Journal of Molecular Pathology

Research

12 pages, 2139 KiB

Open AccessFeature PaperArticle

Analysis of Copy Number Variations in Solid Tumors Using a Next Generation Sequencing Custom Panel

by Marta Vives-Usano, Beatriz García Pelaez, Ruth Román Lladó, Mónica Garzón Ibañez, Erika Aldeguer, Sonia Rodriguez, Andrés Aguilar, Francesc Pons, Santiago Viteri, Carlos Cabrera, Maria José Catalán, Irene Moya, María Gonzalez Cao, Juan José García-Mosquera, Alejandro Martinez-Bueno, Ekaterina Meshoulam, Nuria Jordana, Laura Berrocal, Rafael Rosell, Miguel Angel Molina and Clara Mayo de las Casas Show full author list Hide full author list

J. Mol. Pathol. 2021, 2(2), 123-134; https://doi.org/10.3390/jmp2020013 - 21 May 2021

Cited by 6 | Viewed by 5249

Abstract

Somatic copy number variations (CNV; i.e., amplifications and deletions) have been implicated in the origin and development of multiple cancers and some of these aberrations are designated targets for therapies. Although FISH is still considered the gold standard for CNV detection, the increasing [...] Read more.

Somatic copy number variations (CNV; i.e., amplifications and deletions) have been implicated in the origin and development of multiple cancers and some of these aberrations are designated targets for therapies. Although FISH is still considered the gold standard for CNV detection, the increasing number of potentially druggable amplifications to be assessed makes a gene-by-gene approach time- and tissue-consuming. Here we investigated the potential of next generation sequencing (NGS) custom panels to simultaneously determine CNVs across FFPE solid tumor samples. DNA was purified from cell lines and FFPE samples and analyzed by NGS sequencing using a 20-gene custom panel in the GeneReader Platform^®. CNVs were identified using an in-house algorithm based on the UMI read coverage. Retrospective validation of in-house algorithm to identify CNVs showed 97.1% concordance rate with the NGS custom panel. The prospective analysis was performed in a cohort of 243 FFPE samples from patients arriving at our hospital, which included 74 NSCLC tumors, 148 CRC tumors, and 21 other tumors. Of them, 33% presented CNVs by NGS and in 14 cases (5.9%) the CNV was the only alteration detected. We have identified CNV alterations in about one-third of our cohort, including FGFR1, CDK6, CDK4, EGFR, MET, ERBB2, BRAF, or KRAS. Our work highlights the need to include CNV testing as a part of routine NGS analysis in order to uncover clinically relevant gene amplifications that can guide the selection of therapies. Full article

(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)

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13 pages, 3586 KiB

Open AccessFeature PaperArticle

Different Methods in HPV Genotyping of Anogenital and Oropharyngeal Lesions: Comparison between VisionArray^® Technology, Next Generation Sequencing, and Hybrid Capture Assay

by Giorgia Acquaviva, Michela Visani, Viviana Sanza, Antonio De Leo, Thais Maloberti, Paola Pierotti, Paola Crucitti, Guido Collina, Cecilia Chiarelli Olivari, Annalisa Pession, Giovanni Tallini and Dario de Biase

J. Mol. Pathol. 2021, 2(1), 29-41; https://doi.org/10.3390/jmp2010004 - 4 Mar 2021

Viewed by 3831

Abstract

(1) Background: Human papillomaviruses (HPVs) are known to be related to the development of about 5% of all human cancers. The clinical relevance of HPV infection has been deeply investigated in carcinomas of the oropharyngeal area, uterine cervix, and anogenital area. To date, [...] Read more.

(1) Background: Human papillomaviruses (HPVs) are known to be related to the development of about 5% of all human cancers. The clinical relevance of HPV infection has been deeply investigated in carcinomas of the oropharyngeal area, uterine cervix, and anogenital area. To date, several different methods have been used for detecting HPV infection. The aim of the present study was to compare three different methods for the diagnosis of the presence of the HPV genome. (2) Methods: A total of 50 samples were analyzed. Twenty-five of them were tested using both next generation sequencing (NGS) and VisionArray^® technology, the other 25 were tested using Hybrid Capture (HC) II assay and VisionArray^® technology. (3) Results: A substantial agreement was obtained using NGS and VisionArray^® (κ = 0.802), as well as between HC II and VisionArray^® (κ = 0.606). In both analyses, the concordance increased if only high risk HPVs I(HR-HPVs) were considered as “positive”. (4) Conclusions: Our data highlighted the importance of technical choice in HPV characterization, which should be guided by the clinical aims, costs, starting material, and turnaround time for results. Full article

