Research

15 pages, 1780 KiB

Open AccessArticle

Combined BRCA2 and MAGEC3 Expression Predict Outcome in Advanced Ovarian Cancers

by Emmanuel B. Omole, Iqbal Aijaz, James Ellegate, Jr., Emily Isenhart, Mohamed M. Desouki, Michalis Mastri, Kristen Humphrey, Emily M. Dougherty, Spencer R. Rosario, Kent L. Nastiuk, Joyce E. Ohm and Kevin H. Eng

Cancers 2022, 14(19), 4724; https://doi.org/10.3390/cancers14194724 - 28 Sep 2022

Cited by 2 | Viewed by 1432

Abstract

Like BRCA2, MAGEC3 is an ovarian cancer predisposition gene that has been shown to have prognostic significance in ovarian cancer patients. Despite the clinical significance of each gene, no studies have been conducted to assess the clinical significance of their combined expression. [...] Read more.

Like BRCA2, MAGEC3 is an ovarian cancer predisposition gene that has been shown to have prognostic significance in ovarian cancer patients. Despite the clinical significance of each gene, no studies have been conducted to assess the clinical significance of their combined expression. We therefore sought to determine the relationship between MAGEC3 and BRCA2 expression in ovarian cancer and their association with patient characteristics and outcomes. Immunohistochemical staining was quantitated on tumor microarrays of human tumor samples obtained from 357 patients with epithelial ovarian cancer to ascertain BRCA2 expression levels. In conjunction with our previously published MAGEC3 expression data, we observed a weak inverse correlation of MAGEC3 with BRCA2 expression (r = −0.15; p < 0.05) in cases with full-length BRCA2. Patients with optimal cytoreduction, loss of MAGEC3, and detectable BRCA2 expression had better overall (median OS: 127.9 vs. 65.3 months, p = 0.035) and progression-free (median PFS: 85.3 vs. 18.8 months, p = 0.002) survival compared to patients that were BRCA2 expressors with MAGEC3 normal levels. Our results suggest that combined expression of MAGEC3 and BRCA2 serves as a better predictor of prognosis than each marker alone. Full article

(This article belongs to the Special Issue Feature Paper in Section "Cancer Biomarkers" in 2022)

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15 pages, 1741 KiB

Open AccessArticle

Plasma Copy Number Alteration-Based Prognostic and Predictive Multi-Gene Risk Score in Metastatic Castration-Resistant Prostate Cancer

by Jinyong Huang, Meijun Du, Alex Soupir, Liewei Wang, Winston Tan, Krishna R. Kalari, Deepak Kilari, Jong Park, Chiang-Ching Huang, Manish Kohli and Liang Wang

Cancers 2022, 14(19), 4714; https://doi.org/10.3390/cancers14194714 - 28 Sep 2022

Viewed by 1507

Abstract

Prostate cancer (PCa) accounted for more than 34,000 deaths in US males [...] Full article

(This article belongs to the Special Issue Feature Paper in Section "Cancer Biomarkers" in 2022)

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14 pages, 1542 KiB

Open AccessArticle

Contributions of Circulating microRNAs for Early Detection of Lung Cancer

by Jody Vykoukal, Johannes F. Fahrmann, Nikul Patel, Masayoshi Shimizu, Edwin J. Ostrin, Jennifer B. Dennison, Cristina Ivan, Gary E. Goodman, Mark D. Thornquist, Matt J. Barnett, Ziding Feng, George A. Calin and Samir M. Hanash

Cancers 2022, 14(17), 4221; https://doi.org/10.3390/cancers14174221 - 30 Aug 2022

Cited by 15 | Viewed by 3091

Abstract

There is unmet need to develop circulating biomarkers that would enable earlier interception of lung cancer when more effective treatment options are available. Here, a set of 30 miRNAs, selected from a review of the published literature were assessed for their predictive performance [...] Read more.

