Journal of Personalized Medicine

Editorial

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3 pages, 188 KiB

Open AccessEditorial

Special Issue “Cancer Biomarker Research and Personalized Medicine”

by James Meehan

J. Pers. Med. 2022, 12(4), 585; https://doi.org/10.3390/jpm12040585 - 5 Apr 2022

Viewed by 1442

Abstract

While the term biomarker is thought to have first been used in the 1970s, the concept itself is considered to be much older [...] Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

Research

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11 pages, 959 KiB

Open AccessArticle

Circulating Tumor Cell Detection during Neoadjuvant Chemotherapy to Predict Early Response in Locally Advanced Oropharyngeal Cancers: A Prospective Pilot Study

by Arnaud Gauthier, Pierre Philouze, Alexandra Lauret, Gersende Alphonse, Céline Malesys, Dominique Ardail, Léa Payen, Philippe Céruse, Anne-Sophie Wozny and Claire Rodriguez-Lafrasse

J. Pers. Med. 2022, 12(3), 445; https://doi.org/10.3390/jpm12030445 - 11 Mar 2022

Cited by 6 | Viewed by 2092

Abstract

Patients with locally advanced oropharyngeal carcinoma treated with neoadjuvant chemotherapy are reassessed both radiologically and clinically to adapt their treatment after the first cycle. However, some responders show early tumor progression after adjuvant radiotherapy. This cohort study evaluated circulating tumor cells (CTCs) from [...] Read more.

Patients with locally advanced oropharyngeal carcinoma treated with neoadjuvant chemotherapy are reassessed both radiologically and clinically to adapt their treatment after the first cycle. However, some responders show early tumor progression after adjuvant radiotherapy. This cohort study evaluated circulating tumor cells (CTCs) from a population of locally advanced oropharyngeal carcinoma patients treated with docetaxel, cisplatin, and 5-fluorouracil (DCF) induction chemotherapy or DCF with a modified dose and fractioned administration. The counts and phenotypes of CTCs were assessed at baseline and at day 21 of treatment, after isolation using the RosetteSep^TM technique based on negative enrichment. At baseline, 6 out of 21 patients had CTCs (28.6%). On day 21, 5 out of 11 patients had CTCs (41.6%). There was no significant difference in the overall and progression-free survival between patients with or without CTCs at baseline (p = 0.44 and 0.78) or day 21 (p = 0.88 and 0.5). Out of the 11 patients tested at day 21, 4 had a positive variation of CTCs (33%). Patients with a positive variation of CTCs display a lower overall survival. Our findings suggest that the variation in the number of CTCs would be a better guide to the management of treatment, with possible early changes in treatment strategy. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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24 pages, 4915 KiB

Open AccessArticle

Associations between the Levels of Estradiol-, Progesterone-, and Testosterone-Sensitive MiRNAs and Main Clinicopathologic Features of Breast Cancer

by Tatiana Kalinina, Vladislav Kononchuk, Efim Alekseenok, Grigory Abdullin, Sergey Sidorov, Vladimir Ovchinnikov and Lyudmila Gulyaeva

J. Pers. Med. 2022, 12(1), 4; https://doi.org/10.3390/jpm12010004 - 21 Dec 2021

Cited by 11 | Viewed by 3352

Abstract

Despite the existing advances in the diagnosis and treatment of breast cancer (BC), the search for markers associated with the clinicopathological features of BC is still in demand. MiRNAs (miRs) have potential as markers, since a change in the miRNA expression profile accompanies [...] Read more.

Despite the existing advances in the diagnosis and treatment of breast cancer (BC), the search for markers associated with the clinicopathological features of BC is still in demand. MiRNAs (miRs) have potential as markers, since a change in the miRNA expression profile accompanies the initiation and progression of malignant diseases. The receptors for estrogen, androgen, and progesterone (ER, AR, and PR) play an important role in breast carcinogenesis. Therefore, to search for miRNAs that may function as markers in BC, using bioinformatic analysis and the literature data, we selected 13 miRNAs whose promoter regions contain binding sites for ER or AR, or putative binding sites for ER, AR, and PR. We quantified their expression in MCF-7 cells treated with estradiol, progesterone, or testosterone. The levels of miRNAs sensitive to one or more of these hormones were quantified in BC samples (n = 196). We discovered that high expression levels of miR-190b in breast tumor tissue indicate a positive ER status, and miR-423 and miR-200b levels differ between patients with and without HER2 amplification. The miR-193b, -423, -190a, -324, and -200b levels were associated with tumor size or lymph node status in BC patients, but the presence of these associations depended on the status and expression level of ER, PR, HER2, and Ki-67. We also found that miR-21 expression depends on HER2 expression in ER- and/or PR-positive BC. The levels of miRNA were significantly different between HER2 0 and HER2 1+ tumors (p = 0.027), and between HER2 0 and HER2 2+, 3+ tumors (p = 0.005). Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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23 pages, 3297 KiB

Open AccessFeature PaperArticle

Exosomes Derived from Radioresistant Breast Cancer Cells Promote Therapeutic Resistance in Naïve Recipient Cells

by Chantell Payton, Lisa Y. Pang, Mark Gray and David J. Argyle

J. Pers. Med. 2021, 11(12), 1310; https://doi.org/10.3390/jpm11121310 - 6 Dec 2021

Cited by 12 | Viewed by 2830

Abstract

Radiation resistance is a significant challenge in the treatment of breast cancer in humans. Human breast cancer is commonly treated with surgery and adjuvant chemotherapy/radiotherapy, but recurrence and metastasis upon the development of therapy resistance results in treatment failure. Exosomes are extracellular vesicles [...] Read more.