(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)

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13 pages, 1357 KiB

Open AccessFeature PaperArticle

ROC Analysis Identifies Baseline and Dynamic NLR and dNLR Cut-Offs to Predict ICI Outcome in 402 Advanced NSCLC Patients

by Simona Carnio, Annapaola Mariniello, Pamela Pizzutilo, Gianmauro Numico, Gloria Borra, Alice Lunghi, Hector Soto Parra, Roberta Buosi, Tiziana Vavalà, Ilaria Stura, Silvia Genestroni, Alessandra Alemanni, Francesca Arizio, Annamaria Catino, Michele Montrone, Fabrizio Tabbò, Domenico Galetta, Giuseppe Migliaretti and Silvia Novello

J. Mol. Pathol. 2020, 1(1), 19-31; https://doi.org/10.3390/jmp1010004 - 15 Sep 2020

Cited by 2 | Viewed by 3887

Abstract

Background: Neutrophil-to-Lymphocyte Ratio (NLR) and derived Neutrophils-to-(Leukocytes minus neutrophils) Ratio (dNLR) have been proposed as possible biomarkers of response to immune checkpoint inhibitors (ICI). However, in non-small cell lung cancer (NSCLC) studies, various NLR and/or dNLR cut-offs have been used, manly based on [...] Read more.

Background: Neutrophil-to-Lymphocyte Ratio (NLR) and derived Neutrophils-to-(Leukocytes minus neutrophils) Ratio (dNLR) have been proposed as possible biomarkers of response to immune checkpoint inhibitors (ICI). However, in non-small cell lung cancer (NSCLC) studies, various NLR and/or dNLR cut-offs have been used, manly based on previous reports on melanoma. Methods: In this Italian multicenter retrospective study, NLR, dNLR, platelet-to-lymphocyte ratio, albumin, and lactate dehydrogenase (LDH) were longitudinally assessed in patients with stage IV non-small cell lung cancer (NSCLC) treated with ICI. The primary objective was to evaluate if baseline parameters predicted response to ICI, using Receiver Operating Characteristic (ROC) curves. Secondary endpoint was to evaluate if dynamic changing of NLR and dNLR also predicted response. Results: Data of 402 patients were collected and analyzed. Among the baseline parameters considered, NLR and dNLR were the most appropriate biomarkers according to the ROC analyses, which also identified meaningful cut-offs (NLR = 2.46; dNLR = 1.61). Patients with low ratios reported a significantly improved outcome, in terms of overall survival (p = 0.0003 for NLR; p = 0.0002 for dNLR) and progression free survival (p = 0.0004 for NLR; p = 0.005 for dNLR). The role of NLR and dNLR as independent biomarkers of response was confirmed in the Cox regression model. When assessing NLR and dNLR dynamics from baseline to cycle 3, a decrease ≥1.04 for NLR and ≥0.41 for dNLR also predicted response. Conclusions in our cohort, we confirmed that NLR and dNLR, easily assessable on peripheral blood, can predict response at baseline and early after ICI initiation. For both baseline and dynamic assessment, we identified clinically meaningful cut-offs, using ROC curves. Full article

(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)

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Review

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16 pages, 921 KiB

Open AccessReview

Micro-RNA in Cholangiocarcinoma: Implications for Diagnosis, Prognosis, and Therapy

by Anna Barbato, Fabiola Piscopo, Massimiliano Salati, Luca Reggiani-Bonetti, Brunella Franco and Pietro Carotenuto

J. Mol. Pathol. 2022, 3(2), 88-103; https://doi.org/10.3390/jmp3020009 - 9 May 2022

Cited by 12 | Viewed by 3709

Abstract

Bile-duct cancers (BDC) are a group of solid tumors arising from the biliary tree. Despite their classification as rare cancers, the incidence of BDC is increasing worldwide. Poor prognosis is a common feature of this type of cancer and is mainly determined by [...] Read more.

