Molecular Biology of Cancer: Translation to the Clinic: 95 (Progress in Molecular Biology and Transl

Molecular Biology of Cancer: Translation to the Clinic, Volume 95 (Progress in Molecular Biology and Translational Science): Medicine.
Table of contents

On the other hand, there may be molecules like miRNAs which are detectable in a variety of patient specimens like blood, tissues and even fine needle aspirates, making them clinically applicable and potentially useful biomarkers since they can be evaluated in a variety of such patient specimens. It is the detectability of biomolecules in a variety of patient body samples that determines whether a particular biomolecule will in future have potential clinical use in the diagnostic arena.

In the current clinical context, cancer diagnosis involves the use of biomarkers examining molecules at the cellular level. Cancer diagnosis today is not just the recognition of the morphological phenotype through microscopic examination, but it is a complex blend of these microscopic features with immunohistochemical stains and molecular approaches to add value to the diagnostic report. The current standardized surgical pathology reporting formats make use of the available molecular markers to communicate prognostic and therapeutic implications with the clinicians.

Another test useful in the molecular monitoring of leukemia is the multiplex RT-PCR followed by liquid bead array detection. It is a rapid and flexible method which provides additional information for accurate diagnosis and prognosis [ 31 ]. These methods are easy to incorporate into the clinical laboratory workflow and generally complement the standard cytogenetic methods.

Real time RT-PCR assay is currently being used in the clinical diagnostic arena for the relative quantification of the ABL1 fusion transcripts in establishing new diagnosis, determining relapse and monitoring remission by using clinical patient specimens including whole blood and bone marrows [ 32 — 34 ]. Likewise, PCR assay is also being currently clinically used to identify mutations in KRAS gene for predicting response to targeted therapies [ 37 , 38 ].

The microRNAs miRNAs are recently described emerging biomarkers for cancer diagnosis and prognosis with potential future implications in therapeutic interventions [ 2 , 3 , 12 , 13 , 39 , 40 ]. They have widespread clinical application due to several advantages including their application to a variety of biological specimens including blood, tissue, sputum and stool [ 7 , 41 , 42 ]. These are novel molecules since they have downstream effects on several genes and signaling pathways by their up or down regulation [ 43 ].

The biggest advantage of using the miRNAs based approaches in cancer diagnosis, prognosis and therapeutics is the ability of miRNAs to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. Another advantage of using miRNAs is the fact that they are stable in body fluid and tissue samples. Recently several novel high-throughput methods have been developed for the detection of miRNAs in the cancer diagnosis and prognosis.

These include electrically magnetic-controllable electrochemical biosensors [ 44 ], bead-based suspension array [ 45 ], power-free microfluidic chip [ 46 ] and one-step real time RT-PCR for detection of miRNAs [ 47 ]. For hematological malignancies, flow cytometry and molecular genomics has been an integral part of cancer diagnosis. Based on the WHO classification of hematological malignancies, genomic alterations are a composite part of the cancer diagnosis [ 48 ].

This has implications in the selection of the right treatment protocol based on these molecular changes. Further, the prognosis and risk stratification is based on these criteria. Several novel diagnostic biomarkers have been identified for clinical diagnosis of cancers as demonstrated in Figure 2. Each day the repertoire of targeted therapies is rapidly expanding. These include markers for hematological malignancies e. Additionally, besides tumor markers, tumor microenvironment consisting of host immune cells may control tumor behavior or function as a useful biomarker [ 51 ].

These diagnostic approaches for cancer have far reaching consequences in the therapeutic management of cancer patients. These molecules have already been incorporated in the clinical patient management for early and accurate diagnosis, determining prognosis and risk stratification of disease, as well as designing targeted molecular therapeutics. Novel diagnostic biomarkers used in the clinic for various types of cancers and their targeted drug therapy. There also has been a significant progress in the development of novel antibodies for immunohistochemical detection of proteins which is the end result of the translation due to DNA and RNA alterations that have translated from the research bench [ 52 ] and now proven to have clinical utility in the diagnosis and risk stratification of cancers [ 53 ].

