Cancer Biomarkers - Volume Pre-press, issue Pre-press

Authors: Paez, Rafael | Rowe, Dianna J. | Deppen, Stephen A. | Grogan, Eric L. | Kaizer, Alexander | Bornhop, Darryl J. | Kussrow, Amanda K. | Barón, Anna E. | Maldonado, Fabien | Kammer, Michael N.

Article Type: Research Article

Abstract: BACKGROUND: Assessing the clinical utility of biomarkers is a critical step before clinical implementation. The reclassification of patients across clinically relevant subgroups is considered one of the best methods to estimate clinical utility. However, there are important limitations with this methodology. We recently proposed the intervention probability curve (IPC) which models the likelihood that a provider will choose an intervention as a continuous function of the probability, or risk, of disease. OBJECTIVE: To assess the potential impact of a new biomarker for lung cancer using the IPC. METHODS: The IPC derived from the …National Lung Screening Trial was used to assess the potential clinical utility of a biomarker for suspected lung cancer. The summary statistics of the change in likelihood of intervention over the population can be interpreted as the expected clinical impact of the added biomarker. RESULTS: The IPC analysis of the novel biomarker estimated that 8% of the benign nodules could avoid an invasive procedure while the cancer nodules would largely remain unchanged (0.1%). We showed the benefits of this approach compared to traditional reclassification methods based on thresholds. CONCLUSIONS: The IPC methodology can be a valuable tool for assessing biomarkers prior to clinical implementation. Show more

Keywords: Biomarkers, clinical utility, Intervention Probability Curve, indeterminate pulmonary nodule, net reclassification index

DOI: 10.3233/CBM-230054

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-8, 2023

Authors: Zhang, Zhixiang | Guo, Jipeng | Gong, Chongwen | Wu, Sai | Sun, Yanlei

Article Type: Research Article

Abstract: BACKGROUND: N6-methyladenosine (m6 A) modification has been associated with non-small cell lung cancer (NSCLC) tumorigenesis. OBJECTIVES: This study aimed to determine the functions of Vir-like m6 A methyltransferase-associated (KIAA1429) and relaxin family peptide receptor 1 (RXFP1) in NSCLC. METHODS: A quantitative real-time polymerase chain reaction was used to analyze the mRNA levels of KIAA1429 and RXFP1 in NSCLC. After silencing KIAA1429 or RXFP1 in NSCLC cells, changes in the malignant phenotypes of NSCLC cells were assessed using cell counting kit-8, colony formation, and transwell assays. Finally, the m6 A modification of RXFP1 mediated …by KIAA1429 was confirmed using luciferase, methylated RNA immunoprecipitation, and western blot assays. RESULTS: KIAA1429 and RXFP1 were upregulated and downregulated in NSCLC, respectively. Silencing of KIAA1429 attenuated the viability, migration, and invasion of NSCLC cells, whereas silencing of RXFP1 showed the opposite function in NSCLC cells. Moreover, RXFP1 expression was inhibited by KIAA1429 via m6 A-modification. Therefore, silencing RXFP1 reversed the inhibitory effect of KIAA1429 knockdown in NSCLC cells. CONCLUSION: Our findings confirmed that the KIAA1429/RXFP1 axis promotes NSCLC tumorigenesis. This is the first study to reveal the inhibitory function of RXFP1 in NSCLC via KIAA1429-mediated m6 A-modification. These findings may help identify new biomarkers for targeted NSCLC therapy. Show more

Keywords: N6-methyladenosine, KIAA1429, RXFP1, non-small cell lung cancer

DOI: 10.3233/CBM-230188

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-12, 2024

Authors: Kim, Roger Y.

