Mutational Burden Research Articles

Identifying subtypes and developing prognostic models based on N6-methyladenosine and immune microenvironment related genes in breast cancer

Breast cancer (BC) is the most prevalent cancer in women globally. The tumor microenvironment (TME), comprising epithelial tumor cells and stromal elements, is vital for breast tumor development. N6-methyladenosine (m6A) modification plays a key role in RNA metabolism, influencing its various aspects such as stability and translation. There is a notable link between m6A methylation and immune cells in the TME, although this relationship is complex and not fully deciphered. In this research, BC expression and clinicopathological data from TCGA were scrutinized to assess expression profiles, mutations, and CNVs of 31 m6A genes and immune microenvironment-related genes, examining their correlations, functions, and prognostic impacts. Lasso and Cox regression identified prognostic genes for constructing a nomogram. Single-cell analyses mapped the distribution and patterns of these genes in BC cell development. We investigated associations between gene-derived risk scores and factors like immune infiltration, TME, checkpoints, TMB, CSC indices, and drug response. As a complement to computational analyses, in vitro experiments were conducted to confirm these expression patterns. We included 31 m6A regulatory genes and discovered a correlation between these genes and the extent of immune cell infiltration. Subsequently, a 7-gene risk score was generated, encompassing HSPA2, TAP1, ULBP2, CXCL1, RBP1, STC2, and FLT3. It was observed that the low-risk group exhibited better overall survival (OS) in BC, with higher immune scores but lower tumor mutational burden (TMB) and cancer stem cell (CSC) indices, as well as lower IC50 values for commonly used drugs. To enhance clinical applicability, age and stage were incorporated into the risk score, and a more comprehensive nomogram was constructed to predict OS. This nomogram was validated and demonstrated good predictive performance, with area under the curve (AUC) values for 1-year, 3-year, and 5-year OS being 0.848, 0.807, and 0.759, respectively. Our findings highlight the profound impact of prognostic-related genes on BC immune response and prognostic outcomes, suggesting that modulation of the m6A-immune pathway could offer new avenues for personalized BC treatment and potentially improve clinical outcomes.

Multiregion exome sequencing indicates a monoclonal origin of esophageal spindle-cell squamous cell carcinoma.

Esophageal spindle-cell squamous cell carcinoma (ESS) is a rare biphasic neoplasm composed of a carcinomatous component (CaC) and a sarcomatous component (SaC). However, the genomic origin and gene signature of ESS remain unclear. Using whole-exome sequencing of laser-capture microdissection (LCM) tumor samples, we determined that CaC and SaC showed high mutational commonality, with the same top high-frequency mutant genes, mutation signatures, and tumor mutation burden; paired samples shared a median of 25.5% mutation sites. Focal gains were found on chromosomes 3q29, 5p15.33, and 11q13.3. Altered genes were mainly enriched in the RTK-RAS signaling pathway. Phylogenetic trees showed a monoclonal origin of ESS. The most frequently mutated oncogene in the trunk was TP53, followed by NFE2L2, KMT2D, and MUC16. Prognostic associations were found for CDC27, LRP2, APC, and SNAPC4. Our data highlight the monoclonal origin of ESS with TP53 as a potent driver oncogene, suggesting new targeted therapies and immunotherapies as treatment options. © 2024 The Pathological Society of Great Britain and Ireland.

Blood Tumor Mutational Burden Alone Is Not a Good Predictive Biomarker for Response to Immune Checkpoint Inhibitors in Patients With Gastrointestinal Tumors.