This immunohistochemical detection of proteins nowadays assists in routine diagnosis in Surgical Pathology. Recent advances in the field of cancer diagnosis have seen a plethora of rapid and accurate high throughput diagnostic tests. Initially used as research tools [ 2 , 3 , 6 , 11 , 12 , 54 ], these molecular diagnostic tests have now been demonstrated to be applicable in the clinical scenario [ 4 , 7 , 13 ]. The use of these biomarkers in cancer diagnosis has been facilitated by the availability of several high throughput and high resolution technologies for the detection of these novel biomarker abnormalities as presented in Table 1.

These would also be applicable in surveillance, follow-up and monitoring treatment outcome of cancer patient. It can be used for single-nucleotide polymorphism SNP detection, gene expression profiling and also quantification of viral load in infection associated cancers. Gel electrophoresis has its limitations including low resolution, poor precision, and results not being quantifiable. Hence, capillary electrophoresis has been developed with widespread application in detecting gene rearrangements, single nucleotide polymorphism SNP , and loss of heterozygosity LOH [ 56 ].

Incorporation of bioinformatics has enabled evaluation of multiple genes and miRNAs in parallel for identifying clinical algorithms for cancer diagnosis [ 13 ]. However with the detection of KRAS mutation in lung cancers the drugs are currently under development.

Clinical Advances in Molecular Biomarkers for Cancer Diagnosis and Therapy

With the use of recent high throughput technologies like the Sequenom Maldi-TOF spectrometry gene panels can be evaluated for diagnosis of cancers [ 48 , 58 ]. These studies allow multiplexing with up to 15 patients and 11 genes in two days. Apart from genetic alterations for assisting the cancer diagnosis, these methodologies can also be used for SNP genotyping, methylation assay and even quantitative gene expression analysis [ 58 ].

The molecular targets identified for cancer diagnosis have implications in the treatment protocols. It has also contributed in identifying variants which may influence drug metabolism or interaction of a drug with its cellular target, allowing customization of choice of drugs and dosage. In the clinical arena, its objectives are to avoid adverse drug reactions, maximize drug efficacy and to select responsive patients [ 62 ]. In cancer diagnosis, the role of the Pathologist is to link the phenotypic expression of the tumor visualized microscopically with the variation in molecular genotype.

For personalized medicine the genetic alterations occurring in cancers are used not only for diagnosis but also for targeted drug therapy as displayed in Figure 2. Several recent reports suggested that aspirin usage improves colon cancer mortalities [ 67 — 69 ] especially among patients with mutated-PIK3CA, indicating PIK3CA as potential biomarker in colon cancer [ 68 , 69 ].

The second major genomic instability pathway involved in pathogenesis of colon cancer is the microsatellite instability MSI pathway caused by mutations in the DNA mismatch repair genes MMR. Deficiency in MMR genes in tumors has been related to improved prognosis, and thus represents one of the most promising molecular markers for chemo-sensitivity [ 70 , 71 ]. ERBB2 amplification in breast cancers is targeted with Trastuzumab and Lapatinib [ 72 ] but these are only some recent examples.

Molecular genetics complexity impeding research progress in breast and ovarian cancers (Review)

To assist the diagnosis of cancers, there are commercially available cancer panels like the Oncocarta [ 13 ] and the Ampliseq cancer panels [ 60 ]. The Ampliseq is a panel comprising of n hotspot cancer mutations in 46 genes involving hematological and solid tumor cancers. The recent application of microarray technology to analyze the expression analysis of more than miRNAs simultaneously has helped in the diagnosis of multiple cancers [ 7 , 12 , 13 ]. In Oncotype Dx 21 genes are profiled based on which the recurrence risk is predicted at the time of diagnosis [ 73 ].

