the second LC was significantly higher among BC survivors than non-BC participants (231 vs. 172 per 100,000 person-years). The adjusted hazard ratio (HR) for the second primary LC associated with BC diagnosis was 1.24 (95% CI: 1.03-1.49).</p><p><strong>Conclusions: </strong>BC diagnosis was an independent risk factor for the development of second primary LC. Consequently, BC survivors may derive benefits from enhanced LC screening interventions.</p>","PeriodicalId":519964,"journal":{"name":"BJC reports","volume":"3 1","pages":"33"},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of HER2 amplification or overexpression with overall survival in advanced upper gastrointestinal adenocarcinomas.","authors":"Minggui Pan, Arun Dang, Tina Huang, Jack Stover, Meng M Tong, Chen Jiang, Ninah S Achacoso, Jeffrey Bien, Aleyda V Solorzano, Pamela Tse, Elaine Chung, Vishnu P Kanakaveti, Dean Felsher, George A Fisher, Sachdev Thomas, Laurel Habel","doi":"10.1038/s44276-025-00148-z","DOIUrl":"https://doi.org/10.1038/s44276-025-00148-z","url":null,"abstract":"<p><strong>Background: </strong>Advanced esophageal (EAC), gastroesophageal junction (GEJAC) and gastric (GAC) adenocarcinomas with HER2 amplification or overexpression (HER2+) are routinely treated with trastuzumab. However, it remains unclear if HER2+ is associated with superior overall survival (OS).</p><p><strong>Methods: </strong>The cohort included recurrent or de novo metastatic GAC, GEJAC and EAC from Kaiser Permanente Northern California. We used Cox regression modelling to examine association between HER2+ and OS, adjusting for demographics, performance status, CCI, receipt of chemotherapy and p53 (mutp53), KRAS (mutKRAS), CDKN2A, PIK3CA co-mutations and MYC amplification.</p><p><strong>Results: </strong>Of 875 total eligible patients, 173 had EAC, 276 had GEJAC and 426 had GAC. HER2+ was associated with better OS among the full cohort (HR = 0.74, 95% CI [0.60-0.93]), among EAC (HR = 0.62; [95% CI, 0.40-0.96]) and GEJAC (HR = 0.59; [95% CI, 0.38-0.87]), but not among GAC (HR = 0.89; [95% CI, 0.59-1.35]) patients. GEJAC had better OS than EAC (HR = 0.68, [95% CI, 0.54-0.86]). Trastuzumab treatment was associated with better OS (HR = 0.40, 95% CI [0.21-0.77]). In addition, HER2+ was associated with better OS across the molecular subgroups except that of KRAS mutation (mutKRAS). Our data also show that GEJAC, EAC and GAC were differentially associated with mutp53, mutKRAS and MYC amplification.</p><p><strong>Conclusion: </strong>HER2+ and treatment with trastuzumab in HER2+ patients were associated with superior OS in upper gastrointestinal adenocarcinomas across molecular subgroups except that of mutKRAS. These results reaffirm the importance of anti-HER2 treatment in HER2+ patients and provide insight on the prognostic and biological divergence among these anatomically linked upper gastrointestinal adenocarcinomas.</p>","PeriodicalId":519964,"journal":{"name":"BJC reports","volume":"3 1","pages":"31"},"PeriodicalIF":0.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increasing incidence of early-onset kidney cancer in young adults aged <50 years in England: an analysis of the national cancer registration data by age and gender, 1985-2020.","authors":"Anjum Memon, Yalda Salari, Manraj Bawa, Paimaun Zakikhani","doi":"10.1038/s44276-025-00149-y","DOIUrl":"https://doi.org/10.1038/s44276-025-00149-y","url":null,"abstract":"<p><strong>Background: </strong>The incidence of kidney cancer, which is 34% attributable to obesity and smoking, has been steadily increasing over the past few decades in many countries in Europe, North America and Oceania. In recent years, there have been several reports of increasing incidence of early-onset cancer in young adults aged <50 years. We conducted a retrospective population-based cohort study to examine whether there have been changes in the incidence of kidney cancer in England during the past four decades.</p><p><strong>Methods: </strong>Individual-level, national (population-based) cancer registration data for patients diagnosed with kidney cancer (ICD-10 code, C64) in England from 1985-2020 were obtained from the Office for National Statistics/Public Health England. Average annual incidence rates (AAIR) were calculated by two age categories (<50, 50+ years) and gender during the six five-year time periods (1985-89 to 2010-14) and the recent six-year period (2015-20). The percentage change in the incidence rates in each age group and gender was calculated as the change in the AAIR from the first (1985-89) to the last time period (2015-20). The Average Annual Percentage Change (AAPC, year-on-year increase in incidence rates during 1985-2000) was estimated using the slope of the linear trend line fitted to the incidence rates by year of diagnosis.