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Molecular Diagnostics and Genomics of Tumors

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 20 August 2025 | Viewed by 12317

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Prof. Dr. Petra Korać

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Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10 000 Zagreb, Croatia
Interests: cancer; tumor; diagnosis; genetics
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

As you are aware, in the last few decades, tumor genomics, transcriptomics and proteomics became requisite information for precise diagnostics that leads to precise and effective therapy. With the development of molecular methods and accumulation of knowledge about tumor biology, behavior and progression, new biomarkers arise almost daily. In this Special Issue, we aim to collect recent advances in the field—both basic research-oriented papers from the field of tumor genomics and papers about development of new approaches in applied genomics. We hope that this issue will cover one of many subjects in this promising field, such as:

Genomic as a basis for molecular diagnostics;
Description of new cancer biomarkers;
Cancer genomics insights;
Development of precision medicine;
Prediction methods in cancer biology;
Clinical relevance of tumor genomics data.

Prof. Dr. Petra Korać
Guest Editor

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Keywords

tumor biology
cancer genomics
molecular diagnostics
biomarkers
precision medicine

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Published Papers (9 papers)

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Research

19 pages, 11575 KiB

Open AccessArticle

NID2 Affects Prognosis of Glioma via Activating the Akt Signaling Pathway

by Zhangzhang Lan, Yanlin Xiao, Youyou Liao, Xuan Li, Yi Zhang, Huajie Wang and Wenyong Zhang

Int. J. Mol. Sci. 2025, 26(8), 3859; https://doi.org/10.3390/ijms26083859 - 18 Apr 2025

Viewed by 300

Abstract

Nidogen-2 (NID2) is a critical component of the extracellular matrix (ECM), which plays a regulatory role in cell adhesion, migration, differentiation, and survival. Previous studies have shown that NID2 is deregulated in several types of cancer, but its role in glioma is unknown. The present study investigated the prognostic value of NID2 in glioma and its associated molecular pathways and functional roles in malignant progression. The performed analyses included investigating the NID2 expression profile using the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and tumor tissue microarray. The findings demonstrated that NID2 high expression predicts worse patient survival by both univariable and multivariable analyses. There is a strong correlation between NID2 upregulation and tumor grade. In stably NID2-overexpressed glioma cells, RNA-Seq analysis revealed coactivation of oncogenic functional pathways, including cell proliferation, survival, epithelial–mesenchymal transition, ECM organization, and migration. Overexpression of NID2 in U87MG and T98G cells promoted cell proliferation, migration, and invasion. TUNEL assay showed NID2 overexpression protected cells from apoptosis. Western blotting analysis showed activation of Akt and Bcl-xL in NID2-overexpressed cells. Our results show that NID2 is a promising prognostic marker in glioma. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Genomics of Tumors)

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18 pages, 6066 KiB

Open AccessArticle

Diagnostic and Prognostic Value of hsa_piR_022710, hsa_piR_019822, and hsa_piR_020840 in Early-Stage Non-Small-Cell Lung Cancer: Implications for Recurrence and Survival in Squamous Cell Carcinoma Patients

by Yangyi He, Antonio Altuna-Coy, Melissa Acosta-Plasencia, Laureano Molins, David Sánchez-Lorente, Daniel Martinez, Tania Díaz, Risha Na, Ramón M. Marrades and Alfons Navarro

Int. J. Mol. Sci. 2025, 26(7), 2870; https://doi.org/10.3390/ijms26072870 - 21 Mar 2025