Bile-duct cancers (BDC) are a group of solid tumors arising from the biliary tree. Despite their classification as rare cancers, the incidence of BDC is increasing worldwide. Poor prognosis is a common feature of this type of cancer and is mainly determined by the following factors: late diagnosis, lack of effective therapeutic approaches, and resistance to conventional treatments. In the past few years, next-generation sequencing technologies has allowed us to study the genome, exome, and transcriptome of BDC deeper, revealing a previously underestimated class of RNA: the noncoding RNA (ncRNA). MicroRNAs (miRNAs) are small ncRNAs that play an important regulatory role in gene expression. The aberrant expression of miRNAs and their pivotal role as oncogenes or tumor suppressors in biliary carcinogenesis has been widely described in BDC. Due to their ability to regulate multiple gene networks, miRNAs are involved in all cancer hallmarks, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing/accessing vasculature, activating invasion and metastasis, reprogramming cellular metabolism, and avoiding immune destruction. Their use as diagnostic, prognostic, and predictive biomarkers has been widely explored in several human cancers, including BDC. Furthermore, miRNA-based therapeutic strategies are currently the subject of numerous clinical trials that are providing evidence of their efficacy as potent anticancer agents. In this review, we will provide a detailed update of miRNAs affecting BDC, discussing their regulatory function in processes underlying the molecular pathology of BDC. Finally, an overview of their potential use as biomarkers or therapeutic tools in BDC will be further addressed. Full article

(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)

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14 pages, 1244 KiB

Open AccessReview

The Multifaceted Profile of Thyroid Disease in the Background of DICER1 Germline and Somatic Mutations: Then, Now and Future Perspectives

by Sule Canberk, Marcelo Correia, Ana Rita Lima, Massimo Bongiovanni, Manuel Sobrinho-Simões, Paula Soares and Valdemar Máximo

J. Mol. Pathol. 2022, 3(1), 1-14; https://doi.org/10.3390/jmp3010001 - 11 Jan 2022

Cited by 2 | Viewed by 3943

Abstract

DICER1 protein is a member of the ribonuclease (RNAse) III family with a key role in the biogenesis of microRNAs (miRNA) and in microRNA processing, potentially affecting gene regulation at the post-transcriptional level. The role of DICER1 and its relevance to thyroid cellular [...] Read more.

DICER1 protein is a member of the ribonuclease (RNAse) III family with a key role in the biogenesis of microRNAs (miRNA) and in microRNA processing, potentially affecting gene regulation at the post-transcriptional level. The role of DICER1 and its relevance to thyroid cellular processes and tumorigenesis have only recently been explored, following the acknowledgement that DICER1 germline and somatic changes can contribute not only to non-toxic multinodule goiter (MNG) lesions detected in individuals of affected families but also to a series of childhood tumours, including thyroid neoplasms, which can be identified from early infancy up until the decade of 40s. In a context of DICER1 germline gene mutation, thyroid lesions have recently been given importance, and they may represent either an index event within a syndromic context or the isolated event that may trigger a deeper and broader genomic analysis screening of individuals and their relatives, thereby preventing the consequences of a late diagnosis of malignancy. Within the syndromic context MNG is typically the most observed lesion. On the other hand, in a DICER1 somatic mutation context, malignant tumours are more common. In this review we describe the role of DICER protein, the genomic events that affect the DICER1 gene and their link to tumorigenesis as well as the frequency and pattern of benign and malignant thyroid lesions and the regulation of DICER1 within the thyroidal environment. Full article

(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)

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19 pages, 2638 KiB

Open AccessReview

Liquid Biopsy for Biomarker Testing in Non-Small Cell Lung Cancer: A European Perspective

by Umberto Malapelle, Marcello Tiseo, Ana Vivancos, Joshua Kapp, M. Josè Serrano and Markus Tiemann

J. Mol. Pathol. 2021, 2(3), 255-273; https://doi.org/10.3390/jmp2030022 - 18 Aug 2021

Cited by 25 | Viewed by 13006

Abstract

The development of targeted therapies has improved survival rates for patients with advanced non-small cell lung cancer (NSCLC). However, tissue biopsy is unfeasible or inadequate in many patients, limiting biomarker testing and access to targeted therapies. The increasing numbers of established and emerging [...] Read more.

The development of targeted therapies has improved survival rates for patients with advanced non-small cell lung cancer (NSCLC). However, tissue biopsy is unfeasible or inadequate in many patients, limiting biomarker testing and access to targeted therapies. The increasing numbers of established and emerging biomarkers with available targeted treatments highlights the challenges associated with sequential single-gene testing and limited tissue availability. Multiplex next-generation sequencing (NGS) offers an attractive alternative and represents a logical next step, and in cases where the tumour is inaccessible, tissue biopsy yields insufficient tumour content, or when the patient’s performance status does not allow a tissue biopsy, liquid biopsy can provide valuable material for molecular diagnosis. Here, we explore the role of liquid biopsy (i.e., circulating cell-free DNA analysis) in Europe. Liquid biopsies could be used as a complementary approach to increase rates of molecular diagnosis, with the ultimate aim of improving patient access to appropriate targeted therapies. Expert opinion is also provided on potential future applications of liquid biopsy in NSCLC, including for cancer prevention, detection of early stage and minimum residual disease, monitoring of response to therapy, selection of patients for immunotherapy, and monitoring of tumour evolution to enable optimal adaptation/combination of drug therapies. Full article