The MammaPrint is a 70 gene microarray panel for risk stratification [ 59 ]. In both Oncotype Dx and MammaPrint, the patients with low score are given only hormonal therapy and high risk ones are also given chemotherapy. Afirma gene expression profiling is used in the classification of thyroid nodules [ 61 ]. It sub classifies cases which need further surgery if suspicious on fine-needle aspirates FNA. Deep understanding of the pathogenesis of cancer has led to unearthing of novel molecular diagnostic tools for cancer diagnosis.

High throughput technology of molecular genetics and genomic analysis of sub-cellular molecules has rapidly changed the diagnostic landscape of cancer testing [ 13 ]. High-resolution molecular cytogenetic analysis has enables detection of deletions and duplications of DNA, RNA and miRNA, well below the resolution of the light microscope. The advent of massively parallel next-generation sequencing facilitates the analysis of multiple genes and now is being used to sequence the coding regions of the genome the exome for clinical testing.

Exome sequencing requires bioinformatics analysis of the thousands of variants that are identified to find one that is contributing to the pathology; there is also a possibility of incidental identification of other medically significant variants, which may complicate genetic counseling. DNA testing can also be used to identify variants that influence drug metabolism or interaction of a drug with its cellular target, allowing customization of choice of drugs and dosage.

Exome and genome sequencing are being applied to identify specific gene changes in cancer cells to guide therapy, to identify inherited cancer risk, and to estimate prognosis. Genomic testing may be used to identify risk factors for common disorders, although the clinical utility of such testing is unclear. Genetic and genomic tests may raise new ethical, legal, and social issues, some of which may be addressed by existing genetic nondiscrimination legislation, but which also must be addressed in the course of genetic counseling.

Advances in molecular microbiology have also had far reaching consequences and impact on cancer diagnosis.

Bio-molecules 07 Central Dogma of Biology in Tamil

This includes the detection of viruses in cancers which have prognostic implications. A typical example of this is the utilization of the HPV detection in head and neck cancers which assist in the risk stratification of cases [ 74 ].

In future, these molecular features would become an integral part of all cancer diagnosis with implications in treatment management protocols. Most hematological malignancies have already seen that trend and solid tumors are following the same route, which would likely revolutionize cancer diagnosis and personalized therapy. In conclusion, the diagnosis of cancer has undergone a paradigm shift. No longer is cancer diagnosed only based on morphological parameters. Multiple platforms and high throughput technological advances enable faster and cheaper analysis of all these as well as the whole genome.

This is having a significant impact on how medicine is now being practiced in a personalized approach leading to the development of precision medicine based on pharmacogenomics. The ultimate goal of cancer diagnosis in personalized medicine would be to identify the correct diagnosis and guide the therapy so that every patient received precision medicine that is the right drug at the right dose. National Center for Biotechnology Information , U. Int J Mol Sci. Published online Jul Philip , 2 and Fazlul H. Find articles by Shadan Ali.

Find articles by Philip A. Find articles by Fazlul H. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license http: This article has been cited by other articles in PMC. Abstract Cancer diagnosis is currently undergoing a paradigm shift with the incorporation of molecular biomarkers as part of routine diagnostic panel. Introduction Recent years have seen a remarkable progress in the basic, translational and clinical research in cancers. Cancer Cell Alterations as an Aid to Cancer Diagnosis As the tumors progress and develop invasive and metastatic capabilities, these molecular changes are deregulated due to inherent biologic properties of the cancer cell.

Open in a separate window. Clinical Application of Cancer Diagnostic Modalities The current oncology practice is rapidly undergoing a change. Implications of Cancer Diagnostic Tests on Treatment Several novel diagnostic biomarkers have been identified for clinical diagnosis of cancers as demonstrated in Figure 2.

Novel Cancer Diagnostic Technologies Recent advances in the field of cancer diagnosis have seen a plethora of rapid and accurate high throughput diagnostic tests. Table 1 Current high throughput tests for cancer diagnosis. Conclusions In conclusion, the diagnosis of cancer has undergone a paradigm shift. Conflict of Interest The authors have no conflict of interest to declare.