Radiation resistance is a significant challenge in the treatment of breast cancer in humans. Human breast cancer is commonly treated with surgery and adjuvant chemotherapy/radiotherapy, but recurrence and metastasis upon the development of therapy resistance results in treatment failure. Exosomes are extracellular vesicles secreted by most cell types and contain biologically active cargo that, when transferred to recipient cells, can influence the cells’ genome and proteome. We propose that exosomes secreted by radioresistant (RR) cells may be able to disseminate the RR phenotype throughout the tumour. Here, we isolated exosomes from the human breast cancer cell line, MDA-MB-231, and the canine mammary carcinoma cell line, REM134, and their RR counterparts to investigate the effects of exosomes derived from RR cells on non-RR recipient cells. Canine mammary cancer cells lines have previously been shown to be excellent translational models of human breast cancer. This is consistent with our current data showing that exosomes derived from RR cells can increase cell viability and colony formation in naïve recipient cells and increase chemotherapy and radiotherapy resistance, in both species. These results are consistent in cancer stem cell and non-cancer stem cell populations. Significantly, exosomes derived from RR cells increased the tumoursphere-forming ability of recipient cells compared to exosomes derived from non-RR cells. Our results show that exosomes are potential mediators of radiation resistance that could be therapeutically targeted. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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18 pages, 5400 KiB

Open AccessArticle

Circulating p16-Positive and p16-Negative Tumor Cells Serve as Independent Prognostic Indicators of Survival in Patients with Head and Neck Squamous Cell Carcinomas

by Pei-Hung Chang, Hung-Ming Wang, Yung-Chia Kuo, Li-Yu Lee, Chia-Jung Liao, Hsuan-Chih Kuo, Cheng-Lung Hsu, Chun-Ta Liao, Sanger Hung-Chi Lin, Pei-Wei Huang, Tyler Min-Hsien Wu and Jason Chia-Hsun Hsieh

J. Pers. Med. 2021, 11(11), 1156; https://doi.org/10.3390/jpm11111156 - 7 Nov 2021

Cited by 3 | Viewed by 3023

Abstract

Background: Decisions regarding the staging, prognosis, and treatment of patients with head and neck squamous cell carcinomas (HNSCCs) are made after determining their p16 expression levels and human papillomavirus (HPV) infection status. Methods: We investigated the prognostic roles of p16-positive and p16-negative circulating [...] Read more.

Background: Decisions regarding the staging, prognosis, and treatment of patients with head and neck squamous cell carcinomas (HNSCCs) are made after determining their p16 expression levels and human papillomavirus (HPV) infection status. Methods: We investigated the prognostic roles of p16-positive and p16-negative circulating tumor cells (CTCs) and their cell counts in HNSCC patients. We enrolled patients with locally advanced HNSCCs who received definitive concurrent chemoradiotherapy for final analysis. We performed CTC testing and p16 expression analysis before chemoradiotherapy. We analyzed the correlation between p16-positive and p16-negative CTCs and HPV genotyping, tissue p16 expression status, response to chemoradiotherapy, disease-free survival, and overall survival. Results: Forty-one patients who fulfilled the study criteria were prospectively enrolled for final analysis. The detection rates of p16-positive (>0 cells/mL blood) and p16-negative (≥3 cells/mL blood) CTCs were 51.2% (n = 21/41) and 70.7%, respectively. The best responses of chemoradiotherapy and the p16 positivity of CTCs are independent prognostic factors of disease progression, with hazard ratios of 1.738 (95% confidence interval (CI): 1.031–2.927), 5.497 (95% CI: 1.818–16.615), and 0.176 (95% CI: 0.056–0.554), respectively. The p16 positivity of CTCs was a prognostic factor for cancer death, with a hazard ratio of 0.294 (95% CI: 0.102–0.852). Conclusions: The p16-positive and p16-negative CTCs could predict outcomes in HNSCC patients receiving definitive chemoradiotherapy. This non-invasive CTC test could help stratify the risk and prognosis before chemoradiotherapy in clinical practice and enable us to perform de-intensifying therapies. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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21 pages, 4160 KiB

Open AccessArticle

The Application Value of Lipoprotein Particle Numbers in the Diagnosis of HBV-Related Hepatocellular Carcinoma with BCLC Stage 0-A

by Duo Zuo, Haohua An, Jianhua Li, Jiawei Xiao and Li Ren

J. Pers. Med. 2021, 11(11), 1143; https://doi.org/10.3390/jpm11111143 - 4 Nov 2021

Cited by 4 | Viewed by 2089

Abstract

Early diagnosis is essential for improving the prognosis and survival of patients with hepatocellular carcinoma (HCC). This study aims to explore the clinical value of lipoprotein subfractions in the diagnosis of hepatitis B virus (HBV)-related HCC. Lipoprotein subfractions were detected by ¹H-NMR [...] Read more.

Early diagnosis is essential for improving the prognosis and survival of patients with hepatocellular carcinoma (HCC). This study aims to explore the clinical value of lipoprotein subfractions in the diagnosis of hepatitis B virus (HBV)-related HCC. Lipoprotein subfractions were detected by ¹H-NMR spectroscopy, and the pattern-recognition method and binary logistic regression were performed to classify distinct serum profiles and construct prediction models for HCC diagnosis. Differentially expressed proteins associated with lipid metabolism were detected by LC-MS/MS, and the potential prognostic significance of the mRNA expression was evaluated by Kaplan–Meier survival analysis. The diagnostic panel constructed from the serum particle number of very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL-1~LDL-6) achieved higher accuracy for the diagnosis of HBV-related HCC and HBV-related benign liver disease (LD) than that constructed from serum alpha-fetoprotein (AFP) alone in the training set (AUC: 0.850 vs. AUC: 0.831) and validation set (AUC: 0.926 vs. AUC: 0.833). Furthermore, the panel achieved good diagnostic performance in distinguishing AFP-negative HCC from AFP-negative LD (AUC: 0.773). We also found that lipoprotein lipase (LPL) transcript levels showed a significant increase in cancerous tissue and that high expression was significantly positively correlated with the poor prognosis of patients. Our research provides new insight for the development of diagnostic biomarkers for HCC, and abnormal lipid metabolism and LPL-mediated abnormal serum lipoprotein metabolism may be important factors in promoting HCC development. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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8 pages, 663 KiB

Open AccessArticle

Low Preoperative Lymphocyte-to-Monocyte Ratio Is Predictive of the 5-Year Recurrence of Bladder Tumor after Transurethral Resection

by Kyungmi Kim, Jihion Yu, Jun-Young Park, Sungwoon Baek, Jai-Hyun Hwang, Woo-Jong Choi and Young-Kug Kim

J. Pers. Med. 2021, 11(10), 947; https://doi.org/10.3390/jpm11100947 - 23 Sep 2021

Cited by 3 | Viewed by 1756

Abstract

Many studies have investigated the prognostic significance of peripheral blood parameters—including lymphocyte-to-monocyte ratio (LMR)—in several cancers in recent decades. We evaluated the prognostic factors for five-year tumor recurrence after the transurethral resection of a bladder tumor (TURBT). In total, 151 patients with non-muscle [...] Read more.