Article Type: Research Article

Abstract: Pulmonary nodules are ubiquitously found on computed tomography (CT) imaging either incidentally or via lung cancer screening and require careful diagnostic evaluation and management to both diagnose malignancy when present and avoid unnecessary biopsy of benign lesions. To engage in this complex decision-making, clinicians must first risk stratify pulmonary nodules to determine what the best course of action should be. Recent developments in imaging technology, computer processing power, and artificial intelligence algorithms have yielded radiomics-based computer-aided diagnosis tools that use CT imaging data including features invisible to the naked human eye to predict pulmonary nodule malignancy risk and are designed …to be used as a supplement to routine clinical risk assessment. These tools vary widely in their algorithm construction, internal and external validation populations, intended-use populations, and commercial availability. While several clinical validation studies have been published, robust clinical utility and clinical effectiveness data are not yet currently available. However, there is reason for optimism as ongoing and future studies aim to target this knowledge gap, in the hopes of improving the diagnostic process for patients with pulmonary nodules. Show more

Keywords: Radiomics, artificial intelligence, lung cancer, risk stratification, pulmonary nodule

DOI: 10.3233/CBM-230360

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-11, 2024

Authors: Karataş, Fatih | Acat, Murat | Karatas, Hatice Gulsah | İnci, Fatih | Dikiş, Özlem Sengören

Article Type: Research Article

Abstract: BACKGROUND: Despite Non-small cell lung cancer (NSCLC) ranks among the most deadly cancers worldwide, and currently, apart from a low percentage, targetable molecules have not been identified in its etiopathogenesis. The relationship between the proteoglycans decorin and biglycan, which are present in the extracellular matrix of cells, and transforming growth factor Beta-1 (TGF-B1), has been shown in many cancers. We investigated the significance of these molecules in NSCLC. METHODS: Fasting serum levels of decorin, biglycan, and TGF-B1 were obtained from 48 newly diagnosed NSCLC patients and compared with those of 48 adult control subjects matched for …age and demographics. Demographic data, baseline laboratory values, and ELISA results were compared between the groups. RESULTS: The median age was 65(39–83) similar in both groups. There was no relation between demographic and clinical parameters and the levels of decorin, biglycan, and TGF-B1 in the NSCLC group. However, in comparison to the control group, NSCLC patients had significantly higher levels of biglycan (42.55 ± 27.40 vs. 24.38 ± 12.05 ng/mL, p = 0.026) and TGF-B1 (15.55 ± 9.16 vs. 10.07 ± 7.8 pg/mL, p = 0.001), while decorin levels were significantly lower (6.64 ± 1.92 vs. 10.28 ± 3.13 ng/mL, p = 0.002). In the multivariate regression analysis; Decorin < 8.13 ng/mL (OR, 10.96; 95% CI: 3.440–34.958), current smoking (OR, 3.81; 95% CI: 1.320–10.998), COPD (OR, 43.6; 95% CI: 2.082–913.081), and lower BMI (OR, 1.22; 95% CI: 1.070–1.405, p = 0.003) were identified as independent predictive markers for NSCLC diagnosis. CONCLUSION: The decreased serum decorin level is an independent marker for NSCLC. Further studies are needed to investigate the prognostic significance of decorin on survival and its potential as a target in treatment. Show more

Keywords: Non small cell, lung cancer, decorin, biglycan, TGF-B1

DOI: 10.3233/CBM-230238

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-6, 2023

Authors: Singh, Varsha | Katiyar, Amit | Malik, Prabhat | Kumar, Sunil | Mohan, Anant | Singh, Harpreet | Jain, Deepali

