Research

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15 pages, 1905 KiB

Open AccessArticle

Mutation Hotspots Found in Bladder Cancer Aid Prediction of Carcinogenic Risk in Normal Urothelium

by Sydney R. Grant, Li Tang, Lei Wei, Barbara A. Foster, Gyorgy Paragh and Wendy J. Huss

Int. J. Mol. Sci. 2023, 24(9), 7852; https://doi.org/10.3390/ijms24097852 - 25 Apr 2023

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More than 80,000 new cases of bladder cancer are estimated to be diagnosed in 2023. However, the 5-year survival rate for bladder cancer has not changed in decades, highlighting the need for prevention. Numerous cancer-causing mutations are present in the urothelium long before [...] Read more.

More than 80,000 new cases of bladder cancer are estimated to be diagnosed in 2023. However, the 5-year survival rate for bladder cancer has not changed in decades, highlighting the need for prevention. Numerous cancer-causing mutations are present in the urothelium long before signs of cancer arise. Mutation hotspots in cancer-driving genes were identified in non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) tumor samples. Mutation burden within the hotspot regions was measured in normal urothelium with a low and high risk of cancer. A significant correlation was found between the mutation burden in normal urothelium and bladder cancer tissue within the hotspot regions. A combination of measured hotspot burden and personal risk factors was used to fit machine learning classification models. The efficacy of each model to differentiate between adjacent benign urothelium from bladder cancer patients and normal urothelium from healthy donors was measured. A random forest model using a combination of personal risk factors and mutations within MIBC hotspots yielded the highest AUC of 0.9286 for the prediction of high- vs. low-risk normal urothelium. Currently, there are no effective biomarkers to assess subclinical field disease and early carcinogenic progression in the bladder. Our findings demonstrate novel differences in mutation hotspots in NMIBC and MIBC and provide the first evidence for mutation hotspots to aid in the assessment of cancer risk in the normal urothelium. Early risk assessment and identification of patients at high risk of bladder cancer before the clinical presentation of the disease can pave the way for targeted personalized preventative therapy. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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11 pages, 1302 KiB

Open AccessArticle

Genetic Analysis of Multiple Primary Malignant Tumors in Women with Breast and Ovarian Cancer

by Alina Savkova, Lyudmila Gulyaeva, Aleksey Gerasimov and Sergey Krasil’nikov

Int. J. Mol. Sci. 2023, 24(7), 6705; https://doi.org/10.3390/ijms24076705 - 04 Apr 2023

Viewed by 1593

Abstract

Familial cancer syndromes, which are commonly caused by germline mutations in oncogenes and tumor suppressor genes, are generally considered to be the cause of primary multiple malignant neoplasias (PMMNs). Using targeted genomic sequencing, we screened for eight germline mutations: BRCA1 185delAG, BRCA1 T300G, [...] Read more.

Familial cancer syndromes, which are commonly caused by germline mutations in oncogenes and tumor suppressor genes, are generally considered to be the cause of primary multiple malignant neoplasias (PMMNs). Using targeted genomic sequencing, we screened for eight germline mutations: BRCA1 185delAG, BRCA1 T300G, BRCA1 2080delA, BRCA1 4153delA, BRCA1 5382insC, BRCA2 6174delT, CHEK2 1100delC, and BLM C1642T, which provoke the majority of cases of hereditary breast and ovary cancer syndrome (HBOC), in genomic (blood) DNA from 60 women with PMMNs, including breast (BC) and/or ovarian cancer(s) (OC). Pathogenic allelic forms were discovered in nine samples: in seven instances, it was BRCA1 5382insC, and in the following two, BRCA1 4153delA and BRCA1 T300G. The age of onset in these patients (46.8 years) was younger than in the general Russian population (61.0) for BC but was not for OC: 58.3 and 59.4, correspondingly. There were invasive breast carcinomas of no special type and invasive serous ovarian carcinomas in all cases. Two or more tumors of HBOC-spectrum were only in five out of nine families of mutation carriers. Nevertheless, every mutation carrier has relatives who have developed malignant tumors. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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18 pages, 2399 KiB