Viewed by 473

Abstract

Despite significant advancements in early detection and treatment, non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. Specifically, in early-stage cases, recurrence after surgery continues to be the principal cause of death for these patients. The urgent need for novel diagnostic and prognostic biomarkers has directed attention towards PIWI-interacting RNAs (piRNAs), a group of small RNAs that regulate genomic stability and epigenetics. Some piRNAs, including hsa_piR_022710, hsa_piR_019822, and hsa_piR_020840, have been described as deregulated in various cancers. This study investigated the expression of these three piRNAs by RT-qPCR in 277 NSCLC patients and developed survival and CART classification models to predict recurrence risk, overall survival (OS), and disease-free survival (DFS). hsa_piR_019822 and hsa_piR_020840 were able to discriminate between tumor and normal tissue, as well as between adenocarcinoma and squamous cell carcinoma (LUSC) patients. Elevated expression of hsa_piR_019822 and hsa_piR_022710 was correlated with an increased risk of recurrence and poorer DFS and OS in LUSC patients. Patients with high hsa_piR_022710 expression more greatly benefited from adjuvant treatment. In summary, higher piRNA levels were associated with an increased risk of recurrence and poorer survival outcomes, especially in LUSC patients, where they may help guide personalized treatment strategies. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Genomics of Tumors)

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16 pages, 3477 KiB

Open AccessArticle

In Silico Validation of OncoOrigin: An Integrative AI Tool for Primary Cancer Site Prediction with Graphical User Interface to Facilitate Clinical Application

by Petar Brlek, Luka Bulić, Nidhi Shah, Parth Shah and Dragan Primorac

Int. J. Mol. Sci. 2025, 26(6), 2568; https://doi.org/10.3390/ijms26062568 - 13 Mar 2025

Viewed by 711

Abstract

Cancers of unknown primary (CUPs) represent a significant diagnostic and therapeutic challenge in the field of oncology. Due to the limitations of current diagnostic tools in these cases, novel approaches must be brought forward to improve treatment outcomes for these patients. The objective of this study was to develop a machine-learning-based software for primary cancer site prediction (OncoOrigin), based on genetic data acquired from tumor DNA sequencing. By design, this was an in silico diagnostic study, conducted using data from the cBioPortal database (accessed on 21 September 2024) and several data processing and machine learning Python libraries. The study involved over 20,000 tumor samples with information on patient age, sex, and the presence of genetic variants in over 600 genes. The main outcome of interest was machine-learning-based discrimination between cancer site classes. Model quality was assessed by training set cross-validation and evaluation on a segregated test set. Finally, the optimal model was incorporated with a graphical user interface into the OncoOrigin software. Feature importance for class discrimination was also determined on the optimal model. Out of the four tested machine learning estimators, the XGBoostClassifier-based model proved superior in test set evaluation, with a top-2 accuracy of 0.91 and ROC-AUC of 0.97. Unlike other machine learning models published in the literature, OncoOrigin stands out as the only one integrated with a graphical user interface, which is crucial for facilitating its use by oncology specialists in everyday clinical practice, where its application and implementation will have the greatest value in the future. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Genomics of Tumors)

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15 pages, 5075 KiB

Open AccessArticle

Novel De Novo BRCA2 Variant in an Early-Onset Ovarian Cancer Reveals a Unique Tumor Evolution Pathway

by Gianmaria Miolo, Giovanni Canil, Maurizio Polano, Michele Dal Bo, Alessia Mondello, Antonio Palumbo, Fabio Puglisi and Giuseppe Corona

Int. J. Mol. Sci. 2025, 26(5), 2295; https://doi.org/10.3390/ijms26052295 - 5 Mar 2025