Many studies have investigated the prognostic significance of peripheral blood parameters—including lymphocyte-to-monocyte ratio (LMR)—in several cancers in recent decades. We evaluated the prognostic factors for five-year tumor recurrence after the transurethral resection of a bladder tumor (TURBT). In total, 151 patients with non-muscle invasive bladder tumors who underwent TURBT under spinal anesthesia were selected for this retrospective analysis. The time to tumor recurrence was determined by the number of days from surgery until there was a pathological confirmation of tumor recurrence. The preoperative and postoperative laboratory values were defined as results within one month prior to and one month after TURBT. Univariate and multivariate Cox regression analyses were performed. Seventy-one patients (47.0%) developed recurrent bladder tumors within five years after the first TURBT surgery. The multivariate Cox regression analysis revealed that preoperative LMR (hazard ratio, 0.839; 95% confidence interval, 0.739–0.952; p = 0.006) and multiple tumor sites (hazard ratio, 2.072; 95% confidence interval, 1.243–3.453; p = 0.005) were independent recurrence predictors in patients with recurrent bladder tumors within five years after the TURBT. A low preoperative LMR is an important predictor for the recurrence of a bladder tumor during a five-year follow-up period after surgery. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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26 pages, 5546 KiB

Open AccessArticle

A Novel Approach for the Discovery of Biomarkers of Radiotherapy Response in Breast Cancer

by James Meehan, Mark Gray, Carlos Martínez-Pérez, Charlene Kay, Jimi C. Wills, Ian H. Kunkler, J. Michael Dixon and Arran K. Turnbull

J. Pers. Med. 2021, 11(8), 796; https://doi.org/10.3390/jpm11080796 - 14 Aug 2021

Cited by 11 | Viewed by 4235

Abstract

Radiotherapy (RT) is an important treatment modality for the local control of breast cancer (BC). Unfortunately, not all patients that receive RT will obtain a therapeutic benefit, as cancer cells that either possess intrinsic radioresistance or develop resistance during treatment can reduce its [...] Read more.

Radiotherapy (RT) is an important treatment modality for the local control of breast cancer (BC). Unfortunately, not all patients that receive RT will obtain a therapeutic benefit, as cancer cells that either possess intrinsic radioresistance or develop resistance during treatment can reduce its efficacy. For RT treatment regimens to become personalised, there is a need to identify biomarkers that can predict and/or monitor a tumour’s response to radiation. Here we describe a novel method to identify such biomarkers. Liquid chromatography-mass spectrometry (LC-MS) was used on conditioned media (CM) samples from a radiosensitive oestrogen receptor positive (ER⁺) BC cell line (MCF-7) to identify cancer-secreted biomarkers which reflected a response to radiation. A total of 33 radiation-induced secreted proteins that had higher (up to 12-fold) secretion levels at 24 h post-2 Gy radiation were identified. Secretomic results were combined with whole-transcriptome gene expression experiments, using both radiosensitive and radioresistant cells, to identify a signature related to intrinsic radiosensitivity. Gene expression analysis assessing the levels of the 33 proteins showed that 5 (YBX3, EIF4EBP2, DKK1, GNPNAT1 and TK1) had higher expression levels in the radiosensitive cells compared to their radioresistant derivatives; 3 of these proteins (DKK1, GNPNAT1 and TK1) underwent in-lab and initial clinical validation. Western blot analysis using CM samples from cell lines confirmed a significant increase in the release of each candidate biomarker from radiosensitive cells 24 h after treatment with a 2 Gy dose of radiation; no significant increase in secretion was observed in the radioresistant cells after radiation. Immunohistochemistry showed that higher intracellular protein levels of the biomarkers were associated with greater radiosensitivity. Intracellular levels were further assessed in pre-treatment biopsy tissues from patients diagnosed with ER⁺ BC that were subsequently treated with breast-conserving surgery and RT. High DKK1 and GNPNAT1 intracellular levels were associated with significantly increased recurrence-free survival times, indicating that these two candidate biomarkers have the potential to predict sensitivity to RT. We suggest that the methods highlighted in this study could be utilised for the identification of biomarkers that may have a potential clinical role in personalising and optimising RT dosing regimens, whilst limiting the administration of RT to patients who are unlikely to benefit. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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12 pages, 1188 KiB

Open AccessArticle

Circulating Tumor Cell Persistence Associates with Long-Term Clinical Outcome to a Therapeutic Cancer Vaccine in Prostate Cancer

by Ingrid Jenny Guldvik, Lina Ekseth, Amar U. Kishan, Andreas Stensvold, Else Marit Inderberg and Wolfgang Lilleby

J. Pers. Med. 2021, 11(7), 605; https://doi.org/10.3390/jpm11070605 - 26 Jun 2021

Cited by 5 | Viewed by 3788

Abstract

De novo metastatic or recurrence of prostate cancer (PC) remains life-threatening. Circulating tumor cells (CTCs) are noninvasive biomarkers and provide unique information that could enable tailored treatment. This study evaluated the impact of CTCs in PC patients eligible for peptide vaccine therapy. Twenty-seven [...] Read more.