There is unmet need to develop circulating biomarkers that would enable earlier interception of lung cancer when more effective treatment options are available. Here, a set of 30 miRNAs, selected from a review of the published literature were assessed for their predictive performance in identifying lung cancer cases in the pre-diagnostic setting. The 30 miRNAs were assayed using sera collected from 102 individuals diagnosed with lung cancer within one year following blood draw and 212 controls matched for age, sex, and smoking status. The additive performance of top-performing miRNA candidates in combination with a previously validated four-protein marker panel (4MP) consisting of the precursor form of surfactant protein B (Pro-SFTPB), cancer antigen 125 (CA125), carcinoembryonic antigen (CEA) and cytokeratin-19 fragment (CYFRA21-1) was additionally assessed. Of the 30 miRNAs evaluated, five (miR-320a-3p, miR-210-3p, miR-92a-3p, miR-21-5p, and miR-140-3p) were statistically significantly (Wilcoxon rank sum test p < 0.05) elevated in case sera compared to controls, with individual AUCs ranging from 0.57–0.62. Compared to the 4MP alone, the combination of 3-miRNAs + 4MP improved sensitivity at 95% specificity by 19.1% ((95% CI of difference 0.0–28.6); two-sided p: 0.006). Our findings demonstrate utility for miRNAs for early detection of lung cancer in combination with a four-protein marker panel. Full article

(This article belongs to the Special Issue Feature Paper in Section "Cancer Biomarkers" in 2022)

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15 pages, 1662 KiB

Open AccessArticle

Screening a Targeted Panel of Genes by Next-Generation Sequencing Improves Risk Stratification in Real World Patients with Acute Myeloid Leukemia

by Sónia Matos, Paulo Bernardo, Susana Esteves, Aida Botelho de Sousa, Marcos Lemos, Patrícia Ribeiro, Madalena Silva, Albertina Nunes, Joana Lobato, Maria de Jesus Frade, Maria Gomes da Silva, Sérgio Chacim, José Mariz, Graça Esteves, João Raposo, Ana Espadana, José Carda, Pedro Barbosa, Vânia Martins, Maria Carmo-Fonseca and Joana Desterro Show full author list Hide full author list

Cancers 2022, 14(13), 3236; https://doi.org/10.3390/cancers14133236 - 30 Jun 2022

Viewed by 2182

Abstract

Although mutation profiling of defined genes is recommended for classification of acute myeloid leukemia (AML) patients, screening of targeted gene panels using next-generation sequencing (NGS) is not always routinely used as standard of care. The objective of this study was to prospectively assess [...] Read more.

Although mutation profiling of defined genes is recommended for classification of acute myeloid leukemia (AML) patients, screening of targeted gene panels using next-generation sequencing (NGS) is not always routinely used as standard of care. The objective of this study was to prospectively assess whether extended molecular monitoring using NGS adds clinical value for risk assessment in real-world AML patients. We analyzed a cohort of 268 newly diagnosed AML patients. We compared the prognostic stratification of our study population according to the European LeukemiaNet recommendations, before and after the incorporation of the extended mutational profile information obtained by NGS. Without access to NGS data, 63 patients (23%) failed to be stratified into risk groups. After NGS data, only 27 patients (10%) failed risk stratification. Another 33 patients were re-classified as adverse-risk patients once the NGS data was incorporated. In total, access to NGS data refined risk assessment for 62 patients (23%). We further compared clinical outcomes with prognostic stratification, and observed unexpected outcomes associated with FLT3 mutations. In conclusion, this study demonstrates the prognostic utility of screening AML patients for multiple gene mutations by NGS and underscores the need for further studies to refine the current risk classification criteria. Full article

(This article belongs to the Special Issue Feature Paper in Section "Cancer Biomarkers" in 2022)

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14 pages, 1731 KiB

Open AccessArticle

MCC Gene Silencing Is a CpG Island Methylator Phenotype-Associated Factor That Predisposes Colon Cancer Cells to Irinotecan and Olaparib

by Zeenat Jahan, Fahad A. Benthani, Nicola Currey, Hannah W. Parker, Jane E. Dahlstrom, C. Elizabeth Caldon and Maija R. J. Kohonen-Corish

Cancers 2022, 14(12), 2859; https://doi.org/10.3390/cancers14122859 - 09 Jun 2022

Cited by 1 | Viewed by 1866

Abstract

Chemotherapy is a mainstay of colorectal cancer treatment, and often involves a combination drug regime. CpG island methylator phenotype (CIMP)-positive tumors are potentially more responsive to the topoisomerase-inhibitor irinotecan. The mechanistic basis of the increased sensitivity of CIMP cancers to irinotecan is poorly [...] Read more.