Article Type: Research Article

Abstract: OBJECTIVES: Significant progress has been made in the treatment of patients with pulmonary adenocarcinoma (ADCA) based on molecular profiling. However, no such molecular target exists for squamous cell carcinoma (SQCC). An exome sequence may provide new markers for personalized medicine for lung cancer patients of all subtypes. The current study aims to discover new genetic markers that can be used as universal biomarkers for non-small cell lung cancer (NSCLC). METHODS: WES of 19 advanced NSCLC patients (10 ADCA and 9 SQCC) was performed using Illumina HiSeq 2000. Variant calling was performed using GATK HaplotypeCaller and then …the impacts of variants on protein structure or function were predicted using SnpEff and ANNOVAR. The clinical impact of somatic variants in cancer was assessed using cancer archives. Somatic variants were further prioritized using a knowledge-driven variant interpretation approach. Sanger sequencing was used to validate functionally important variants. RESULTS: We identified 24 rare single-nucleotide variants (SNVs) including 17 non-synonymous SNVs, and 7 INDELs in 18 genes possibly linked to lung carcinoma. Variants were classified as known somatic (n = 10), deleterious (n = 8), and variant of uncertain significance (n = 6). We found TBP and MPRIP genes exclusively associated with ADCA subtypes, FBOX6 with SQCC subtypes and GPRIN2, KCNJ18 and TEKT4 genes mutated in all the patients. The Sanger sequencing of 10 high-confidence somatic SNVs showed 100% concordance in 7 genes, and 80% concordance in the remaining 3 genes. CONCLUSIONS: Our bioinformatics analysis identified KCNJ18, GPRIN2, TEKT4, HRNR, FOLR3, ESSRA, CTBP2, MPRIP, TBP, and FBXO6 may contribute to progression in NSCLC and could be used as new biomarkers for the treatment. The mechanism by which GPRIN2, KCNJ12, and TEKT4 contribute to tumorigenesis is unclear, but our results suggest they may play an important role in NSCLC and it is worth investigating in future. Show more

Keywords: Non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, biomarker, whole-exome sequencing

DOI: 10.3233/CBM-220211

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-18, 2023

Authors: Zhu, Ziwen | Jiang, Weizhen | Zhou, Danhong | Zhu, Weidong | Chen, Cheng

Article Type: Research Article

Abstract: BACKGROUND: In clinical practice, preoperative identification of mixed ground-glass opacity (mGGO) nodules with micropapillary component (MPC) to facilitate the implementation of individualized therapeutic strategies and avoid unnecessary surgery is increasingly important OBJECTIVE: This study aimed to build a predictive model based on clinical and radiological variables for the early identification of MPC in lung adenocarcinoma presenting as mGGO nodules. METHODS: The enrolled 741 lung adenocarcinoma patients were randomly divided into a training cohort and a validation cohort (3:1 ratio). The pathological specimens and preoperative images of malignant mGGO nodules from the study subjects …were retrospectively reviewed. Furthermore, in the training cohort, selected clinical and radiological variables were utilized to construct a predictive model for MPC prediction. RESULTS: The MPC was found in 228 (43.3%) patients in the training cohort and 72 (41.1%) patients in the validation cohort. Based on the predictive nomogram, the air bronchogram was defined as the most dominant independent risk factor for MPC of mGGO nodules, followed by the maximum computed tomography (CT) value (> 200), adjacent to pleura, gender (male), and vacuolar sign. The nomogram demonstrated good discriminative ability with a C-index of 0.783 (95%[CI] 0.744–0.822) in the training cohort and a C-index of 0.799 (95%[CI] 0.732–0.866) in the validation cohort Additionally, by using the bootstrapping method, this predictive model calculated a corrected AUC of 0.774 (95% CI: 0.770–0.779) in the training cohort. CONCLUSIONS: This study proposed a predictive model for preoperative identification of MPC in known lung adenocarcinomas presenting as mGGO nodules to facilitate individualized therapy. This nomogram model needs to be further externally validated by subsequent multicenter studies. Show more

Keywords: Mixed ground-glass opacity (mGGO), micropapillary component (MPC), lung adenocarcinoma, predictive model, nomogram

DOI: 10.3233/CBM-230104

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-11, 2023

Authors: Heredia, David | Bolaño-Guerra, Laura | Valencia-Velarde, Angel | Santoyo, Edgar Varela | Lara-Mejía, Luis | Cárdenas-Fernández, Daniela | Orozco, Mario | Cruz-Rico, Graciela | Arrieta, Oscar