De novo metastatic or recurrence of prostate cancer (PC) remains life-threatening. Circulating tumor cells (CTCs) are noninvasive biomarkers and provide unique information that could enable tailored treatment. This study evaluated the impact of CTCs in PC patients eligible for peptide vaccine therapy. Twenty-seven patients were tested for CTCs with the CellCollector^® device (Detector CANCER01(DC01)) during short-term androgen deprivation therapy (ADT) before cancer vaccine treatment (cohort 1) or salvage radiation (cohort 2). CTC counts were compared to clinicopathological parameters. In cohort 1, CTCs were correlated to immune responses, serum protein profiles, and clinical outcomes. In cohort 2, captured CTCs were further profiled for expression of PSMA, PAP, and PD-L1. Nine out of 22 patients (40.9%) in cohort 1 were CTC positive. These patients demonstrated vaccine-specific immune response (p = 0.009) and long-term prostate cancer-specific survival (log-rank, p = 0.008). All five patients in cohort 2 had CTCs at recurrence (count range 18–31), and 4/5 had CTCs positive for PSMA, PAP, and PD-L1. The DC01 CTC detection provides information beyond current clinical practice. Despite the small size of cohort 1, a correlation between CTC detection and outcome was shown. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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13 pages, 2111 KiB

Open AccessArticle

Detection of Aberrant Glycosylation of Serum Haptoglobin for Gastric Cancer Diagnosis Using a Middle-Up-Down Glycoproteome Platform

by Seunghyup Jeong, Unyong Kim, Myung Jin Oh, Jihyeon Nam, Se Hoon Park, Yoon Jin Choi, Dong Ho Lee, Jaehan Kim and Hyun Joo An

J. Pers. Med. 2021, 11(6), 575; https://doi.org/10.3390/jpm11060575 - 18 Jun 2021

Cited by 7 | Viewed by 3334

Abstract

Gastric cancer is a frequently occurring cancer and is the leading cause of cancer-related deaths. Recent studies have shown that aberrant glycosylation of serum haptoglobin is closely related to gastric cancer and has enormous potential for use in diagnosis. However, there is no [...] Read more.

Gastric cancer is a frequently occurring cancer and is the leading cause of cancer-related deaths. Recent studies have shown that aberrant glycosylation of serum haptoglobin is closely related to gastric cancer and has enormous potential for use in diagnosis. However, there is no platform with high reliability and high reproducibility to comprehensively analyze haptoglobin glycosylation covering microheterogeneity to macroheterogeneity for clinical applications. In this study, we developed a middle-up-down glycoproteome platform for fast and accurate monitoring of haptoglobin glycosylation. This platform utilizes an online purification of LC for sample desalting, and an in silico haptoglobin glycopeptide library constructed by combining peptides and N-glycans to readily identify glycopeptides. In addition, site-specific glycosylation with glycan heterogeneity can be obtained through only a single MS analysis. Haptoglobin glycosylation in clinical samples consisting of healthy controls (n = 47) and gastric cancer patients (n = 43) was extensively investigated using three groups of tryptic glycopeptides: GP1 (including Asn184), GP2 (including Asn207 and Asn211), and GP3 (including Asn241). A total of 23 individual glycopeptides were determined as potential biomarkers (p < 0.00001). In addition, to improve diagnostic efficacy, we derived representative group biomarkers with high AUC values (0.929 to 0.977) through logistic regression analysis for each GP group. It has been found that glycosylation of haptoglobin is highly associated with gastric cancer, especially the glycosite Asn241. Our assay not only allows to quickly and easily obtain information on glycosylation heterogeneity of a target glycoprotein but also makes it an efficient tool for biomarker discovery and clinical diagnosis. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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18 pages, 10277 KiB

Open AccessArticle

Identification of Novel Mutations in Colorectal Cancer Patients Using AmpliSeq Comprehensive Cancer Panel

by Bader Almuzzaini, Jahad Alghamdi, Alhanouf Alomani, Saleh AlGhamdi, Abdullah A. Alsharm, Saeed Alshieban, Ahood Sayed, Abdulmohsen G. Alhejaily, Feda S. Aljaser, Manal Abudawood, Faisal Almajed, Abdulhadi Samman, Mohammed A. Al Balwi and Mohammad Azhar Aziz

J. Pers. Med. 2021, 11(6), 535; https://doi.org/10.3390/jpm11060535 - 9 Jun 2021

Cited by 6 | Viewed by 3472

Abstract

Biomarker discovery would be an important tool in advancing and utilizing the concept of precision and personalized medicine in the clinic. Discovery of novel variants in local population provides confident targets for developing biomarkers for personalized medicine. We identified the need to generate [...] Read more.

Biomarker discovery would be an important tool in advancing and utilizing the concept of precision and personalized medicine in the clinic. Discovery of novel variants in local population provides confident targets for developing biomarkers for personalized medicine. We identified the need to generate high-quality sequencing data from local colorectal cancer patients and understand the pattern of occurrence of variants. In this report, we used archived samples from Saudi Arabia and used the AmpliSeq comprehensive cancer panel to identify novel somatic variants. We report a comprehensive analysis of next-generation sequencing results with a coverage of >300X. We identified 466 novel variants which were previously unreported in COSMIC and ICGC databases. We analyzed the genes associated with these variants in terms of their frequency of occurrence, probable pathogenicity, and clinicopathological features. Among pathogenic somatic variants, 174 were identified for the first time in the large intestine. APC, RET, and EGFR genes were most frequently mutated. A higher number of variants were identified in the left colon. Occurrence of variants in ERBB2 was significantly correlated with those of EGFR and ATR genes. Network analyses of the identified genes provide functional perspective of the identified genes and suggest affected pathways and probable biomarker candidates. This report lays the ground work for biomarker discovery and identification of driver gene mutations in local population. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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10 pages, 1022 KiB

Open AccessArticle

Lincp21-RNA as Predictive Response Marker for Preoperative Chemoradiotherapy in Rectal Cancer

by Jose Carlos Benitez, Marc Campayo, Tania Díaz, Carme Ferrer, Melissa Acosta-Plasencia, Mariano Monzo, Luis Cirera, Benjamin Besse and Alfons Navarro

J. Pers. Med. 2021, 11(5), 420; https://doi.org/10.3390/jpm11050420 - 16 May 2021

Cited by 6 | Viewed by 2427

Abstract

Preoperative chemoradiotherapy (CRT) is a standard treatment for locally advanced rectal cancer (RC) patients, but its use in non-responders can be associated with increased toxicities and resection delay. LincRNA-p21 is a long non-coding RNA involved in the p53 pathway and angiogenesis regulation. We [...] Read more.