</p><p><strong>Results: </strong>During the 36-year study period (1985-2020), a total of 206,816 cases (62.4% males, 37.6% females) of kidney cancer were registered in England. In young adults aged <50 years, the AAIRs (per 100,000 population) increased by 157% in males and 133% in females (from 1.4 in 1985-89 to 3.6 in 2015-20 in males and from 0.9 in 1985-89 to 2.1 in 2015-20 in females). In older adults aged 50+ years, the AAIRs increased by 127% in males and 144% in females (from 24.5 in 1985-89 to 55.5 in 2015-20 in males and from 11.9 in 1985-89 to 29.0 in 2015-20 in females). The AAPC during the 36-year period was 5.0% in people aged <50 years compared to 4.7% in those aged 50+ years.</p><p><strong>Conclusion: </strong>There has been a steady and substantial increase in the incidence of kidney cancer in England over the past four decades. This was partly driven by the largest and unexpected increase in the incidence of early-onset kidney cancer in young adults aged <50 years, which was steepest in males. Some of this increase is in analogy with the increasing prevalence of obesity; nevertheless, other causes driving this increase in early-onset kidney cancer in young adults remain elusive and need further investigation.</p>","PeriodicalId":519964,"journal":{"name":"BJC reports","volume":"3 1","pages":"32"},"PeriodicalIF":0.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomics and integrative clinical data machine learning scoring model to ascertain likely Lynch syndrome patients.","authors":"Ramadhani Chambuso, Takudzwa Nyasha Musarurwa, Alessandro Pietro Aldera, Armin Deffur, Hayli Geffen, Douglas Perkins, Raj Ramesar","doi":"10.1038/s44276-025-00140-7","DOIUrl":"https://doi.org/10.1038/s44276-025-00140-7","url":null,"abstract":"<p><strong>Background: </strong>Lynch syndrome (LS) screening methods include multistep molecular somatic tumor testing to distinguish likely-LS patients from sporadic cases, which can be costly and complex. Also, direct germline testing for LS for every diagnosed solid cancer patient is a challenge in resource limited settings. We developed a unique machine learning scoring model to ascertain likely-LS cases from a cohort of colorectal cancer (CRC) patients.</p><p><strong>Methods: </strong>We used CRC patients from the cBioPortal database (TCGA studies) with complete clinicopathologic and somatic genomics data. We determined the rate of pathogenic/likely pathogenic variants in five (5) LS genes (MLH1, MSH2, MSH6, PMS2, EPCAM), and the BRAF mutations using a pre-designed bioinformatic annotation pipeline. Annovar, Intervar, Variant Effect Predictor (VEP), and OncoKB software tools were used to functionally annotate and interpret somatic variants detected. The OncoKB precision oncology knowledge base was used to provide information on the effects of the identified variants. We scored the clinicopathologic and somatic genomics data automatically using a machine learning model to discriminate between likely-LS and sporadic CRC cases. The training and testing datasets comprised of 80% and 20% of the total CRC patients, respectively. Group regularisation methods in combination with 10-fold cross-validation were performed for feature selection on the training data.</p><p><strong>Results: </strong>Out of 4800 CRC patients frorm the TCGA datasets with clinicopathological and somatic genomics data, we ascertained 524 patients with complete data. The scoring model using both clinicopathological and genetic characteristics for likely-LS showed a sensitivity and specificity of 100%, and both had the maximum accuracy, area under the curve (AUC) and AUC for precision-recall (AUCPR) of 1. In a similar analysis, the training and testing models that only relied on clinical or pathological characteristics had a sensitivity of 0.88 and 0.50, specificity of 0.55 and 0.51, accuracy of 0.58 and 0.51, AUC of 0.74 and 0.61, and AUCPR of 0.21 and 0.19, respectively.</p><p><strong>Conclusions: </strong>Simultaneous scoring of LS clinicopathological and somatic genomics data can improve prediction and ascertainment for likely-LS from all CRC cases. This approach can increase accuracy while reducing the reliance on expensive direct germline testing for all CRC patients, making LS screening more accessible and cost-effective, especially in resource-limited settings.</p>","PeriodicalId":519964,"journal":{"name":"BJC reports","volume":"3 1","pages":"30"},"PeriodicalIF":0.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12053672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}