There has been a controversy about the predictive value of tissue-TMB-H for immune checkpoint inhibitors (ICIs) with limited data regarding blood-TMB (bTMB) in GI tumors. We aim to evaluate the predictive value of bTMB compared with MSI-H in GI tumors. Patients with unresectable/metastatic GI cancer, harboring either MSS with bTMB-H (≥10mut/Mb) or dMMR/MSI-H who received ICI were included. We compared ICIs' efficacy between MSS-bTMB-H (N=45) versus MSI-H (N=50) in GI tumors. Ninety-five patients were identified with the majority having colorectal (49.5%) or esophagogastric (34.7%) cancers. MSS-bTMB-H group had more esophagogastric cancer and later-line ICI recipients, with no significant differences in other known prognostic variables. At a median follow-up of 9.4 months, MSI-H group showed superior ORR (58.0% vs. 26.7%), DCR (84.0% vs. 42.2%), DoR (not-reached vs. 7.6mo), PFS (22.5 vs. 3.8mo), and OS (Not-reached vs. 10.1mo) compared with MSS-bTMB-H. Multivariable analysis showed that MSI-H was an independent favorable factor over MSS-bTMB-H for PFS (HR=0.31, CI 0.15-0.63, P=0.001) and OS (HR=0.33, CI 0.14-0.80, P=0.014). MSI-H group showed favorable outcomes compared with MSS-bTMB-16+ (ORR: 58.0% vs. 26.9%; DCR: 84.0% vs. 42.3%; PFS:22.5 vs. 4.0mo) and MSS-bTMB-20+ (ORR: 58.0% vs. 31.6%; DCR: 84.0% vs. 42.1%; PFS:22.5 vs. 3.2mo). There was no difference between MSS-bTMB10-15 compared with MSS-bTMB-16+ in ORR, DCR, and PFS, or between MSS-bTMB10-19 compared with MSS-bTMB20+. Regardless of bTMB cutoff at 10, 16, or 20, bTMB-H did not appear to be a predictive biomarker in MSS GI tumors in this retrospective analysis.

AURKB promotes immunogenicity and immune infiltration in clear cell renal cell carcinoma

BackgroundChromatin regulators (CRs) are capable of causing epigenetic alterations, which are significant features of cancer. However, the function of CRs in controlling Clear Cell Renal Cell Carcinoma (ccRCC) is not well understood. This research aims to discover a CRs prognostic signature in ccRCC and to elucidate the roles of CRs-related genes in tumor microenvironment (TME).MethodsExpression profiles and relevant clinical annotations were retrieved from the Cancer Genome Atlas (TCGA) and UCSC Xena platform for progression-free survival (PFS) data. The R package "limma" was used to identify differentially expressed CRs. A predictive model based on five CRs was developed using LASSO-Cox analysis. The model's predictive power and applicability were validated using K-M curves, ROC curves, nomograms, comparisons with other models, stratified survival analyses, and validation with the ICGC cohort. GO and GSEA analyses were performed to investigate mechanisms differentiating low and high riskScore groups. Immunogenicity was assessed using Tumor Mutational Burden (TMB), immune cell infiltrations were inferred, and immunotherapy was evaluated using immunophenogram analysis and the expression patterns of human leukocyte antigen (HLA) and checkpoint genes. Differentially expressed CRs (DECRs) between low and high riskScore groups were identified using log2|FC|> 1 and FDR < 0.05. AURKB, one of the high-risk DECRs and a component of our prognostic model, was selected for further analysis.ResultsWe constructed a 5 CRs signature, which demonstrated a strong capacity to predict survival and greater applicability in ccRCC. Elevated immunogenicity and immune infiltration in the high riskScore group were associated with poor prognosis. Immunotherapy was more effective in the high riskScore group, and certain chemotherapy medications, including cisplatin, docetaxel, bleomycin, and axitinib, had lower IC50 values. Our research shows that AURKB is critical for the immunogenicity and immune infiltration of the high riskScore group.ConclusionOur study produced a reliable prognostic prediction model using only 5 CRs. We found that AURKB promotes immunogenicity and immune infiltration. This research provides crucial support for the development of prognostic biomarkers and treatment strategies for ccRCC.

Assessing the Efficacy of Bortezomib and Dexamethasone for Induction and Maintenance Therapy in Relapsed/Refractory Cutaneous T-Cell Lymphoma: A Phase II CISL1701/BIC Study.