(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)

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16 pages, 1026 KiB

Open AccessFeature PaperReview

Modern Challenges for Early-Phase Clinical Trial Design and Biomarker Discovery in Metastatic Non-Small-Cell Lung Cancer

by Antonio Rossi, Sara Pilotto, Luisa Carbognin, Miriam Grazia Ferrara, Lorenzo Belluomini, Gennaro Daniele and Emilio Bria

J. Mol. Pathol. 2021, 2(3), 207-222; https://doi.org/10.3390/jmp2030018 - 23 Jun 2021

Viewed by 5090

Abstract

Oncology research has changed extensively due to the possibility to categorize each cancer type into smaller subgroups based on histology and particularly on different genetic alterations due to their heterogeneity. The consequences of this heterogeneity are particularly evident in the management of metastatic [...] Read more.

Oncology research has changed extensively due to the possibility to categorize each cancer type into smaller subgroups based on histology and particularly on different genetic alterations due to their heterogeneity. The consequences of this heterogeneity are particularly evident in the management of metastatic non-small-cell lung cancer (NSCLC). This review will discuss the benefits and challenges of incorporating precision medicine into early- through late-phase metastatic NSCLC clinical trials, discussing examples of drug development programs in oncogene- and non-oncogene-addicted NSCLC. The experiences of clinical development of crizotinib, gefitinib and osimertinib are depicted showing that when a targeted drug is administrated in a study population not selected by any biomarker, trials could produce negative results. However, the early detection of biomarker-driven biology helps to obtain a greater benefit for a selected population and can reduce the required time for drug approval. Early clinical development programs involving nivolumab, pembrolizumab and avelumab, immune checkpoint inhibitors, taught us that, beyond safety and activity, the optimal selection of patients should be based on pre-specified biomarkers. Overall, the identification of predictive biomarkers is one of the greatest challenges of NSCLC research that should be optimized with solid methodological trial designs to maximize the clinical outcomes. Full article

(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)

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10 pages, 275 KiB

Open AccessFeature PaperReview

Emerging Biomarkers for the Selection of Advanced NSCLC-Affected Immunotherapy Patients

by Luigi Della Gravara, Ciro Battiloro, Antonietta Letizia, Rosa Cantile, Vito D'Agnano, Giacomo Sica and Danilo Rocco

J. Mol. Pathol. 2021, 2(2), 197-206; https://doi.org/10.3390/jmp2020017 - 10 Jun 2021

Cited by 2 | Viewed by 3419

Abstract

Immunotherapy in the form of ICIs has revolutionized advanced NSCLC treatment algorithms, with ICI-containing combination treatments being the latest addition to approved regimens. However, PD-L1 still represents the only routinely assessed and validated biomarker apart from genetic drivers testing, impairing our capacity to [...] Read more.

Immunotherapy in the form of ICIs has revolutionized advanced NSCLC treatment algorithms, with ICI-containing combination treatments being the latest addition to approved regimens. However, PD-L1 still represents the only routinely assessed and validated biomarker apart from genetic drivers testing, impairing our capacity to personalize and guide treatment. Therefore, this paper aims to analyze the most promising emerging predictive biomarkers that could help us in the near future to select patients more effectively. Full article

(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)

24 pages, 3803 KiB

Open AccessFeature PaperReview

Non-Small Cell Lung Cancer Harboring Concurrent EGFR Genomic Alterations: A Systematic Review and Critical Appraisal of the Double Dilemma

by Valerio Gristina, Maria La Mantia, Antonio Galvano, Sofia Cutaia, Nadia Barraco, Marta Castiglia, Alessandro Perez, Marco Bono, Federica Iacono, Martina Greco, Katia Calcara, Valentina Calò, Sergio Rizzo, Lorena Incorvaia, Maria Chiara Lisanti, Giulia Santanelli, Delia Sardo, Sara Inguglia, Lavinia Insalaco, Luisa Castellana, Stefania Cusenza, Gianni Pantuso, Antonio Russo and Viviana Bazan Show full author list Hide full author list

J. Mol. Pathol. 2021, 2(2), 173-196; https://doi.org/10.3390/jmp2020016 - 4 Jun 2021

Cited by 15 | Viewed by 6773

Abstract

The molecular pathways which promote lung cancer cell features have been broadly explored, leading to significant improvement in prognostic and diagnostic strategies. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have dramatically altered the treatment approach for patients with metastatic non-small cell [...] Read more.