Viewed by 802

Abstract

Ovarian cancer (OC) is a highly heterogeneous malignancy, often characterized by complex genomic alterations that drive tumor progression and therapy resistance. In this paper, we report a novel de novo BRCA2 germline variant NM_000059.3:c.(8693_8695delinsGT) associated with early-onset OC that featured two regions with differential MMR (Mismatch Repair) gene expression. To date, only six cases of de novo BRCA2 variants have been reported, none of which were associated with early-onset high-grade serous OC. The immunohistochemical analysis of MMR genes revealed two distinct tumor areas, separated by a clear topographic boundary, with the heterogeneous expression of MLH1 and PMS2 proteins. Seventy-five percent of the tumor tissue showed positivity, while the remaining 25% exhibited a complete absence of expression, underscoring the spatial variability in MMR gene expression within the tumor. Integrated comparative spatial genomic profiling identified several tumor features associated with the genetic variant as regions of loss of heterozygosity (LOH) that involved BRCA2 and MLH1 genes, along with a significantly higher mutational tumor burden in the tumor area that lacked MLH1 and PMS2 expression, indicating its further molecular evolution. The following variants were acquired: c.6572C>T in NOTCH2, c.1852C>T in BCL6, c.191A>T in INHBA, c.749C>T in CUX1, c.898C>A in FANCG, and c.1712G>C in KDM6A. Integrated comparative spatial proteomic profiles revealed defects in the DNA repair pathways, as well as significant alterations in the extracellular matrix (ECM). The differential expression of proteins involved in DNA repair, particularly those associated with MMR and Base Excision Repair (BER), highlights the critical role of defective repair mechanisms in driving genomic instability. Furthermore, ECM components, such as collagen isoforms, Fibrillin-1, EMILIN-1, Prolargin, and Lumican, were found to be highly expressed in the MLH1/PMS2-deficient tumor area, suggesting a connection between DNA repair deficiencies, ECM remodeling, and tumor progression. Thus, the identification of the BRCA2 variant sheds light on the poorly understood interplay between DNA repair deficiencies and ECM remodeling in OC, providing new insights into their dual role in shaping tumor evolution and suggesting potential targets for novel therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Genomics of Tumors)

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17 pages, 5396 KiB

Open AccessArticle

Regulation of Age-Related Lipid Metabolism in Ovarian Cancer

by Jihua Feng, Clay Douglas Rouse, Lila Taylor, Santiago Garcia, Ethan Nguyen, Isabella Coogan, Olivia Byrd, Andrew Berchuck, Susan K. Murphy and Zhiqing Huang

Int. J. Mol. Sci. 2025, 26(1), 320; https://doi.org/10.3390/ijms26010320 - 1 Jan 2025

Viewed by 1767

Abstract

The mortality rate of ovarian cancer (OC) remains the highest among female gynecological malignancies. Advanced age is the highest risk factor for OC development and progression, yet little is known about the role of the aged tumor microenvironment (TME). We conducted RNA sequencing and lipidomic analysis of young and aged gonadal adipose tissue from rat xenografts before and after OC formation. The rates of tumor formation (p = 0.047) and tumor volume (p = 0.002) were significantly higher in the aged rats than in their young counterparts. RNA sequencing data showed significant differences in gene expression profiles between the groups of young and aged rat adipose tissues (p < 0.05), including S100a8, S100a9, Il1rl1, Lcn2, C3, Hba-a1, Fcna, and Pnpla3. At the time of tumor generation, there were also changes in the lipid components within the gonadal adipose tissues of young and aged rats, with higher levels of free fatty acids (FFAs) and triglycerides (TGs) in aged rats. Furthermore, the aged TME showed changes in immune cell composition, especially inflammation-related cells, including neutrophils, myeloid dendritic cells, CD4+ T cells (non-regulatory), and mast cell activation (p < 0.05). The correlation between S100a8, S100a9, neutrophil, and omega-5, FFA 18:3 levels was also determined. Additionally, omega-5, which is downregulated in aged rats, inhibited OC cell proliferation in vitro (p < 0.001). Our study suggests that the aged TME promotes OC proliferation resulting from age-related changes in gene/pathway expression, lipid metabolism, and immune cell distribution. Targeting the aging adipose microenvironment, particularly lipid metabolism, is a promising therapeutic strategy for OC and warrants further investigation. Significance: The aging microenvironment contributes to OC development and progression because of changes in the immune response regulatory genes S100a8 and S100a9, secreted by adipocytes, preadipocytes, or neutrophils, and by altering omega-5 metabolism. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Genomics of Tumors)

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15 pages, 2611 KiB

Open AccessArticle

Dynamic Changes in Circulating Tumor DNA During Immunotherapy for Head and Neck Cancer: SHIZUKU-HN Study

by Rika Noji, Kohki Tohyama, Shin Nakamura, Takahiro Naito, Yu Oikawa, Takeshi Kuroshima, Hirofumi Tomioka, Yasuyuki Michi, Sadakatsu Ikeda, Takahiro Asakage, Masahiko Miura, Yasuo Hamamoto, Hiroyuki Harada and Yoshihito Kano