Chemotherapy is a mainstay of colorectal cancer treatment, and often involves a combination drug regime. CpG island methylator phenotype (CIMP)-positive tumors are potentially more responsive to the topoisomerase-inhibitor irinotecan. The mechanistic basis of the increased sensitivity of CIMP cancers to irinotecan is poorly understood. Mutated in Colorectal Cancer (MCC) is emerging as a multifunctional tumor suppressor gene in colorectal and liver cancers, and has been implicated in drug responsiveness. Here, we found that CIMP tumors undergo MCC loss almost exclusively via promoter hypermethylation rather than copy number variation or mutations. A subset of cancers display hypomethylation which is also associated with low MCC expression, particularly in rectal cancer, where CIMP is rare. MCC knockdown or deletion was found to sensitize cells to SN38 (the active metabolite of irinotecan) or the PARP-inhibitor Olaparib. A synergistic effect on cell death was evident when these drugs were used concurrently. The improved SN38/irinotecan efficacy was accompanied by the down-regulation of DNA repair genes. Thus, differential methylation of MCC is potentially a valuable biomarker to identify colorectal cancers suitable for irinotecan therapy, possibly in combination with PARP inhibitors. Full article

(This article belongs to the Special Issue Feature Paper in Section "Cancer Biomarkers" in 2022)

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16 pages, 2809 KiB

Open AccessArticle

Combining TMEM Doorway Score and Mena^Calc Score Improves the Prediction of Distant Recurrence Risk in HR+/HER2− Breast Cancer Patients

by Xianjun Ye, Maja H. Oktay, Xiaonan Xue, Thomas E. Rohan, Paula S. Ginter, Timothy D’Alfonso, Elizabeth N. Kornaga, Don G. Morris, David Entenberg and John S. Condeelis

Cancers 2022, 14(9), 2168; https://doi.org/10.3390/cancers14092168 - 26 Apr 2022

Cited by 2 | Viewed by 2291

Abstract

Purpose: to develop several digital pathology-based machine vision algorithms for combining TMEM and Mena^Calc scores and determine if a combination of these biomarkers improves the ability to predict development of distant metastasis over and above that of either biomarker alone. Methods: This [...] Read more.

Purpose: to develop several digital pathology-based machine vision algorithms for combining TMEM and Mena^Calc scores and determine if a combination of these biomarkers improves the ability to predict development of distant metastasis over and above that of either biomarker alone. Methods: This retrospective study included a subset of 130 patients (65 patients with no recurrence and 65 patients with a recurrence at 5 years) from the Calgary Tamoxifen cohort of breast cancer patients. Patients had confirmed invasive breast cancer and received adjuvant tamoxifen therapy. Of the 130 patients, 86 cases were suitable for analysis in this study. Sequential sections of formalin-fixed paraffin-embedded patient samples were stained for TMEM doorways (immunohistochemistry triple staining) and Mena^Calc (immunofluorescence staining). Stained sections were imaged, aligned, and then scored for TMEM doorways and Mena^Calc. Different ways of combining TMEM doorway and Mena^Calc scores were evaluated and compared to identify the best performing combined marker by using the restricted mean survival time (RMST) difference method. Results: the best performing combined marker gave an RMST difference of 5.27 years (95% CI: 1.71–8.37), compared to 3.56 years (95% CI: 0.95–6.1) for the associated standalone TMEM doorway analysis and 2.94 years (95% CI: 0.25–5.87) for the associated standalone Mena^Calc analysis. Conclusions: combining TMEM doorway and Mena^Calc scores as a new biomarker improves prognostication over that observed with TMEM doorway or Mena^Calc Score alone in this cohort of 86 patients. Full article