Preoperative chemoradiotherapy (CRT) is a standard treatment for locally advanced rectal cancer (RC) patients, but its use in non-responders can be associated with increased toxicities and resection delay. LincRNA-p21 is a long non-coding RNA involved in the p53 pathway and angiogenesis regulation. We aimed to study whether lincRNA-p21 expression levels can act as a predictive biomarker for neoadjuvant CRT response. We analyzed RNAs from pretreatment biopsies from 70 RC patients treated with preoperative CRT. Pathological response was classified according to the tumor regression grade (TRG) Dworak classification. LincRNA-p21 expression was determined by RTqPCR. The results showed that lincRNA-p21 was upregulated in stage III tumors (p = 0.007) and in tumors with the worst response regarding TRG (p = 0.027) and downstaging (p = 0.016). ROC curve analysis showed that lincRNA-p21 expression had the capacity to distinguish a complete response from others (AUC:0.696; p = 0.014). LincRNA-p21 was shown as an independent marker of preoperative CRT response (p = 0.047) and for time to relapse (TTR) (p = 0.048). In conclusion, lincRNA-p21 is a marker of advanced disease, worse response to neoadjuvant CRT, and shorter TTR in locally advanced RC patients. The study of lincRNA-p21 may be of value in the individualization of pre-operative CRT in RC. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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13 pages, 3774 KiB

Open AccessArticle

Identification of Novel Biomarkers and Candidate Drug in Ovarian Cancer

by Chia-Jung Li, Li-Te Lin, Pei-Yi Chu, An-Jen Chiang, Hsiao-Wen Tsai, Yi-Han Chiu, Mei-Shu Huang, Zhi-Hong Wen and Kuan-Hao Tsui

J. Pers. Med. 2021, 11(4), 316; https://doi.org/10.3390/jpm11040316 - 19 Apr 2021

Cited by 18 | Viewed by 3205

Abstract

This paper investigates the expression of the CREB1 gene in ovarian cancer (OV) by deeply excavating the gene information in the multiple databases and the mechanism thereof. In short, we found that the expression of the CREB1 gene in ovarian cancer tissue was [...] Read more.

This paper investigates the expression of the CREB1 gene in ovarian cancer (OV) by deeply excavating the gene information in the multiple databases and the mechanism thereof. In short, we found that the expression of the CREB1 gene in ovarian cancer tissue was significantly higher than that of normal ovarian tissue. Kaplan–Meier survival analysis showed that the overall survival was significantly shorter in patients with high expression of the CREB1 gene than those in patients with low expression of the CREB1 gene, and the prognosis of patients with low expression of the CREB1 gene was better. The CREB1 gene may play a role in the occurrence and development of ovarian cancer by regulating the process of protein. Based on differentially expressed genes, 20 small-molecule drugs that potentially target CREB1 with abnormal expression in OV were obtained from the CMap database. Among these compounds, we found that naloxone has the greatest therapeutic value for OV. The high expression of the CREB1 gene may be an indicator of poor prognosis in ovarian cancer patients. Targeting CREB1 may be a potential tool for the diagnosis and treatment of OV. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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19 pages, 18909 KiB

Open AccessArticle

IL13Rα2 Is Involved in the Progress of Renal Cell Carcinoma through the JAK2/FOXO3 Pathway

by Mi-Ae Kang, Jongsung Lee, Chang Min Lee, Ho Sung Park, Kyu Yun Jang and See-Hyoung Park

J. Pers. Med. 2021, 11(4), 284; https://doi.org/10.3390/jpm11040284 - 8 Apr 2021

Cited by 5 | Viewed by 3373

Abstract

Previously, we reported a close relationship between type II IL4Rα and IL13Rα1 complex and poor outcomes in renal cell carcinoma (RCC). In this study, we investigated the clinicopathologically significant oncogenic role of IL13Rα2, a kind of the independent receptor for IL13, in 229 [...] Read more.

Previously, we reported a close relationship between type II IL4Rα and IL13Rα1 complex and poor outcomes in renal cell carcinoma (RCC). In this study, we investigated the clinicopathologically significant oncogenic role of IL13Rα2, a kind of the independent receptor for IL13, in 229 RCC patients. The high expression of IL13Rα2 was closely related to relapse-free survival in specific cancers in univariate and multivariate analysis. Then, the oncogenic role of IL13Rα2 was evaluated by performing in vitro assays for cell proliferation, cell cycle arrest, and apoptosis in A498, ACHN, Caki1, and Caki2, four kinds of RCC cells after transfection of siRNA against IL13Rα2. Cell proliferation was suppressed, and apoptosis was induced in A498, ACHN, Caki1, and Caki2 cells by knockdown of IL13Rα2. Interestingly, the knockdown of IL13Rα2 decreased the phosphorylation of JAK2 and increased the expression of FOXO3. Furthermore, the knockdown of IL13Rα2 reduced the protein interaction among IL13Rα2, phosphorylated JAK2, and FOXO3. Since phosphorylation of JAK2 was regulated by IL13Rα2, we tried to screen a novel JAK2 inhibitor from the FDA-approved drug library and selected telmisartan, a clinically used medicine against hypertension, as one of the strongest candidates. Telmisartan treatment decreased the cell proliferation rate and increased apoptosis in A498, ACHN, Caki1, and Caki2 cells. Mechanistically, telmisartan treatment decreased the phosphorylation of JAK2 and increased the expression of FOXO3. Taken together, these results suggest that IL13Rα2 regulates the progression of RCC via the JAK2/FOXO3-signaling path pathway, which might be targeted as the novel therapeutic option for RCC patients. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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14 pages, 3232 KiB

Open AccessArticle

GBP5 Serves as a Potential Marker to Predict a Favorable Response in Triple-Negative Breast Cancer Patients Receiving a Taxane-Based Chemotherapy

by Shun-Wen Cheng, Po-Chih Chen, Tzong-Rong Ger, Hui-Wen Chiu and Yuan-Feng Lin

J. Pers. Med. 2021, 11(3), 197; https://doi.org/10.3390/jpm11030197 - 12 Mar 2021

Cited by 12 | Viewed by 3098

Abstract

Pre-operative (neoadjuvant) or post-operative (adjuvant) taxane-based chemotherapy is still commonly used to treat patients with triple-negative breast cancer (TNBC). However, there are still no effective biomarkers used to predict the responsiveness and efficacy of taxane-based chemotherapy in TNBC patients. Here we find that [...] Read more.