The molecular pathways which promote lung cancer cell features have been broadly explored, leading to significant improvement in prognostic and diagnostic strategies. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have dramatically altered the treatment approach for patients with metastatic non-small cell lung cancer (NSCLC). Latest investigations by using next-generation sequencing (NGS) have shown that other oncogenic driver mutations, believed mutually exclusive for decades, could coexist in EGFR-mutated NSCLC patients. However, the exact clinical and pathological role of concomitant genomic aberrations needs to be investigated. In this systematic review, we aimed to summarize the recent data on the oncogenic role of concurrent genomic alterations, by specifically evaluating the characteristics, the pathological significance, and their potential impact on the treatment approach. Full article

(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)

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13 pages, 885 KiB

Open AccessFeature PaperReview

PIK3CA Mutation Assessment in HR+/HER2− Metastatic Breast Cancer: Overview for Oncology Clinical Practice

by Carmen Criscitiello, Antonio Marra and Giuseppe Curigliano

J. Mol. Pathol. 2021, 2(1), 42-54; https://doi.org/10.3390/jmp2010005 - 11 Mar 2021

Cited by 10 | Viewed by 6983

Abstract

Activation of the PI3K–AKT–mTOR pathway occurs in several human cancers, including hormone receptor (HR)-positive breast cancer (BC) where is associated with resistance to endocrine therapy and disease progression. In BC, the most common PI3K–AKT–mTOR pathway alteration is represented by PIK3CA oncogenic mutations. These [...] Read more.

Activation of the PI3K–AKT–mTOR pathway occurs in several human cancers, including hormone receptor (HR)-positive breast cancer (BC) where is associated with resistance to endocrine therapy and disease progression. In BC, the most common PI3K–AKT–mTOR pathway alteration is represented by PIK3CA oncogenic mutations. These mutations can occur throughout several domains of the p110α catalytic subunit, but the majority are found in the helical and kinase domains (exon 9 and 20) that represent the “hotspots”. Considering the central role of the PI3K–AKT–mTOR pathway in HR-positive BC, several inhibitors (both pan-PI3K and isoform-specific) have been developed and tested in clinical trials. Recently, the PI3Kα-selective inhibitor alpelisib was the first PI3K inhibitor approved for clinical use in HR-positive metastatic BC based on the results of the phase III SOLAR-1 trial. Several methods to assess PIK3CA mutational status in tumor samples have been developed and validated, including real-time polymerase chain reaction (PCR), digital droplet PCR (ddPCR), BEAMing assays, Sanger sequencing, and next-generation sequencing (NGS) panels. Several new challenges will be expected once alpelisib is widely available in a clinical setting, including the harmonization of testing procedures for the detection of PI3K–AKT–mTOR pathway alterations. Herein, we provide an overview on PI3K–AKT–mTOR pathway alterations in HR-positive BC, discuss their role in determining prognosis and resistance to endocrine therapy and highlight practical considerations about diagnostic methods for the detection of PI3K–AKT–mTOR pathway activation status. Full article

(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)

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10 pages, 274 KiB

Open AccessFeature PaperReview

A Comparison Between First-, Second- and Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Non-Small-Cell Lung Cancer and Brain Metastases

by Salvatore Caponnetto, Ornella Cantale, Alex Friedlaender, Fabio Gomes, Sunil Daryanani, Alain Gelibter, Alessio Cortellini, Dario Giuffrida, Alfredo Addeo and Giuseppe Luigi Banna

J. Mol. Pathol. 2021, 2(1), 1-10; https://doi.org/10.3390/jmp2010001 - 12 Jan 2021

Cited by 5 | Viewed by 6956

Abstract

Patients with non-small-cell lung cancer (NSCLC), harboring Epidermal Growth Factor Receptor (EGFR) mutations, are more susceptible to brain metastases (BM). Comparisons of the efficacy of different-generation EGFR-tyrosine kinase inhibitors (TKI) on BMs from NSCLC are currently limited. We identified studies comparing different EGFR-TKIs [...] Read more.