(This article belongs to the Special Issue Feature Paper in Section "Cancer Biomarkers" in 2022)

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17 pages, 3816 KiB

Open AccessArticle

Hypoalbuminemia Is a Hepatocellular Carcinoma Independent Risk Factor for Tumor Progression in Low-Risk Bridge to Transplant Candidates

by Kelley G. Núñez, Tyler Sandow, Jai Patel, Mina Hibino, Daniel Fort, Ari J. Cohen and Paul Thevenot

Cancers 2022, 14(7), 1684; https://doi.org/10.3390/cancers14071684 - 25 Mar 2022

Cited by 5 | Viewed by 2863

Abstract

Due to active hepatocellular carcinoma (HCC) surveillance, many patients are diagnosed with early-stage disease and are usually amendable to curative treatments. These patients lack poor prognostic factors associated with Milan Criteria and alpha fetoprotein (AFP) biomarker levels. There are currently limited strategies to [...] Read more.

Due to active hepatocellular carcinoma (HCC) surveillance, many patients are diagnosed with early-stage disease and are usually amendable to curative treatments. These patients lack poor prognostic factors associated with Milan Criteria and alpha fetoprotein (AFP) biomarker levels. There are currently limited strategies to assess prognosis in the patients who remain at risk of post-treatment HCC progression. In a cohort of liver transplant (LT) candidates with HCC, this study seeks to identify factors prior to liver-directed therapy (LDT) associated with time to progression (TTP). This is a retrospective analysis of prospectively collected data from LT candidates with recently diagnosed HCC and receiving LDT as a bridge to LT at three interventional oncology programs within a single system (n = 373). Demographics, clinical hepatology and serology, and factors related to HCC burden were extracted and analyzed for associations with TTP risk. Albumin level below the cohort median (3.4 g/dL) emerged as an independent risk factor for TTP controlling for AFP > 20 ng/mL as well as Milan, T-stage, and Barcelona Clinic Liver Cancer (BCLC) stage individually. In modality-specific subgroup survival analysis, albumin-based TTP stratification was restricted to patients receiving first cycle microwave ablation (p = 0.007). In n = 162 patients matching all low-risk criteria for Milan, T-stage, BCLC stage, and AFP, the effect of albumin < 3.4 g/dL remained significant for TTP (p = 0.004) with 2-year TTP rates of 68% (<3.4 g/dL) compared to 95% (≥3.4 g/dL). In optimal bridge to LT candidates with small HCC and low AFP biomarker levels, albumin level at treatment baseline provides an HCC-independent positive prognostic factor for risk of HCC progression prior to LT. Full article

(This article belongs to the Special Issue Feature Paper in Section "Cancer Biomarkers" in 2022)

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16 pages, 1632 KiB

Open AccessArticle

Tumor BRCA Testing in Epithelial Ovarian Cancers: Past and Future—Five-Years’ Single-Institution Experience of 762 Consecutive Patients

by Caterina Fumagalli, Ilaria Betella, Alessandra Rappa, Maria di Giminiani, Michela Gaiano, Luigi Antonio De Vitis, Benedetta Zambetti, Davide Vacirca, Francesco Multinu, Konstantinos Venetis, Nicoletta Colombo, Massimo Barberis and Elena Guerini Rocco

Cancers 2022, 14(7), 1638; https://doi.org/10.3390/cancers14071638 - 23 Mar 2022

Cited by 3 | Viewed by 2865

Abstract

The establishment of PARP inhibitors in the treatment of epithelial ovarian carcinoma (EOC) has prompt BRCA assessment at the time of diagnosis. We described our five years of experience of tumor BRCA testing, as part of a multidisciplinary workflow for the management of [...] Read more.