Int. J. Mol. Sci. 2025, 26(1), 235; https://doi.org/10.3390/ijms26010235 - 30 Dec 2024

Cited by 1 | Viewed by 1375

Abstract

Immune checkpoint inhibitors (ICIs) are effective in treating recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but only 20% of patients achieve durable responses. This study evaluated circulating tumor DNA (ctDNA) as a real-time biomarker for monitoring treatment response in HNSCC. The SHIZUKU-HN study prospectively collected and analyzed serial plasma samples (n = 27) from HNSCC patients undergoing ICIs, using Guardant360 to assess ctDNA variant allele frequency (VAF) and genetic mutations. Tumor volumes were quantified using 3D reconstruction of CT scans, and data from Japan’s C-CAT database (n = 2255) provided insights into ctDNA testing in HNSCC. C-CAT data showed that ctDNA testing was underutilized, performed in only 7% of head and neck cancer cases. In SHIZUKU-HN, mean VAF significantly correlated with tumor volume (Spearman’s ρ = 0.70, p = 0.001), often preceding radiographic progression. BRAF and APC mutations disappeared in partial responders, while GNAS mutations varied. EGFR and PIK3CA amplifications, detectable via ctDNA but missed in tissue biopsies, indicated emerging resistance mechanisms. The SHIZUKU-HN study demonstrates the potential of ctDNA as a dynamic biomarker in HNSCC, offering early insights into treatment efficacy and informing personalized ICI therapy. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Genomics of Tumors)

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13 pages, 2942 KiB

Open AccessArticle

SIGMAR1 Knockdown Enhances Oral Cancer Cell Chemosensitivity to Cisplatin via Decreased PD-L1 Expression

by Pablo Shimaoka Chagas, Cristiana Bernadelli Garcia, Lucas Oliveira Sousa, Gabriel da Silva, Graziella Ribeiro de Sousa, Rodolfo Cabral Marcelino, Leandro Luongo de Matos, Luiz Paulo Kowalski, Évila Salles, Lei Wang, Babak Baban and Andréia Machado Leopoldino

Int. J. Mol. Sci. 2024, 25(22), 11856; https://doi.org/10.3390/ijms252211856 - 5 Nov 2024

Cited by 3 | Viewed by 2568

Abstract

Emerging evidence suggests that aberrant expression levels of Sigma1 (SIGMAR1, also known as sigma-1 receptor) have been implicated in the progression of various diseases, including cancer. However, its significance in oral cancer (OC) has not been thoroughly explored. To advance in this field, the present study aimed to investigate the impact of SIGMAR1 knockdown in oral cancer cells. To do so, we included in this study our cohort of human OC samples and OC cell lines, which were utilized for experimental verification through several in vitro assays. Our findings revealed that SIGMAR1 overexpression was associated with poor survival rates and positively correlated with PD-L1 overexpression in human oral cancer samples. Furthermore, SIGMAR1 inhibition led to a decrease in PD-L1 expression and sensitized oral cancer cells to cisplatin treatment by enhancing apoptosis. These results suggest that SIGMAR1 knockdown may present a promising strategy worthy of further exploration in the management of oral cancer. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Genomics of Tumors)

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32 pages, 9671 KiB

Open AccessArticle

Ten Hypermethylated lncRNA Genes Are Specifically Involved in the Initiation, Progression, and Lymphatic and Peritoneal Metastasis of Epithelial Ovarian Cancer

by Eleonora A. Braga, Alexey M. Burdennyy, Leonid A. Uroshlev, Danila M. Zaichenko, Elena A. Filippova, Svetlana S. Lukina, Irina V. Pronina, Iana R. Astafeva, Marina V. Fridman, Tatiana P. Kazubskaya, Vitaly I. Loginov, Alexey A. Dmitriev, Aleksey A. Moskovtsev and Nikolay E. Kushlinskii