Article Type: Research Article

Abstract: BACKGROUND: Liquid biopsy (LB) is used to detect epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) and has been demonstrated to have prognostic and predictive value. OBJECTIVE: To associate the rates of EGFR and T790M mutations detected by LB during disease progression after first- or second-generation EGFR-TKIs with clinical characteristics and survival outcomes. METHODS: From January 2018 to December 2021, 295 patients with advanced EGFR mutant (EGFRm) NSCLC treated with first- or second-generation EGFR-TKIs were retrospectively analyzed. LB was collected at the time of progression. The frequency of …EGFR T790M mutations, overall survival (OS), and the clinical characteristics associated with LB positivity were determined. RESULTS: The prevalence of EGFR T790M mutation detected using LB was 44%. In patients with negative vs. positive LB, the median OS was 45.0 months vs. 25.0 months (p = 0.0001), respectively. Patients with a T790M mutation receiving osimertinib had a median OS of 44 months (95% CI [33.05–54.99]). Clinical characteristics associated with positive LB at progression extra-thoracic involvement, > 3 metastatic sites, and bone metastases. CONCLUSIONS: Our findings showed that LB positivity was associated with worse survival outcomes and specific clinical characteristics. This study also confirmed the feasibility and detection rate of T790M mutation in a Latin American population. Show more

Keywords: EGFRm NSCLC, liquid biopsy, T790M mutation, osimertinib, ctDNA

DOI: 10.3233/CBM-230124

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-11, 2023

Authors: Li, Thomas Z. | Xu, Kaiwen | Chada, Neil C. | Chen, Heidi | Knight, Michael | Antic, Sanja | Sandler, Kim L. | Maldonado, Fabien | Landman, Bennett A. | Lasko, Thomas A.

Article Type: Research Article

Abstract: BACKGROUND: Large community cohorts are useful for lung cancer research, allowing for the analysis of risk factors and development of predictive models. OBJECTIVE: A robust methodology for (1) identifying lung cancer and pulmonary nodules diagnoses as well as (2) associating multimodal longitudinal data with these events from electronic health record (EHRs) is needed to optimally curate cohorts at scale. METHODS: In this study, we leveraged (1) SNOMED concepts to develop ICD-based decision rules for building a cohort that captured lung cancer and pulmonary nodules and (2) clinical knowledge to define time windows for …collecting longitudinal imaging and clinical concepts. We curated three cohorts with clinical data and repeated imaging for subjects with pulmonary nodules from our Vanderbilt University Medical Center. RESULTS: Our approach achieved an estimated sensitivity 0.930 (95% CI: [0.879, 0.969]), specificity of 0.996 (95% CI: [0.989, 1.00]), positive predictive value of 0.979 (95% CI: [0.959, 1.000]), and negative predictive value of 0.987 (95% CI: [0.976, 0.994]) for distinguishing lung cancer from subjects with SPNs. CONCLUSION: This work represents a general strategy for high-throughput curation of multi-modal longitudinal cohorts at risk for lung cancer from routinely collected EHRs. Show more

Keywords: Pulmonary nodules, lung cancer, EHR mining, multimodal longitudinal cohorts

DOI: 10.3233/CBM-230340

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-9, 2024

Authors: Xie, Kai | Wang, Bin | Pang, Pei | Li, Guangbin | Yang, Qianqian | Fang, Chen | Jiang, Wei | Feng, Yu | Ma, Haitao