Patients with non-small-cell lung cancer (NSCLC), harboring Epidermal Growth Factor Receptor (EGFR) mutations, are more susceptible to brain metastases (BM). Comparisons of the efficacy of different-generation EGFR-tyrosine kinase inhibitors (TKI) on BMs from NSCLC are currently limited. We identified studies comparing different EGFR-TKIs for NSCLC through Pubmed literature search and selected those with neurological outcome data. By two retrospective analyses, Erlotinib showed longer neurological time-to-progression (30 months vs. 15.8 months, P = 0.024) and reduced the risk of central nervous system (CNS) progression (Hazard Ratio (HR) 0.25; 95% CI, 0.08–0.81; P = 0.021) compared to Gefitinib. In a phase 2b randomized trial, 16% of patients with BMs had a similar Progression Free Survival (PFS) (HR 0.76, 95% CI 0.41–1.44) or Overall Survival (OS) (HR 1.16, 95% CI 0.61–2.21) with Afatinib versus Gefitinib; a lower risk of developing subsequent BMs with Afatinib than Gefitinib (HR 0.49; 95% CI 0.34–0.71; P < 0.001) was reported by a retrospective study. A randomized phase 3 trial proved that patients with BMs treated with Osimertinib had longer PFS (HR 0.47, 95% CI 0.30–0.74) and OS (HR 0.79, 95% CI 0.61–1.01) than with Gefitinib, and lower incidence of CNS progression (6% vs. 15%, respectively). Although there is limited evidence, differences in CNS activity may exist between EGFR-TKIs. Full article

(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)

Other

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7 pages, 243 KiB

Open AccessOpinion

From Information Overload to Actionable Insights: Digital Solutions for Interpreting Cancer Variants from Genomic Testing

by Stephanie J. Yaung and Adeline Pek

J. Mol. Pathol. 2021, 2(4), 312-318; https://doi.org/10.3390/jmp2040027 - 21 Nov 2021

Cited by 4 | Viewed by 3984

Abstract

Given the increase in genomic testing in routine clinical use, there is a growing need for digital technology solutions to assist pathologists, oncologists, and researchers in translating variant calls into actionable knowledge to personalize patient management plans. In this article, we discuss the [...] Read more.

Given the increase in genomic testing in routine clinical use, there is a growing need for digital technology solutions to assist pathologists, oncologists, and researchers in translating variant calls into actionable knowledge to personalize patient management plans. In this article, we discuss the challenges facing molecular geneticists and medical oncologists in working with test results from next-generation sequencing for somatic oncology, and propose key considerations for implementing a decision support software to aid the interpretation of clinically important variants. In addition, we review results from an example decision support software, NAVIFY Mutation Profiler. NAVIFY Mutation Profiler is a cloud-based software that provides curation, annotation, interpretation, and reporting of somatic variants identified by next-generation sequencing. The software reports a tiered classification based on consensus recommendations from AMP, ASCO, CAP, and ACMG. Studies with NAVIFY Mutation Profiler demonstrated that the software provided timely updates and accurate curation, as well as interpretation of variant combinations, demonstrating that decision support tools can help advance implementation of precision oncology. Full article

(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)

8 pages, 279 KiB

Open AccessOpinion

Mismatch Repair Status Characterization in Oncologic Pathology: Taking Stock of the Real-World Possibilities

by Roberto Piciotti, Konstantinos Venetis, Elham Sajjadi and Nicola Fusco

J. Mol. Pathol. 2021, 2(2), 93-100; https://doi.org/10.3390/jmp2020009 - 1 Apr 2021

Cited by 8 | Viewed by 4819

Abstract

The mismatch repair (MMR) system has a key role in supporting the DNA polymerase proofreading function and in maintaining genome stability. Alterations in the MMR genes are driving events of tumorigenesis, tumor progression, and resistance to therapy. These genetic scars may occur in [...] Read more.

The mismatch repair (MMR) system has a key role in supporting the DNA polymerase proofreading function and in maintaining genome stability. Alterations in the MMR genes are driving events of tumorigenesis, tumor progression, and resistance to therapy. These genetic scars may occur in either hereditary or sporadic settings, with different frequencies across tumor types. Appropriate characterization of the MMR status is a crucial task in oncologic pathology because it allows for both the tailored clinical management of cancer patients and surveillance of individuals at risk. The currently available MMR testing methods have specific strengths and weaknesses, and their application across different tumor types would require a tailored approach. This article highlights the indications and challenges in MMR status assessment for molecular pathologists, focusing on the possible strategies to overcome analytical and pre-analytical issues. Full article

(This article belongs to the Special Issue Molecular Pathology in Solid Tumors)

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