Pre-operative (neoadjuvant) or post-operative (adjuvant) taxane-based chemotherapy is still commonly used to treat patients with triple-negative breast cancer (TNBC). However, there are still no effective biomarkers used to predict the responsiveness and efficacy of taxane-based chemotherapy in TNBC patients. Here we find that guanylate-binding protein 5 (GBP5), compared to other GBPs, exhibits the strongest prognostic significance in predicting TNBC recurrence and progression. Whereas GBP5 upregulation showed no prognostic significance in non-TNBC patients, a higher GBP5 level predicted a favorable recurrence and progression-free condition in the TNBC cohort. Moreover, we found that GBP5 expression negatively correlated with the 50% inhibitory concentration (IC₅₀) of paclitaxel in a panel of TNBC cell lines. The gene knockdown of GBP5 increased the IC₅₀ of paclitaxel in the tested TNBC cells. In TNBC patients receiving neoadjuvant or adjuvant chemotherapy, a higher GBP5 level strongly predicted a good responsiveness. Computational simulation by the Gene Set Enrichment Analysis program and cell-based assays demonstrated that GBP5 probably enhances the cytotoxic effectiveness of paclitaxel via activating the Akt/mTOR signaling axis and suppressing autophagy formation in TNBC cells. These findings suggest that GBP5 could be a good biomarker to predict a favorable outcome in TNBC patients who decide to receive a taxane-based neoadjuvant or adjuvant therapy. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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16 pages, 2066 KiB

Open AccessArticle

Preoperative Predicting the WHO/ISUP Nuclear Grade of Clear Cell Renal Cell Carcinoma by Computed Tomography-Based Radiomics Features

by Claudia-Gabriela Moldovanu, Bianca Boca, Andrei Lebovici, Attila Tamas-Szora, Diana Sorina Feier, Nicolae Crisan, Iulia Andras and Mircea Marian Buruian

J. Pers. Med. 2021, 11(1), 8; https://doi.org/10.3390/jpm11010008 - 23 Dec 2020

Cited by 16 | Viewed by 2817

Abstract

Nuclear grade is important for treatment selection and prognosis in patients with clear cell renal cell carcinoma (ccRCC). This study aimed to determine the ability of preoperative four-phase multiphasic multidetector computed tomography (MDCT)-based radiomics features to predict the WHO/ISUP nuclear grade. In all [...] Read more.

Nuclear grade is important for treatment selection and prognosis in patients with clear cell renal cell carcinoma (ccRCC). This study aimed to determine the ability of preoperative four-phase multiphasic multidetector computed tomography (MDCT)-based radiomics features to predict the WHO/ISUP nuclear grade. In all 102 patients with histologically confirmed ccRCC, the training set (n = 62) and validation set (n = 40) were randomly assigned. In both datasets, patients were categorized according to the WHO/ISUP grading system into low-grade ccRCC (grades 1 and 2) and high-grade ccRCC (grades 3 and 4). The feature selection process consisted of three steps, including least absolute shrinkage and selection operator (LASSO) regression analysis, and the radiomics scores were developed using 48 radiomics features (10 in the unenhanced phase, 17 in the corticomedullary (CM) phase, 14 in the nephrographic (NP) phase, and 7 in the excretory phase). The radiomics score (Rad-Score) derived from the CM phase achieved the best predictive ability, with a sensitivity, specificity, and an area under the curve (AUC) of 90.91%, 95.00%, and 0.97 in the training set. In the validation set, the Rad-Score derived from the NP phase achieved the best predictive ability, with a sensitivity, specificity, and an AUC of 72.73%, 85.30%, and 0.84. We constructed a complex model, adding the radiomics score for each of the phases to the clinicoradiological characteristics, and found significantly better performance in the discrimination of the nuclear grades of ccRCCs in all MDCT phases. The highest AUC of 0.99 (95% CI, 0.92–1.00, p < 0.0001) was demonstrated for the CM phase. Our results showed that the MDCT radiomics features may play a role as potential imaging biomarkers to preoperatively predict the WHO/ISUP grade of ccRCCs. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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Review

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12 pages, 461 KiB

Open AccessFeature PaperReview

Prognostic Genomic Tissue-Based Biomarkers in the Treatment of Localized Prostate Cancer

by Gianluca Ingrosso, Emanuele Alì, Simona Marani, Simonetta Saldi, Rita Bellavita and Cynthia Aristei

J. Pers. Med. 2022, 12(1), 65; https://doi.org/10.3390/jpm12010065 - 7 Jan 2022

Cited by 3 | Viewed by 2182

Abstract

In localized prostate cancer clinicopathologic variables have been used to develop prognostic nomograms quantifying the probability of locally advanced disease, of pelvic lymph node and distant metastasis at diagnosis or the probability of recurrence after radical treatment of the primary tumor. These tools [...] Read more.