This multicenter, open-label, phase II trial evaluated the efficacy and safety of bortezomib combined with dexamethasone for the treatment of relapsed/refractory cutaneous T-cell lymphoma (CTCL) in previously treated patients across 14 institutions in South Korea. Between September 2017 and July 2020, 29 patients with histologically confirmed CTCL received treatment, consisting of eight 4-week cycles of induction therapy followed by maintenance therapy, contingent upon response, for up to one year. The primary endpoint was the proportion of patients achieving an objective global response. Thirteen (44.8%) of the 29 patients achieved an objective global response, including two complete responses. The median progression-free survival (PFS) was 5.8 months, with responders showing a median PFS of 14.0 months. Treatment-emergent adverse events were generally mild, with a low incidence of peripheral neuropathy and hematologic toxicities. Despite the trend toward shorter PFS in patients with higher mutation burdens, genomic profiling before and after treatment showed no significant emergence of new mutations indicative of disease progression. This study supports the use of bortezomib and dexamethasone as a viable and safe treatment option for previously treated CTCL, demonstrating substantial efficacy and manageability in adverse effects. Further research with a larger cohort is suggested to validate these findings and explore the prognostic value of mutation profiles.

Next-generation sequencing as a valuable tool for mutational spectrum in advanced-stage NSCLC patients

Background and aim. Lung cancer remains one of the most threatening malignancies, ranking as the second most diagnosed cancer, and it continues to be the leading cause of cancer-related deaths worldwide. Challenges persist with late diagnosis and the high mutational burden characteristic of lung cancer. Methods. Our study focuses on identifying the mutational spectrum of a cohort of advanced-stage non-small cell lung cancer (NSCLC) patients using a minimally invasive method through blood collection. To analyze the mutational landscape of these patients, we employed plasma DNA for the next-generation sequencing (NGS) cancer panel Ion Torrent, which contains 50 of the most mutated genes in lung cancer. All protocols for extraction, quality and quantity control, and library preparation follow the manufacturer’s rules. Bioinformatics analysis was performed to select pathogenic mutations versus non-pathogenic-benign ones. Results. This approach is particularly valuable for patients in advanced stages (III and IV, n=10) of lung adenocarcinoma and lung squamous cell carcinoma, who lack surgical options and limited therapeutic avenues. The comprehensive sequencing analysis revealed that nine of the ten lung cancer patients carried a TP53 mutation. Also, several other mutations exist in various cases, showing heterogeneous profiling. Conclusions. Our findings demonstrate the potential of liquid biopsies in providing crucial genetic insights that can guide personalized treatment strategies, improving the management and outcomes for patients with advanced lung cancer.

Myofibroblasts derived type V collagen promoting tissue mechanical stress and facilitating metastasis and therapy resistance of lung adenocarcinoma cells

Lung cancer is a leading cause of cancer-related mortality globally, with a dismal 5-year survival rate, particularly for Lung Adenocarcinoma (LUAD). Mechanical changes within the tumor microenvironment, such as extracellular matrix (ECM) remodeling and fibroblast activity, play pivotal roles in cancer progression and metastasis. However, the specific impact of the basement membrane (BM) on the mechanical characteristics of LUAD remains unclear. This study aims to identify BM genes influencing internal mechanical stress in tumors, elucidating their effects on LUAD metastasis and therapy resistance, and exploring strategies to counteract these effects. Using Matrigel overlay and Transwell assays, we found that mechanical stress, mimicked by matrix application, augmented LUAD cell migration and invasion, correlating with ECM alterations and activation of the epithelial-mesenchymal transition (EMT) pathway. Employing machine learning, we developed the SVM_Score model based on relevant BM genes, which accurately predicted LUAD patient prognosis and EMT propensity across multiple datasets. Lower SVM_Scores were associated with worse survival outcomes, elevated cancer-related pathways, increased Tumor Mutation Burden, and higher internal mechanical stress in LUAD tissues. Notably, the SVM_Score was closely linked to COL5A1 expression in myofibroblasts, a key marker of mechanical stress. High COL5A1 expression from myofibroblasts promoted tumor invasiveness and EMT pathway activation in LUAD cells. Additionally, treatment with Sorafenib, which targets COL5A1 secretion, attenuated the tumor-promoting effects of myofibroblast-derived COL5A1, inhibiting LUAD cell proliferation, migration, and enhancing chemosensitivity. In conclusion, this study elucidates the complex interplay between mechanical stress, ECM alterations, and LUAD progression. The SVM_Score emerges as a robust prognostic tool reflecting tumor mechanical characteristics, while Sorafenib intervention targeting COL5A1 secretion presents a promising therapeutic strategy to mitigate LUAD aggressiveness. These findings deepen our understanding of the biomechanical aspects of LUAD and offer insights for future research and clinical applications.