The establishment of PARP inhibitors in the treatment of epithelial ovarian carcinoma (EOC) has prompt BRCA assessment at the time of diagnosis. We described our five years of experience of tumor BRCA testing, as part of a multidisciplinary workflow for the management of EOC patients. We used a BRCA next-generation sequencing (NGS) test for profiling formalin-fixed, paraffin-embedded (FFPE) EOCs of 762 consecutive patients, with a success rate of 99.7% and a median turnaround time of 12 days. We found 178 (23.4%) cases with pathogenic/likely pathogenic (P/LP) mutations, 74 (9.7%) cases with variants of uncertain significance and 508 (66.8%) wild type tumors. Among 174 patients without P/LP mutations and investigated with multiple-ligation probe-amplification analysis on peripheral blood, two (1.1%) were positive for large rearrangements. Patients with P/LP alterations and/or with positive family history were referred to genetic counselling. Comparing tumor and blood NGS test results of 256 patients, we obtained a tumor test negative predictive value of 100% and we defined 76% of P/LP alterations as germline and 24% as somatic variants. The proposed workflow may successfully identify EOC patients with BRCA1/2 alteration, guiding both therapeutic and risk assessment clinical decisions. Full article

(This article belongs to the Special Issue Feature Paper in Section "Cancer Biomarkers" in 2022)

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13 pages, 1502 KiB

Open AccessArticle

Systemic Inflammation Index and Tumor Glycolytic Heterogeneity Help Risk Stratify Patients with Advanced Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma Treated with Tyrosine Kinase Inhibitor Therapy

by Kun-Han Lue, Chun-Hou Huang, Tsung-Cheng Hsieh, Shu-Hsin Liu, Yi-Feng Wu and Yu-Hung Chen

Cancers 2022, 14(2), 309; https://doi.org/10.3390/cancers14020309 - 08 Jan 2022

Cited by 4 | Viewed by 1544

Abstract

Tyrosine kinase inhibitors (TKIs) are the first-line treatment for patients with advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma. Over half of patients failed to achieve prolonged survival benefits from TKI therapy. Awareness of a reliable prognostic tool may provide a [...] Read more.

Tyrosine kinase inhibitors (TKIs) are the first-line treatment for patients with advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma. Over half of patients failed to achieve prolonged survival benefits from TKI therapy. Awareness of a reliable prognostic tool may provide a valuable direction for tailoring individual treatments. We explored the prognostic power of the combination of systemic inflammation markers and tumor glycolytic heterogeneity to stratify patients in this clinical setting. One hundred and five patients with advanced EGFR-mutated lung adenocarcinoma treated with TKIs were retrospectively analyzed. Hematological variables as inflammation-induced biomarkers were collected, including the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation index (SII). First-order entropy, as a marker of heterogeneity within the primary lung tumor, was obtained by analyzing ¹⁸F-fluorodeoxyglucose positron emission tomography images. In a univariate Cox regression analysis, sex, smoking status, NLR, LMR, PLR, SII, and entropy were associated with progression-free survival (PFS) and overall survival (OS). After adjusting for confounders in the multivariate analysis, smoking status, SII, and entropy, remained independent prognostic factors for PFS and OS. Integrating SII and entropy with smoking status represented a valuable prognostic scoring tool for improving the risk stratification of patients. The integrative model achieved a Harrell’s C-index of 0.687 and 0.721 in predicting PFS and OS, respectively, outperforming the traditional TNM staging system (0.527 for PFS and 0.539 for OS, both p < 0.001). This risk-scoring model may be clinically helpful in tailoring treatment strategies for patients with advanced EGFR-mutated lung adenocarcinoma. Full article

(This article belongs to the Special Issue Feature Paper in Section "Cancer Biomarkers" in 2022)

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Review

Jump to: Research, Other

25 pages, 1127 KiB

Open AccessReview

Prognostic and Predictive Molecular Markers in Cholangiocarcinoma

by Sandra Pavicevic, Sophie Reichelt, Deniz Uluk, Isabella Lurje, Cornelius Engelmann, Dominik P. Modest, Uwe Pelzer, Felix Krenzien, Nathanael Raschzok, Christian Benzing, Igor M. Sauer, Sebastian Stintzing, Frank Tacke, Wenzel Schöning, Moritz Schmelzle, Johann Pratschke and Georg Lurje