Article Type: Research Article

Abstract: BACKGROUND: Lung adenocarcinoma (LUAD) is a prevalent form of malignancy globally. Disulfidptosis is novel programmed cell death pathway based on disulfide proteins, may have a positive impact on the development of LUAD treatment strategies. OBJECTIVE: To investigate the impact of disulfidptosis-related genes (DRGs) on the prognosis of LUAD, developed a risk model to facilitate the diagnosis and prognostication of patients. We also explored ACTN4 (DRGs) as a new therapeutic biomarker for LUAD. METHODS: We investigated the expression patterns of DRGs in both LUAD and noncancerous tissues. To assess the prognostic value of …the DRGs, we developed risk models through univariate Cox analysis and lasso regression. The expression and function of ACTN4 was evaluated by qRT-PCR, immunohistochemistry and in vitro experiments. The TIMER examined the association between ACTN4 expression and immune infiltration in LUAD. RESULTS: Ten differentially expressed DRGs were identified. And ACTN4 was identified as potential risk factors through univariate Cox regression analysis (P < 0.05). ACTN4 expression and riskscore were used to construct a risk model to predict overall survival in LUAD, and high-risk demonstrated a significantly higher mortality rate compared to the low-risk cohort. qRT-PCR and immunohistochemistry assays indicated ACTN4 was upregulated in LUAD, and the upregulation was associated with clinicopathologic features. In vitro experiments showed the knockdown of ACTN4 expression inhibited the proliferation in LUAD cells. The TIMER analysis demonstrated a correlation between the expression of ACTN4 and the infiltration of diverse immune cells. Elevated ACTN4 expression was associated with a reduction in memory B cell count. Additionally, the ACTN4 expression was associated with m6A modification genes. CONCLUSIONS: Our study introduced a prognostic model based on DRGs, which could forecast the prognosis of patients with LUAD. The biomarker ACTN4 exhibits promise for the diagnosis and management of LUAD, given its correlation with tumor immune infiltration and m6A modification. Show more

Keywords: Disulfidptosis, lung adenocarcinoma, ACTN4, immune infiltration, therapeutic target

DOI: 10.3233/CBM-230276

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-14, 2024

Authors: Kimura, Nozomu | Tsukita, Yoko | Ebina-Shibuya, Risa | Miyauchi, Eisaku | Yamada, Mitsuhiro | Narita, Daisuke | Saito, Ryota | Inoue, Chihiro | Fujino, Naoya | Ichikawa, Tomohiro | Tamada, Tsutomu | Sugiura, Hisatoshi

Article Type: Research Article

Abstract: BACKGROUND: Biomarkers predicting clinical outcomes of treating non-small cell lung cancer (NSCLC) with combination of immune checkpoint inhibitors (ICIs) and chemotherapy would be valuable. OBJECTIVE: This study aims to seek predictors of combination of ICI/chemotherapy response in NSCLC patients using peripheral blood samples. METHODS: Patients diagnosed with advanced NSCLC between July 2019 and May 2021 receiving combination of ICI/chemotherapy were included and assessed for partial responses (PR), stable disease (SD) or progressive disease (PD). We measured circulating immune cells, plasma cytokines and chemokines. RESULTS: Nineteen patients were enrolled. The proportions …of circulating natural killer (NK) cells within CD45 + cells, programmed death 1 (PD-1) + Tim-3 + T cells within CD4 + cells, and the amount of chemokine C-X-C ligand (CXCL10) in the plasma were significantly elevated in PR relative to SD/PD patients (median 8.1%-vs-2.1%, P = 0.0032; median 1.2%-vs-0.3%, P = 0.0050; and median 122.6 pg/ml-vs-76.0 pg/ml, P = 0.0125, respectively). Patients with 2 or 3 elevated factors had longer progression-free survival than patients with 0 or only one (not reached-vs-5.6 months, P = 0.0002). CONCLUSIONS: We conclude that NK cells, CD4 + PD-1 + Tim-3 + T cells, and CXCL10 levels in pre-treatment peripheral blood may predict the efficacy of combination of ICI/chemotherapy in NSCLC. Show more

Keywords: Combination of chemotherapy and immune checkpoint inhibitor, NSCLC, natural killer cells, CD4 + cells, CXCL10

DOI: 10.3233/CBM-230301

Citation: Cancer Biomarkers, vol. Pre-press, no. Pre-press, pp. 1-12, 2024