Open AccessArticle

Germline Variants in 32 Cancer-Related Genes among 700 Chinese Breast Cancer Patients by Next-Generation Sequencing: A Clinic-Based, Observational Study

by Liu Yang, Fei Xie, Chang Liu, Jin Zhao, Taobo Hu, Jinbo Wu, Xiaotao Zhao and Shu Wang

Int. J. Mol. Sci. 2022, 23(19), 11266; https://doi.org/10.3390/ijms231911266 - 24 Sep 2022

Cited by 1 | Viewed by 1643

Abstract

Breast cancer (BC) is associated with hereditary components, and some deleterious germline variants have been regarded as effective therapeutic targets. We conducted a clinic-based, observational study to better understand the distribution of deleterious germline variants and assess any clinicopathological predictors related to the [...] Read more.

Breast cancer (BC) is associated with hereditary components, and some deleterious germline variants have been regarded as effective therapeutic targets. We conducted a clinic-based, observational study to better understand the distribution of deleterious germline variants and assess any clinicopathological predictors related to the variants among Chinese BC patients using a 32 cancer-related genes next-generation sequencing panel. Between November 2020 and February 2022, a total of 700 BC patients were recruited, and 13.1% (92/700) of them carried deleterious germline variants in 15 cancer-related genes, including 37 (37/700, 5.3%) in BRCA2, 29 (29/700, 4.1%) in BRCA1, 8 (8/700, 1.1%) in PALB2, 4 (4/700, 0.6%) in NBN, 3 (3/700, 0.4%) in MRE11A, 3 (3/700, 0.4%) in TP53 and 12 (12/700, 1.7%) in other genes. There were 28 novel variants detected: 5 in BRCA1, 14 in BRCA2, and 9 in non-BRCA1/2 genes. The variants in panel genes, HRR (homologous recombination repair)-related genes, and BRCA1/2 were significantly associated with the following clinicopathological factors: age at the initial diagnosis of BC, family history of any cancer, molecular subtype, Ki-67 index, and hereditary risk. In conclusion, we further expanded the spectrum of germline deleterious variants in Chinese BC patients, and the clinicopathological predictors of variants were identified to facilitate clinical genetic testing and counseling for appropriate individuals. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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20 pages, 3671 KiB

Open AccessArticle

Whole-Exome Sequencing Identifies a Novel Germline Variant in PTK7 Gene in Familial Colorectal Cancer

by Beiping Miao, Diamanto Skopelitou, Aayushi Srivastava, Sara Giangiobbe, Dagmara Dymerska, Nagarajan Paramasivam, Abhishek Kumar, Magdalena Kuświk, Wojciech Kluźniak, Katarzyna Paszkowska-Szczur, Matthias Schlesner, Jan Lubinski, Kari Hemminki, Asta Försti and Obul Reddy Bandapalli

Int. J. Mol. Sci. 2022, 23(3), 1295; https://doi.org/10.3390/ijms23031295 - 24 Jan 2022

Cited by 2 | Viewed by 2580

Abstract

Colorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide. Only 5% of all CRC cases are due to germline mutations in known predisposition genes, and the remaining genetic burden still has to be discovered. In this study, we performed whole-exome sequencing [...] Read more.

Colorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide. Only 5% of all CRC cases are due to germline mutations in known predisposition genes, and the remaining genetic burden still has to be discovered. In this study, we performed whole-exome sequencing on six members of a Polish family diagnosed with CRC and identified a novel germline variant in the protein tyrosine kinase 7 (inactive) gene (PTK7, ENST00000230419, V354M). Targeted screening of the variant in 1705 familial CRC cases and 1674 healthy elderly individuals identified the variant in an additional familial CRC case. Introduction of this variant in HT-29 cells resulted in increased cell proliferation, migration, and invasion; it also caused down-regulation of CREB, p21 and p53 mRNA and protein levels, and increased AKT phosphorylation. These changes indicated inhibition of apoptosis pathways and activation of AKT signaling. Our study confirmed the oncogenic function of PTK7 and supported its role in genetic predisposition of familial CRC. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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13 pages, 3168 KiB

Open AccessArticle

Classification and Functional Analysis between Cancer and Normal Tissues Using Explainable Pathway Deep Learning through RNA-Sequencing Gene Expression

by Sangick Park, Eunchong Huang and Taejin Ahn

Int. J. Mol. Sci. 2021, 22(21), 11531; https://doi.org/10.3390/ijms222111531 - 26 Oct 2021

Cited by 2 | Viewed by 1999

Abstract

Deep learning has proven advantageous in solving cancer diagnostic or classification problems. However, it cannot explain the rationale behind human decisions. Biological pathway databases provide well-studied relationships between genes and their pathways. As pathways comprise knowledge frameworks widely used by human researchers, representing [...] Read more.

Deep learning has proven advantageous in solving cancer diagnostic or classification problems. However, it cannot explain the rationale behind human decisions. Biological pathway databases provide well-studied relationships between genes and their pathways. As pathways comprise knowledge frameworks widely used by human researchers, representing gene-to-pathway relationships in deep learning structures may aid in their comprehension. Here, we propose a deep neural network (PathDeep), which implements gene-to-pathway relationships in its structure. We also provide an application framework measuring the contribution of pathways and genes in deep neural networks in a classification problem. We applied PathDeep to classify cancer and normal tissues based on the publicly available, large gene expression dataset. PathDeep showed higher accuracy than fully connected neural networks in distinguishing cancer from normal tissues (accuracy = 0.994) in 32 tissue samples. We identified 42 pathways related to 32 cancer tissues and 57 associated genes contributing highly to the biological functions of cancer. The most significant pathway was G-protein-coupled receptor signaling, and the most enriched function was the G1/S transition of the mitotic cell cycle, suggesting that these biological functions were the most common cancer characteristics in the 32 tissues. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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23 pages, 1399 KiB

Open AccessArticle

Whole Exome Sequencing Identifies APCDD1 and HDAC5 Genes as Potentially Cancer Predisposing in Familial Colorectal Cancer

by Diamanto Skopelitou, Beiping Miao, Aayushi Srivastava, Abhishek Kumar, Magdalena Kuświk, Dagmara Dymerska, Nagarajan Paramasivam, Matthias Schlesner, Jan Lubinski, Kari Hemminki, Asta Försti and Obul Reddy Bandapalli

Int. J. Mol. Sci. 2021, 22(4), 1837; https://doi.org/10.3390/ijms22041837 - 12 Feb 2021

Cited by 5 | Viewed by 3442

Abstract

Germline mutations in predisposition genes account for only 20% of all familial colorectal cancers (CRC) and the remaining genetic burden may be due to rare high- to moderate-penetrance germline variants that are not explored. With the aim of identifying such potential cancer-predisposing variants, [...] Read more.

Germline mutations in predisposition genes account for only 20% of all familial colorectal cancers (CRC) and the remaining genetic burden may be due to rare high- to moderate-penetrance germline variants that are not explored. With the aim of identifying such potential cancer-predisposing variants, we performed whole exome sequencing on three CRC cases and three unaffected members of a Polish family and identified two novel heterozygous variants: a coding variant in APC downregulated 1 gene (APCDD1, p.R299H) and a non-coding variant in the 5′ untranslated region (UTR) of histone deacetylase 5 gene (HDAC5). Sanger sequencing confirmed the variants segregating with the disease and Taqman assays revealed 8 additional APCDD1 variants in a cohort of 1705 familial CRC patients and no further HDAC5 variants. Proliferation assays indicated an insignificant proliferative impact for the APCDD1 variant. Luciferase reporter assays using the HDAC5 variant resulted in an enhanced promoter activity. Targeting of transcription factor binding sites of SNAI-2 and TCF4 interrupted by the HDAC5 variant showed a significant impact of TCF4 on promoter activity of mutated HDAC5. Our findings contribute not only to the identification of unrecognized genetic causes of familial CRC but also underline the importance of 5’UTR variants affecting transcriptional regulation and the pathogenesis of complex disorders. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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14 pages, 1854 KiB