In localized prostate cancer clinicopathologic variables have been used to develop prognostic nomograms quantifying the probability of locally advanced disease, of pelvic lymph node and distant metastasis at diagnosis or the probability of recurrence after radical treatment of the primary tumor. These tools although essential in daily clinical practice for the management of such a heterogeneous disease, which can be cured with a wide spectrum of treatment strategies (i.e., active surveillance, RP and radiation therapy), do not allow the precise distinction of an indolent instead of an aggressive disease. In recent years, several prognostic biomarkers have been tested, combined with the currently available clinicopathologic prognostic tools, in order to improve the decision-making process. In the following article, we reviewed the literature of the last 10 years and gave an overview report on commercially available tissue-based biomarkers and more specifically on mRNA-based gene expression classifiers. To date, these genomic tests have been widely investigated, demonstrating rigorous quality criteria including reproducibility, linearity, analytical accuracy, precision, and a positive impact in the clinical decision-making process. Albeit data published in literature, the systematic use of these tests in prostate cancer is currently not recommended due to insufficient evidence. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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32 pages, 1781 KiB

Open AccessReview

The IL6-like Cytokine Family: Role and Biomarker Potential in Breast Cancer

by Carlos Martínez-Pérez, Charlene Kay, James Meehan, Mark Gray, J. Michael Dixon and Arran K. Turnbull

J. Pers. Med. 2021, 11(11), 1073; https://doi.org/10.3390/jpm11111073 - 24 Oct 2021

Cited by 10 | Viewed by 4205

Abstract

IL6-like cytokines are a family of regulators with a complex, pleiotropic role in both the healthy organism, where they regulate immunity and homeostasis, and in different diseases, including cancer. Here we summarise how these cytokines exert their effect through the shared signal transducer [...] Read more.

IL6-like cytokines are a family of regulators with a complex, pleiotropic role in both the healthy organism, where they regulate immunity and homeostasis, and in different diseases, including cancer. Here we summarise how these cytokines exert their effect through the shared signal transducer IL6ST (gp130) and we review the extensive evidence on the role that different members of this family play in breast cancer. Additionally, we discuss how the different cytokines, their related receptors and downstream effectors, as well as specific polymorphisms in these molecules, can serve as predictive or prognostic biomarkers with the potential for clinical application in breast cancer. Lastly, we also discuss how our increasing understanding of this complex signalling axis presents promising opportunities for the development or repurposing of therapeutic strategies against cancer and, specifically, breast neoplasms. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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37 pages, 1060 KiB

Open AccessReview

Tissue- and Liquid-Based Biomarkers in Prostate Cancer Precision Medicine

by James Meehan, Mark Gray, Carlos Martínez-Pérez, Charlene Kay, Duncan McLaren and Arran K. Turnbull

J. Pers. Med. 2021, 11(7), 664; https://doi.org/10.3390/jpm11070664 - 15 Jul 2021

Cited by 11 | Viewed by 4153

Abstract

Worldwide, prostate cancer (PC) is the second-most-frequently diagnosed male cancer and the fifth-most-common cause of all cancer-related deaths. Suspicion of PC in a patient is largely based upon clinical signs and the use of prostate-specific antigen (PSA) levels. Although PSA levels have been [...] Read more.

Worldwide, prostate cancer (PC) is the second-most-frequently diagnosed male cancer and the fifth-most-common cause of all cancer-related deaths. Suspicion of PC in a patient is largely based upon clinical signs and the use of prostate-specific antigen (PSA) levels. Although PSA levels have been criticised for a lack of specificity, leading to PC over-diagnosis, it is still the most commonly used biomarker in PC management. Unfortunately, PC is extremely heterogeneous, and it can be difficult to stratify patients whose tumours are unlikely to progress from those that are aggressive and require treatment intensification. Although PC-specific biomarker research has previously focused on disease diagnosis, there is an unmet clinical need for novel prognostic, predictive and treatment response biomarkers that can be used to provide a precision medicine approach to PC management. In particular, the identification of biomarkers at the time of screening/diagnosis that can provide an indication of disease aggressiveness is perhaps the greatest current unmet clinical need in PC management. Largely through advances in genomic and proteomic techniques, exciting pre-clinical and clinical research is continuing to identify potential tissue, blood and urine-based PC-specific biomarkers that may in the future supplement or replace current standard practices. In this review, we describe how PC-specific biomarker research is progressing, including the evolution of PSA-based tests and those novel assays that have gained clinical approval. We also describe alternative diagnostic biomarkers to PSA, in addition to biomarkers that can predict PC aggressiveness and biomarkers that can predict response to certain therapies. We believe that novel biomarker research has the potential to make significant improvements to the clinical management of this disease in the near future. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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17 pages, 1887 KiB

Open AccessReview

The Signal Transducer IL6ST (gp130) as a Predictive and Prognostic Biomarker in Breast Cancer

by Carlos Martínez-Pérez, Jess Leung, Charlene Kay, James Meehan, Mark Gray, J Michael Dixon and Arran K Turnbull

J. Pers. Med. 2021, 11(7), 618; https://doi.org/10.3390/jpm11070618 - 29 Jun 2021

Cited by 14 | Viewed by 5855

Abstract

Novel biomarkers are needed to continue to improve breast cancer clinical management and outcome. IL6-like cytokines, whose pleiotropic functions include roles in many hallmarks of malignancy, rely on the signal transducer IL6ST (gp130) for all their signalling. To date, 10 separate independent studies [...] Read more.

Novel biomarkers are needed to continue to improve breast cancer clinical management and outcome. IL6-like cytokines, whose pleiotropic functions include roles in many hallmarks of malignancy, rely on the signal transducer IL6ST (gp130) for all their signalling. To date, 10 separate independent studies based on the analysis of clinical breast cancer samples have identified IL6ST as a predictor. Consistent findings suggest that IL6ST is a positive prognostic factor and is associated with ER status. Interestingly, these studies include 4 multigene signatures (EndoPredict, EER4, IRSN-23 and 42GC) that incorporate IL6ST to predict risk of recurrence or outcome from endocrine or chemotherapy. Here we review the existing evidence on the promising predictive and prognostic value of IL6ST. We also discuss how this potential could be further translated into clinical practice beyond the EndoPredict tool, which is already available in the clinic. The most promising route to further exploit IL6ST’s promising predicting power will likely be through additional hybrid multifactor signatures that allow for more robust stratification of ER+ breast tumours into discrete groups with distinct outcomes, thus enabling greater refinement of the treatment-selection process. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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12 pages, 3531 KiB

Open AccessReview

Salivary DNA Methylation as an Epigenetic Biomarker for Head and Neck Cancer. Part II: A Cancer Risk Meta-Analysis

by Óscar Rapado-González, Cristina Martínez-Reglero, Ángel Salgado-Barreira, María Arminda Santos, Rafael López-López, Ángel Díaz-Lagares and María Mercedes Suárez-Cunqueiro

J. Pers. Med. 2021, 11(7), 606; https://doi.org/10.3390/jpm11070606 - 26 Jun 2021

Cited by 8 | Viewed by 2772

Abstract

Aberrant methylation of tumor suppressor genes has been reported as an important epigenetic silencer in head and neck cancer (HNC) pathogenesis. Here, we performed a comprehensive meta-analysis to evaluate the overall and specific impact of salivary gene promoter methylation on HNC risk. The [...] Read more.