Permutation-invariant linear classifiers

AbstractInvariant concept classes form the backbone of classification algorithms immune to specific data transformations, ensuring consistent predictions regardless of these alterations. However, this robustness can come at the cost of limited access to the original sample information, potentially impacting generalization performance. This study introduces an addition to these classes—the permutation-invariant linear classifiers. Distinguished by their structural characteristics, permutation-invariant linear classifiers are unaffected by permutations on feature vectors, a property not guaranteed by other non-constant linear classifiers. The study characterizes this new concept class, highlighting its constant capacity, independent of input dimensionality. In practical assessments using linear support vector machines, the permutation-invariant classifiers exhibit superior performance in permutation experiments on artificial datasets and real mutation profiles. Interestingly, they outperform general linear classifiers not only in permutation experiments but also in permutation-free settings, surpassing unconstrained counterparts. Additionally, findings from real mutation profiles support the significance of tumor mutational burden as a biomarker.

Tissue- and liquid-biopsy based NGS profiling in advanced non-small-cell lung cancer in a real-world setting: the IMMINENT study

IntroductionTo date, for all non-small cell lung cancer (NSCLC) cases, it is recommended to test for driver alterations to identify actionable therapeutic targets. In this light, comprehensive genomic profiling (CGP) with next generation sequencing (NGS) has progressively gained increasing importance in clinical practice. Here, with the aim of assessing the distribution and the real-world frequency of gene alterations and their correlation with patient characteristics, we present the outcomes obtained using FoundationOne (F1CDx) and FoundationLiquid CDx (F1L/F1LCDx) NGS-based profiling in a nationwide initiative for advanced NSCLC patients.MethodsF1CDx (324 genes) was used for tissue samples, and F1L (70 genes) or F1LCDx (324 genes) for liquid biopsy, aiming to explore the real-world occurrence of molecular alterations in aNSCLC and their relationship with patients’ characteristics.ResultsOverall, 232 advanced NSCLC patients from 11 Institutions were gathered [median age 63 years; never/former or current smokers 29.3/65.9%; adenocarcinoma/squamous 79.3/12.5%; F1CDx/F1L+F1LCDx 59.5/40.5%]. Alterations were found in 170 different genes. Median number of mutated genes per sample was 4 (IQR 3–6) and 2 (IQR 1–3) in the F1CDx and F1L/F1LCDx cohorts, respectively. TP53 (58%), KRAS (22%), CDKN2A/B (19%), and STK11 (17%) alterations were the most frequently detected. Actionability rates (tier I and II) were comparable: 36.2% F1CDx vs. 34% ctDNA NGS assays (29.5% and 40.9% F1L and F1LCDx, respectively). Alterations in KEAP1 were significantly associated with STK11 and KRAS, so as TP53 with RB1. Median tumor mutational burden was 6 (IQR 3–10) and was significantly higher in smokers. Median OS from metastatic diagnosis was 23 months (IQR 18.5–19.5) and significantly lower in patients harboring ≥3 gene mutations. Conditional three-year survival probabilities increased over time for patients profiled at initial diagnosis and exceeded those of individuals tested later in their clinical history after 12 months.ConclusionThis study confirms that NGS-based molecular profiling of aNSCLC on tissue or blood samples offers valuable predictive and prognostic insights.

Case report: Immunotherapy guided by molecular profiling of tumors: illustrative cases and literature review

Predictive biomarkers are necessary for the identification of immunotherapy-responsive patients. Tumor mutation burden (TMB), as determined by next-generation sequencing (NGS), and PD-L1 expression, as evaluated by Immunohistochemistry (IHC), are the biomarkers most frequently employed in clinical practice. In addition, microsatellite instability (MSI) was the first biomarker to demonstrate immunotherapy efficacy irrespective of the type of tumor and possesses a high predictive value. However, its limited use across most tumor types limits its therapeutic potential. This report describes two cancer patients with positive TMB and PD-L1 expression. The molecular profile of the tumor indicated that the first patient was responsive to Immune checkpoint inhibitors (ICI), while the second patient was resistant. These case studies demonstrate that tumor molecular analysis in combination with immunotherapy predictive biomarkers, such as PD-L1 expression and TMB, can enhance the prediction of response to ICI for specific patients. This methodology enables an individualized and improved approach to the treatment and management of the disease.