Open AccessArticle

Identification of New Genes Involved in Germline Predisposition to Early-Onset Gastric Cancer

by Cristina Herrera-Pariente, Roser Capó-García, Marcos Díaz-Gay, Sabela Carballal, Jenifer Muñoz, Joan Llach, Ariadna Sánchez, Laia Bonjoch, Coral Arnau-Collell, Yasmin Soares de Lima, Mariano Golubicki, Gerhard Jung, Juan José Lozano, Antoni Castells, Francesc Balaguer, Luis Bujanda, Sergi Castellví-Bel and Leticia Moreira

Int. J. Mol. Sci. 2021, 22(3), 1310; https://doi.org/10.3390/ijms22031310 - 28 Jan 2021

Cited by 7 | Viewed by 3126

Abstract

The genetic cause for several families with gastric cancer (GC) aggregation is unclear, with marked relevance in early-onset patients. We aimed to identify new candidate genes involved in GC germline predisposition. Whole-exome sequencing (WES) of germline samples was performed in 20 early-onset GC [...] Read more.

The genetic cause for several families with gastric cancer (GC) aggregation is unclear, with marked relevance in early-onset patients. We aimed to identify new candidate genes involved in GC germline predisposition. Whole-exome sequencing (WES) of germline samples was performed in 20 early-onset GC patients without previous germline mutation identified. WES was also performed in nine tumor samples to analyze the somatic profile using SigProfilerExtractor tool. Sequencing germline data were filtered to select those variants with plausible pathogenicity, rare frequency and previously involved in cancer. Then, a manual filtering was performed to prioritize genes according to current knowledge and function. These genetic variants were prevalidated with Integrative Genomics Viewer 2.8.2 (IGV). Subsequently, a further selection step was carried out according to function and information obtained from tumor samples. After IGV and selection step, 58 genetic variants in 52 different candidate genes were validated by Sanger sequencing. Among them, APC, FAT4, CTNND1 and TLR2 seem to be the most promising genes because of their role in hereditary cancer syndromes, tumor suppression, cell adhesion and Helicobacter pylori recognition, respectively. These encouraging results represent the open door to the identification of new genes involved in GC germline predisposition. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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16 pages, 10420 KiB

Open AccessArticle

NF-Y Overexpression in Liver Hepatocellular Carcinoma (HCC)

by Eugenia Bezzecchi, Mirko Ronzio, Roberto Mantovani and Diletta Dolfini

Int. J. Mol. Sci. 2020, 21(23), 9157; https://doi.org/10.3390/ijms21239157 - 01 Dec 2020

Cited by 19 | Viewed by 2569

Abstract

NF-Y is a pioneer trimeric transcription factor formed by the Histone Fold Domain (HFD) NF-YB/NF-YC subunits and NF-YA. Three subunits are required for DNA binding. CCAAT-specificity resides in NF-YA and transactivation resides in Q-rich domains of NF-YA and NF-YC. They are involved in [...] Read more.