Aberrant methylation of tumor suppressor genes has been reported as an important epigenetic silencer in head and neck cancer (HNC) pathogenesis. Here, we performed a comprehensive meta-analysis to evaluate the overall and specific impact of salivary gene promoter methylation on HNC risk. The methodological quality was assessed using the Newcastle–Ottawa scale (NOS). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association and Egger’s and Begg’s tests were applied to detect publication bias. The frequency of salivary DNA promoter methylation was significantly higher in HNC patients than in healthy controls (OR: 8.34 (95% CI = 6.10–11.39; p < 0.01). The pooled ORs showed a significant association between specific tumor-related genes and HNC risk: p16 (3.75; 95% CI = 2.51–5.60), MGMT (5.72; 95% CI = 3.00–10.91), DAPK (5.34; 95% CI = 2.18–13.10), TIMP3 (3.42; 95% CI = 1.99–5.88), and RASSF1A (7.69; 95% CI = 3.88–15.23). Overall, our meta-analysis provides precise evidence on the association between salivary DNA promoter hypermethylation and HNC risk. Thus, detection of promoter DNA methylation in saliva is a potential biomarker for predicting HNC risk. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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17 pages, 3418 KiB

Open AccessReview

Salivary DNA Methylation as an Epigenetic Biomarker for Head and Neck Cancer. Part I: A Diagnostic Accuracy Meta-Analysis

by Óscar Rapado-González, Cristina Martínez-Reglero, Ángel Salgado-Barreira, Laura Muinelo-Romay, Juan Muinelo-Lorenzo, Rafael López-López, Ángel Díaz-Lagares and María Mercedes Suárez-Cunqueiro

J. Pers. Med. 2021, 11(6), 568; https://doi.org/10.3390/jpm11060568 - 17 Jun 2021

Cited by 17 | Viewed by 3230

Abstract

DNA hypermethylation is an important epigenetic mechanism for gene expression inactivation in head and neck cancer (HNC). Saliva has emerged as a novel liquid biopsy representing a potential source of biomarkers. We performed a comprehensive meta-analysis to evaluate the overall diagnostic accuracy of [...] Read more.

DNA hypermethylation is an important epigenetic mechanism for gene expression inactivation in head and neck cancer (HNC). Saliva has emerged as a novel liquid biopsy representing a potential source of biomarkers. We performed a comprehensive meta-analysis to evaluate the overall diagnostic accuracy of salivary DNA methylation for detecting HNC. PubMed EMBASE, Web of Science, LILACS, and the Cochrane Library were searched. Study quality was assessed by the Quality Assessment for Studies of Diagnostic Accuracy-2, and sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (dOR), and their corresponding 95% confidence intervals (CIs) were calculated using a bivariate random-effect meta-analysis model. Meta-regression and subgroup analyses were performed to assess heterogeneity. Eighty-four study units from 18 articles with 8368 subjects were included. The pooled sensitivity and specificity of salivary DNA methylation were 0.39 and 0.87, respectively, while PLR and NLR were 3.68 and 0.63, respectively. The overall area under the curve (AUC) was 0.81 and the dOR was 8.34. The combination of methylated genes showed higher diagnostic accuracy (AUC, 0.92 and dOR, 36.97) than individual gene analysis (AUC, 0.77 and dOR, 6.02). These findings provide evidence regarding the potential clinical application of salivary DNA methylation for HNC diagnosis. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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29 pages, 1030 KiB

Open AccessReview

Predictive and Diagnostic Biomarkers of Anastomotic Leakage: A Precision Medicine Approach for Colorectal Cancer Patients

by Mark Gray, Jamie R. K. Marland, Alan F. Murray, David J. Argyle and Mark A. Potter

J. Pers. Med. 2021, 11(6), 471; https://doi.org/10.3390/jpm11060471 - 25 May 2021

Cited by 31 | Viewed by 11602

Abstract

Development of an anastomotic leak (AL) following intestinal surgery for the treatment of colorectal cancers is a life-threatening complication. Failure of the anastomosis to heal correctly can lead to contamination of the abdomen with intestinal contents and the development of peritonitis. The additional [...] Read more.

Development of an anastomotic leak (AL) following intestinal surgery for the treatment of colorectal cancers is a life-threatening complication. Failure of the anastomosis to heal correctly can lead to contamination of the abdomen with intestinal contents and the development of peritonitis. The additional care that these patients require is associated with longer hospitalisation stays and increased economic costs. Patients also have higher morbidity and mortality rates and poorer oncological prognosis. Unfortunately, current practices for AL diagnosis are non-specific, which may delay diagnosis and have a negative impact on patient outcome. To overcome these issues, research is continuing to identify AL diagnostic or predictive biomarkers. In this review, we highlight promising candidate biomarkers including ischaemic metabolites, inflammatory markers and bacteria. Although research has focused on the use of blood or peritoneal fluid samples, we describe the use of implantable medical devices that have been designed to measure biomarkers in peri-anastomotic tissue. Biomarkers that can be used in conjunction with clinical status, routine haematological and biochemical analysis and imaging have the potential to help to deliver a precision medicine package that could significantly enhance a patient’s post-operative care and improve outcomes. Although no AL biomarker has yet been validated in large-scale clinical trials, there is confidence that personalised medicine, through biomarker analysis, could be realised for colorectal cancer intestinal resection and anastomosis patients in the years to come. Full article

(This article belongs to the Special Issue Cancer Biomarker Research and Personalized Medicine)

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