Cancers 2022, 14(4), 1026; https://doi.org/10.3390/cancers14041026 - 17 Feb 2022

Cited by 20 | Viewed by 7072

Abstract

Cholangiocarcinoma (CCA) is the second most common primary liver cancer and subsumes a heterogeneous group of malignant tumors arising from the intra- or extrahepatic biliary tract epithelium. A rising mortality from CCA has been reported worldwide during the last decade, despite significant improvement [...] Read more.

Cholangiocarcinoma (CCA) is the second most common primary liver cancer and subsumes a heterogeneous group of malignant tumors arising from the intra- or extrahepatic biliary tract epithelium. A rising mortality from CCA has been reported worldwide during the last decade, despite significant improvement of surgical and palliative treatment. Over 50% of CCAs originate from proximal extrahepatic bile ducts and constitute the most common CCA entity in the Western world. Clinicopathological characteristics such as lymph node status and poor differentiation remain the best-studied, but imperfect prognostic factors. The identification of prognostic molecular markers as an adjunct to traditional staging systems may not only facilitate the selection of patients who would benefit the most from surgical, adjuvant or palliative treatment strategies, but may also be helpful in defining the aggressiveness of the disease and identifying patients at high-risk for tumor recurrence. The purpose of this review is to provide an overview of currently known molecular prognostic and predictive markers and their role in CCA. Full article

(This article belongs to the Special Issue Feature Paper in Section "Cancer Biomarkers" in 2022)

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Other

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16 pages, 2754 KiB

Open AccessSystematic Review

The Association between the Pan-Immune-Inflammation Value and Cancer Prognosis: A Systematic Review and Meta-Analysis

by Deniz Can Guven, Taha Koray Sahin, Enes Erul, Saadettin Kilickap, Thilo Gambichler and Sercan Aksoy

Cancers 2022, 14(11), 2675; https://doi.org/10.3390/cancers14112675 - 27 May 2022

Cited by 43 | Viewed by 3381

Abstract

Background: Prognostic scores derived from the blood count have garnered significant interest as an indirect measure of the inflammatory pressure in cancer. The recently developed pan-immune-inflammation value (PIV), an equation including the neutrophil, platelet, monocyte, and lymphocyte levels, has been evaluated in several [...] Read more.

Background: Prognostic scores derived from the blood count have garnered significant interest as an indirect measure of the inflammatory pressure in cancer. The recently developed pan-immune-inflammation value (PIV), an equation including the neutrophil, platelet, monocyte, and lymphocyte levels, has been evaluated in several cohorts, although with variations in the tumor types, disease stages, cut-offs, and treatments. Therefore, we evaluated the association between survival and PIV in cancer, performing a systematic review and meta-analysis. Methods: We conducted a systematic review from the Pubmed, Medline, and Embase databases to filter the published studies until 17 May 2022. The meta-analyses were performed with the generic inverse-variance method with a random-effects model. Results: Fifteen studies encompassing 4942 patients were included. In the pooled analysis of fifteen studies, the patients with higher PIV levels had significantly increased risk of death than those with lower PIV levels (HR: 2.00, 95% CI: 1.51–2.64, p < 0.001) and increased risk of progression or death (HR: 1.80, 95% CI: 1.39–2.32, p < 0.001). Analyses were consistent across several clinical scenarios, including non-metastatic or metastatic disease, different cut-offs (500, 400, and 300), and treatment with targeted therapy or immunotherapy (p < 0.001 for each). Conclusion: The available evidence demonstrates that PIV could be a prognostic biomarker in cancer. However, further research is needed to explore the promise of PIV as a prognostic biomarker in patients with non-metastatic disease or patients treated without immunotherapy or targeted therapy. Full article

(This article belongs to the Special Issue Feature Paper in Section "Cancer Biomarkers" in 2022)

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