NF-Y is a pioneer trimeric transcription factor formed by the Histone Fold Domain (HFD) NF-YB/NF-YC subunits and NF-YA. Three subunits are required for DNA binding. CCAAT-specificity resides in NF-YA and transactivation resides in Q-rich domains of NF-YA and NF-YC. They are involved in alternative splicing (AS). We recently showed that NF-YA is overexpressed in breast and lung carcinomas. We report here on the overexpression of all subunits in the liver hepatocellular carcinoma (HCC) TCGA database, specifically the short NF-YAs and NF-YC2 (37 kDa) isoforms. This is observed at all tumor stages, in viral-infected samples and independently from the inflammatory status. Up-regulation of NF-YAs and NF-YC, but not NF-YB, is associated to tumors with mutant p53. We used a deep-learning-based method (DeepCC) to extend the partitioning of the three molecular clusters to all HCC TCGA tumors. In iCluster3, CCAAT is a primary matrix found in promoters of up-regulated genes, and cell-cycle pathways are enriched. Finally, clinical data indicate that, globally, only NF-YAs, but not HFD subunits, correlate with the worst prognosis; in iCluster1 patients, however, all subunits correlate. The data show a difference with other epithelial cancers, in that global overexpression of the three subunits is reported and clinically relevant in a subset of patients; yet, they further reinstate the regulatory role of the sequence-specific subunit. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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Review

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10 pages, 565 KiB

Open AccessReview

TMB in NSCLC: A Broken Dream?

by Sara Bravaccini, Giuseppe Bronte and Paola Ulivi

Int. J. Mol. Sci. 2021, 22(12), 6536; https://doi.org/10.3390/ijms22126536 - 18 Jun 2021

Cited by 29 | Viewed by 3874

Abstract

Although immune checkpoint inhibitors have changed the treatment paradigm of a variety of cancers, including non-small-cell lung cancer, not all patients respond to immunotherapy in the same way. Predictive biomarkers for patient selection are thus needed. Tumor mutation burden (TMB), defined as the [...] Read more.

Although immune checkpoint inhibitors have changed the treatment paradigm of a variety of cancers, including non-small-cell lung cancer, not all patients respond to immunotherapy in the same way. Predictive biomarkers for patient selection are thus needed. Tumor mutation burden (TMB), defined as the total number of somatic/acquired mutations per coding area of a tumor genome (Mut/Mb), has emerged as a potential predictive biomarker of response to immune checkpoint inhibitors. We found that the limited use of TMB in clinical practice is due to the difficulty in its detection and compounded by several different biological, methodological and economic issues. The incorporation of both TMB and PD-L1 expression or other biomarkers into multivariable predictive models could result in greater predictive power. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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15 pages, 6492 KiB

Open AccessReview

Future Perspectives in Detecting EGFR and ALK Gene Alterations in Liquid Biopsies of Patients with NSCLC

by Daniela Ferreira, Juliana Miranda, Paula Martins-Lopes, Filomena Adega and Raquel Chaves

Int. J. Mol. Sci. 2021, 22(8), 3815; https://doi.org/10.3390/ijms22083815 - 07 Apr 2021

Cited by 7 | Viewed by 3662

Abstract

Non-small-cell lung cancer (NSCLC) is a major cause of death worldwide. Alterations in such genes as EGFR and ALK are considered important biomarkers in NSCLC due to the existence of targeted therapies with specific tyrosine kinase inhibitors (TKIs). However, specific resistance-related mutations can [...] Read more.

Non-small-cell lung cancer (NSCLC) is a major cause of death worldwide. Alterations in such genes as EGFR and ALK are considered important biomarkers in NSCLC due to the existence of targeted therapies with specific tyrosine kinase inhibitors (TKIs). However, specific resistance-related mutations can occur during TKI treatment, which often result in therapy inefficacy. Liquid biopsies arise as a reliable tool for the early detection of these types of alterations, allowing a non-invasive follow-up of the patients. Furthermore, they can be essential for cancer screening, initial diagnosis and to check surgery success. Despite the great advantages of liquid biopsies in NSCLC and the high input that next-generation sequencing (NGS) approaches can provide in this field, its use in oncology is still limited. With improvement of assay sensitivity and the establishment of clinical guidelines for liquid biopsy analysis, it is expected that they will be used in routine procedures. This review focuses on the usefulness of liquid biopsies of NSCLC patients as a means to detect alterations in EGFR and ALK genes and in disease management, highlighting the impact of NGS methods. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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