Immunotherapy in Breast Cancer

Breast cancer is a disease encompassing a spectrum of molecular subtypes and clinical presentations, each with distinct prognostic implications and treatment responses. Breast cancer has traditionally been considered an immunologically “cold” tumor, unresponsive to immunotherapy. However, clinical trials in recent years have found immunotherapy to be an efficacious therapeutic option for select patients. Breast cancer is categorized into different subtypes ranging from the most common positive hormone receptor (HR+), human epidermal growth factor receptor 2 (HER2)—negative type, to less frequent HER2− positive breast cancer and triple-negative breast cancer (TNBC), highlighting the necessity for tailored treatment strategies aimed at maximizing patient outcomes. Despite notable progress in early detection and new therapeutic modalities, breast cancer remains the second leading cause of cancer death in the USA. Moreover, in recent decades, breast cancer incidence rates have been increasing, especially in women younger than the age of 50. This has prompted the exploration of new therapeutic approaches to address this trend, offering new therapeutic prospects for breast cancer patients. Immunotherapy is a class of therapeutic agents that has revolutionized the treatment landscape of many cancers, namely melanoma, lung cancer, and gastroesophageal cancers, amongst others. Though belatedly, immunotherapy has entered the treatment armamentarium of breast cancer, with the approval of pembrolizumab in combination with chemotherapy in triple-negative breast cancer (TNBC) in the neoadjuvant and advanced settings, thereby paving the path for further research and integration of immune checkpoint inhibitors in other subtypes of breast cancer. Trials exploring various combination therapies to harness the power of immunotherapy in symbiosis with various chemotherapeutic agents are ongoing in hopes of improving response rates and prolonging survival for breast cancer patients. Biomarkers and precise patient selection for the utilization of immunotherapy remain cardinal and are currently under investigation, with some biomarkers showing promise, such as Program Death Lignat-1 (PDL-1) Combined Positive Score, Tumor Mutation Burden (TMB), and Tumor Infiltrating Lymphocytes (TILs). This review will present the current landscape of immunotherapy, particularly checkpoint inhibitors, in different types of breast cancer.

Systematic pan-cancer analysis insights into ICAM1 as an immunological and prognostic biomarker.

Intercellular adhesion molecule 1 (ICAM1) is a cell surface adhesion glycoprotein in the immunoglobulin supergene family. It is associated with several epithelial tumorigenesis processes, as well as with inflammation. However, the function of ICAM1 in the prognosis of tumor immunity is still unclear. This study aimed to examine the immune function of ICAM1 in 33 tumor types and to investigate the prognostic value of tumors. Using datasets from the Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), Cancer Cell Lines Encyclopedia (CCLE), Human Protein Atlas (HPA), and cBioPortal, we investigated the role of ICAM1 in tumors. We explored the potential correlation between ICAM1 expression and tumor prognosis, gene mutations, microsatellite instability, and tumor immune cell levels in various cancers. We observed that ICAM1 is highly expressed in multiple malignant tumors. Furthermore, ICAM1 is negatively or positively associated with different malignant tumor prognoses. The expression levels of ICAM1 were correlated with the tumor mutation burden (TMB) in 11 tumors and with MSI in eight tumors. ICAM1 is a gene associated with immune infiltrating cells, such as M1 macrophages and CD8+ T cells in gastric and colon cancer. Meanwhile, the expression of ICAM1 is associated with several immune-related functions and immune-regulation-related signaling pathways, such as the chemokine signaling pathway. Our study shows that ICAM1 can be used as a prognostic biomarker in many cancer types because of its function in tumorigenesis and malignant tumor immunity.