Int. J. Mol. Sci. 2024, 25(21), 11843; https://doi.org/10.3390/ijms252111843 - 4 Nov 2024

Viewed by 1527

Abstract

Abstract: Our work aimed to evaluate and differentiate the role of ten lncRNA genes (GAS5, HAND2-AS1, KCNK15-AS1, MAGI2-AS3, MEG3, SEMA3B-AS1, SNHG6, SSTR5-AS1, ZEB1-AS1, and ZNF667-AS1) in the development and progression of epithelial ovarian cancer (EOC). A representative set of clinical samples was used: 140 primary tumors from patients without and with metastases and 59 peritoneal metastases. Using MS-qPCR, we demonstrated an increase in methylation levels of all ten lncRNA genes in tumors compared to normal tissues (p < 0.001). Using RT-qPCR, we showed downregulation and an inverse relationship between methylation and expression levels for ten lncRNAs (r_s < −0.5). We further identified lncRNA genes that were specifically hypermethylated in tumors from patients with metastases to lymph nodes (HAND2-AS1), peritoneum (KCNK15-AS1, MEG3, and SEMA3B-AS1), and greater omentum (MEG3, SEMA3B-AS1, and ZNF667-AS1). The same four lncRNA genes involved in peritoneal spread were associated with clinical stage and tumor extent (p < 0.001). Interestingly, we found a reversion from increase to decrease in the hypermethylation level of five metastasis-related lncRNA genes (MEG3, SEMA3B-AS1, SSTR5-AS1, ZEB1-AS1, and ZNF667-AS1) in 59 peritoneal metastases. This reversion may be associated with partial epithelial–mesenchymal transition (EMT) in metastatic cells, as indicated by a decrease in the level of the EMT marker, CDH1 mRNA (p < 0.01). Furthermore, novel mRNA targets and regulated miRNAs were predicted for a number of the studied lncRNAs using the NCBI GEO datasets and analyzed by RT-qPCR and transfection of SKOV3 and OVCAR3 cells. In addition, hypermethylation of SEMA3B-AS1, SSTR5-AS1, and ZNF667-AS1 genes was proposed as a marker for overall survival in patients with EOC. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Genomics of Tumors)

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13 pages, 2194 KiB

Open AccessArticle

Gene Expression Aberrations in Alcohol-Associated Hepatocellular Carcinoma

by Andreja Petrović, Paula Štancl, Paula Gršković, Suzana Hančić, Rosa Karlić, Slavko Gašparov and Petra Korać

Int. J. Mol. Sci. 2024, 25(19), 10558; https://doi.org/10.3390/ijms251910558 - 30 Sep 2024

Viewed by 1352

Abstract

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, ranking as the sixth most common cancer worldwide and the fourth leading cause of cancer-related deaths. Most HCC cases originate from cirrhotic livers, typically due to chronic liver diseases, such as hepatitis B (HBV) and hepatitis C (HCV) infections, and alcoholism. HCC cells often harbor numerous somatic mutations that are implicated in HCC development, but epigenetic factors, such as miRNA interference, can also affect HCC initiation and progress. miRNA-221 has been explored as a factor affecting HCC development in HCC of viral etiology, but little is known about its effects on gene expression in alcohol-associated HCC. This study aimed to explore potentially similar gene expression aberrations underlying viral and alcohol-induced HCC. We analyzed available transcriptome data from non-tumor hepatocytes and viral-induced HCC tissues. The most notable differences in gene expression associated with miRNA-221 between non-tumor hepatocytes and viral-induced HCC involved NTF-3 and MYBL1 genes. To assess these data in alcohol-induced HCC, we examined 111 tissue samples: tumor tissue and cirrhotic tissue samples from 37 HCC patients and 37 samples from non-tumor liver tissue using RT-Q PCR. We found no significant difference in NTF-3 expression, but MYBL1 expression was significantly lower in HCC tissue compared to non-tumor hepatocytes and cirrhotic tissue. Our findings highlight the importance of the MYBL1 gene in HCC development and emphasize the need for diverse approaches in evaluating tumor mechanisms. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Genomics of Tumors)

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