Immunotherapy in Breast Cancer

Breast cancer is a disease encompassing a spectrum of molecular subtypes and clinical presentations, each with distinct prognostic implications and treatment responses. Breast cancer has traditionally been considered an immunologically “cold” tumor, unresponsive to immunotherapy. However, clinical trials in recent years have found immunotherapy to be an efficacious therapeutic option for select patients. Breast cancer is categorized into different subtypes ranging from the most common positive hormone receptor (HR+), human epidermal growth factor receptor 2 (HER2)—negative type, to less frequent HER2− positive breast cancer and triple-negative breast cancer (TNBC), highlighting the necessity for tailored treatment strategies aimed at maximizing patient outcomes. Despite notable progress in early detection and new therapeutic modalities, breast cancer remains the second leading cause of cancer death in the USA. Moreover, in recent decades, breast cancer incidence rates have been increasing, especially in women younger than the age of 50. This has prompted the exploration of new therapeutic approaches to address this trend, offering new therapeutic prospects for breast cancer patients. Immunotherapy is a class of therapeutic agents that has revolutionized the treatment landscape of many cancers, namely melanoma, lung cancer, and gastroesophageal cancers, amongst others. Though belatedly, immunotherapy has entered the treatment armamentarium of breast cancer, with the approval of pembrolizumab in combination with chemotherapy in triple-negative breast cancer (TNBC) in the neoadjuvant and advanced settings, thereby paving the path for further research and integration of immune checkpoint inhibitors in other subtypes of breast cancer. Trials exploring various combination therapies to harness the power of immunotherapy in symbiosis with various chemotherapeutic agents are ongoing in hopes of improving response rates and prolonging survival for breast cancer patients. Biomarkers and precise patient selection for the utilization of immunotherapy remain cardinal and are currently under investigation, with some biomarkers showing promise, such as Program Death Lignat-1 (PDL-1) Combined Positive Score, Tumor Mutation Burden (TMB), and Tumor Infiltrating Lymphocytes (TILs). This review will present the current landscape of immunotherapy, particularly checkpoint inhibitors, in different types of breast cancer.

Detection of PIK3CA gene mutation and its related prognosis in colorectal cancer based on next-generation sequencing

Objectives: To investigate the mutation of PIK3CA in colorectal cancer and to analyze their clinicopathological features, and evaluate their role in clinical treatment and prognostication. Methods: A total of 128 paraffin-embbeded tissue samples of colorectal cancer from Shanxi Cancer Hospital from 2018 to 2021 were collected. DNA was extracted from the samples, and next-generation sequencing (NGS) was used to detect PIK3CA mutation. The relationship between PIK3CA mutation, their clinicopathological features, and prognosis were analyzed. Results: Among the 128 colorectal cancer samples, there were 75 males and 53 females; with aged range 32-86 years, median 61.5 years, 27 (21.09%) had PIK3CA mutations. Colorectal cancer with PIK3CA mutation was more likely to occur in male patients (P=0.007), which was related to tumor site (P=0.032), tumor size (P=0.029) and TP53 wild-type (P=0.001). The common site mutations of PIK3CA mostly occurred in tumors with tumor mutation burden≥10 Muts/Mb (P=0.031).PIK3CA mutation had no significant effect on the survival prognosis of patients, but the efficacy of anti-angiogenic therapy was poor in these patients. Conclusions: PIK3CA mutation is a common mutation in colorectal cancer and plays an important role in the occurrence and development of colorectal cancer. PIK3CA mutation may lead to resistance to anti-angiogenic drugs in colorectal cancer, but its impact on survival and prognosis to patients needs further study.

Preliminary response to Tislelizumab plus chemotherapy drugs in patient with periampullary carcinoma: a report of one case and a literature review

Periampullary carcinoma is a malignant gastrointestinal tumor originating from the head of the pancreas, distal bile duct, duodenum, or the ampulla of Vater. Currently, surgery remains the primary treatment option, yet the postoperative recurrence rate remains high. Chemotherapy is the main approach for controlling postoperative recurrence. Histologically, periampullary carcinoma is categorized into two types: intestinal (IN) and pancreaticobiliary (PB) subtype. Each subtype requires different therapeutic approaches, with the PB type primarily treated with gemcitabine and the IN type with 5-FU. Despite these options, patient outcomes are still unsatisfactory. In recent years, the feasibility of immunotherapy in tumor treatment has been increasingly evidenced, although research on its efficacy in periampullary carcinoma treatment is still limited. In this report, we present a case of a periampullary carcinoma patient who experienced recurrence and metastasis after undergoing radical pancreatoduodenectomy and receiving gemcitabine-based chemotherapy post-surgery. Through next-generation sequencing (NGS), we identified high expression levels of programmed cell death-ligand 1 (PD-L1) with a combined positive score (CPS) of 35, high tumor mutation burden (TMB-H), and high microsatellite instability (MSI-H) in this patient. Therefore, we implemented a combination therapy using Tislelizumab and chemotherapy. According to the latest follow-up, the tumors are effectively controlled. Our utilization of immunotherapy combined with chemotherapy holds significant implication for the treatment of periampullary carcinoma.

Uncovering molecular features driving lung adenocarcinoma heterogeneity in patients who formerly smoked.

An increasing proportion of lung adenocarcinoma (LUAD) occurs in patients even after they have stopped smoking. Here, we aimed to determine whether tobacco smoking induced changes across LUADs from patients who formerly smoked correspond to different biological and clinical factors. Random forest models (RFs) were trained utilizing a smoking associated signature developed from differentially expressed genes between LUAD patients who had never smoked (NS) or currently smoked (CS) from TCGA (n = 193) and BCCA (n = 69) cohorts. The RFs were subsequently applied to 299 and 131 formerly smoking patients from TCGA and MSKCC cohorts, respectively. FS were RF-classified as either CS-like or NS-like and associations with patient characteristics, biological features, and clinical outcomes were determined. We elucidated a 123 gene signature that robustly classified NS and CS in both RNA-seq (AUC = 0.85) and microarray (AUC = 0.92) validation test sets. The RF classified 213 patients who had formerly smoked as CS-like and 86 as NS-like from the TCGA cohort. CS-like and NS-like status in formerly smoking patients correlated poorly with patient characteristics but had substantially different biological features including tumor mutational burden, number of mutations, mutagenic signatures and immune cell populations. NS-like formerly smoking patients had 17.5 months and 18.6 months longer overall survival than CS-like patients from the TCGA and MSKCC cohorts, respectively. Patients who had formerly smoked with LUAD harbor heterogeneous tumor biology. These patients can be divided by smoking induced gene expression to inform prognosis and underlying biological characteristics for treatment selection.

Preliminary response to Tislelizumab plus chemotherapy drugs in patient with periampullary carcinoma: a report of one case and a literature review

Periampullary carcinoma is a malignant gastrointestinal tumor originating from the head of the pancreas, distal bile duct, duodenum, or the ampulla of Vater. Currently, surgery remains the primary treatment option, yet the postoperative recurrence rate remains high. Chemotherapy is the main approach for controlling postoperative recurrence. Histologically, periampullary carcinoma is categorized into two types: intestinal (IN) and pancreaticobiliary (PB) subtype. Each subtype requires different therapeutic approaches, with the PB type primarily treated with gemcitabine and the IN type with 5-FU. Despite these options, patient outcomes are still unsatisfactory. In recent years, the feasibility of immunotherapy in tumor treatment has been increasingly evidenced, although research on its efficacy in periampullary carcinoma treatment is still limited. In this report, we present a case of a periampullary carcinoma patient who experienced recurrence and metastasis after undergoing radical pancreatoduodenectomy and receiving gemcitabine-based chemotherapy post-surgery. Through next-generation sequencing (NGS), we identified high expression levels of programmed cell death-ligand 1 (PD-L1) with a combined positive score (CPS) of 35, high tumor mutation burden (TMB-H), and high microsatellite instability (MSI-H) in this patient. Therefore, we implemented a combination therapy using Tislelizumab and chemotherapy. According to the latest follow-up, the tumors are effectively controlled. Our utilization of immunotherapy combined with chemotherapy holds significant implication for the treatment of periampullary carcinoma.

Uncovering molecular features driving lung adenocarcinoma heterogeneity in patients who formerly smoked

BackgroundAn increasing proportion of lung adenocarcinoma (LUAD) occurs in patients even after they have stopped smoking. Here, we aimed to determine whether tobacco smoking induced changes across LUADs from patients who formerly smoked correspond to different biological and clinical factors.MethodsRandom forest models (RFs) were trained utilizing a smoking associated signature developed from differentially expressed genes between LUAD patients who had never smoked (NS) or currently smoked (CS) from TCGA (n = 193) and BCCA (n = 69) cohorts. The RFs were subsequently applied to 299 and 131 formerly smoking patients from TCGA and MSKCC cohorts, respectively. FS were RF-classified as either CS-like or NS-like and associations with patient characteristics, biological features, and clinical outcomes were determined.ResultsWe elucidated a 123 gene signature that robustly classified NS and CS in both RNA-seq (AUC = 0.85) and microarray (AUC = 0.92) validation test sets. The RF classified 213 patients who had formerly smoked as CS-like and 86 as NS-like from the TCGA cohort. CS-like and NS-like status in formerly smoking patients correlated poorly with patient characteristics but had substantially different biological features including tumor mutational burden, number of mutations, mutagenic signatures and immune cell populations. NS-like formerly smoking patients had 17.5 months and 18.6 months longer overall survival than CS-like patients from the TCGA and MSKCC cohorts, respectively.ConclusionsPatients who had formerly smoked with LUAD harbor heterogeneous tumor biology. These patients can be divided by smoking induced gene expression to inform prognosis and underlying biological characteristics for treatment selection.

Next‐generation sequencing identifies that protein tyrosine phosphatase receptor type D mutation is favorable to immunotherapy in human cancer

AbstractProtein tyrosine phosphatase receptors (PTPRs) play a crucial part in numerous tumor processes. However, the effect of PTPR mutations on the immune checkpoint inhibitor (ICI) response needs to be further clarified. Next‐generation sequencing was performed on 453 cancer patients in our internal cohort. The genomic alterations, tumor mutation burden (TMB), neoantigens, and immune‐related features/pathways of other cohorts were analyzed. Here, protein tyrosine phosphatase receptor type D (PTPRD) has a high mutation frequency and an intensified co‐occurrence with other PTPRs. Patients who responded to ICI therapy were enriched with the PTPRD mutation (PTPRD‐MUT). PTPRD‐MUT patients had a higher objective response rate (44.1% vs. 29.1%), TMB/neoantigens, and longer overall survival time than PTPRD‐wild‐type (PTPRD‐WT) patients. Genomic alterations with a higher mutation frequency of genes (such as LRP1B) were enriched in PTPRD‐MUT patients. More abundant immune cells (including CD8+ T cells and macrophages) and upregulated immune‐related genes were found in PTPRD‐MUT patients. Moreover, Gene sets enrichment analyses showed that multiple antitumor immune pathways are activated in PTPRD‐MUT patients. Therefore, PTPRD‐MUT is beneficial for immunotherapy of multiple cancer types and may be a predictive biomarker of patient clinical outcomes.

Next‐generation sequencing identifies that protein tyrosine phosphatase receptor type D mutation is favorable to immunotherapy in human cancer

AbstractProtein tyrosine phosphatase receptors (PTPRs) play a crucial part in numerous tumor processes. However, the effect of PTPR mutations on the immune checkpoint inhibitor (ICI) response needs to be further clarified. Next‐generation sequencing was performed on 453 cancer patients in our internal cohort. The genomic alterations, tumor mutation burden (TMB), neoantigens, and immune‐related features/pathways of other cohorts were analyzed. Here, protein tyrosine phosphatase receptor type D (PTPRD) has a high mutation frequency and an intensified co‐occurrence with other PTPRs. Patients who responded to ICI therapy were enriched with the PTPRD mutation (PTPRD‐MUT). PTPRD‐MUT patients had a higher objective response rate (44.1% vs. 29.1%), TMB/neoantigens, and longer overall survival time than PTPRD‐wild‐type (PTPRD‐WT) patients. Genomic alterations with a higher mutation frequency of genes (such as LRP1B) were enriched in PTPRD‐MUT patients. More abundant immune cells (including CD8+ T cells and macrophages) and upregulated immune‐related genes were found in PTPRD‐MUT patients. Moreover, Gene sets enrichment analyses showed that multiple antitumor immune pathways are activated in PTPRD‐MUT patients. Therefore, PTPRD‐MUT is beneficial for immunotherapy of multiple cancer types and may be a predictive biomarker of patient clinical outcomes.