Evaluating the clinical utility of tumor markers in oncology. Garcinol regulates EMT and Wnt signaling pathways in vitro and in vivo , leading to anticancer activity against breast cancer cells. Differentially expressed miRNAs in the plasma may provide a molecular signature for aggressive pancreatic cancer. MicroRNA profiling of diagnostic needle aspirates from patients with pancreatic cancer.

Network modeling of CDF treated pancreatic cancer cells reveals a novel c-myc-p73 dependent apoptotic mechanism. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. Comprehensive molecular oncogenomic profiling and miRNA analysis of prostate cancer. Evolving concept of cancer stem cells: Role of micro-RNAs and their implications in tumor aggressiveness. Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR and miR expression by curcumin or its analogue CDF. Long interspersed nuclear element-1 hypomethylation in cancer: Biology and clinical applications.

Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials. Surgical debulking of ovarian cancer: What difference does it make? Recent advancements in prognostic factors of epithelial ovarian carcinoma. Int Sch Res Notices. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum Era: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and Stage IV ovarian cancer.

Histological, molecular and functional subtypes of breast cancers. Histologic grade remains a prognostic factor for breast cancer regardless of the number of positive lymph nodes and tumor Size: A study of cases of breast cancer from the seer program. Arch Pathol Lab Med. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer.

Relative worth of estrogen or progesterone receptor and pathologic characteristics of differentiation as indicators of prognosis in node negative breast cancer patients: Immunohistochemical detection using the new rabbit monoclonal antibody sp1 of estrogen receptor in breast cancer is superior to mouse monoclonal antibody 1d5 in predicting survival. Expressions of estrogen and progesterone receptors in epithelial ovarian cancer: Estrogen and progesterone receptors in ovarian epithelial tumors. Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: Updated findings from national surgical adjuvant breast and bowel project clinical trials.

American society of clinical oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: Cianfrocca M and Goldstein LJ: Sex steroid hormone receptor expression affects ovarian cancer survival. Mammaglobin B is an independent prognostic marker in epithelial ovarian cancer and its expression is associated with reduced risk of disease recurrence. Patterns of gene expression that characterize long-term survival in advanced stage serous ovarian cancers.

Validated gene targets associated with curatively treated advanced serous ovarian carcinoma.

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Gene expression profiling of advanced-stage serous ovarian cancers distinguishes novel subclasses and implicates ZEB2 in tumor progression and prognosis. Nasi ML and Castiglione M: Cyclooxygenase-2 COX-2 a new prognostic and predictive factor for ovarian cancer? Are all the criteria fulfilled?

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Comprehensive molecular portraits of invasive lobular breast cancer. Genomic characterization of primary invasive lobular breast cancer.

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The impact of expression profiling on prognostic and predictive testing in breast cancer. Strategies for subtypes-dealing with the diversity of breast cancer: Highlights of the St. Cancer Genome Atlas Network,. Comprehensive molecular portraits of human breast tumours. Sequence analysis of mutations and translocations across breast cancer subtypes. Diverse somatic mutation patterns and pathway alterations in human cancers. Activating ESR1 mutations in hormone-resistant metastatic breast cancer.

ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.

Gene profiling assay and application: The predictive role in primary therapy. Profiling Studies in Ovarian Cancer: Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. Survival-related profile, pathways, and transcription factors in ovarian cancer.

A gene signature predicting for survival in suboptimally debulked patients with ovarian cancer. E2F5 status significantly improves malignancy diagnosis of epithelial ovarian cancer. Development of a highly specialized cDNA array for the study and diagnosis of epithelial ovarian cancer. The detection of differentially expressed microRNAs from the serum of ovarian cancer patients using a novel real-time PCR platform. Increased expression of miRb in ovarian carcinoma and its clinical significance. MicroRNA signatures in human ovarian cancer. Circulating biomarkers for detection of ovarian cancer and predicting cancer outcomes.

A microRNA signature defines chemoresistance in ovarian cancer through modulation of angiogenesis. Gene expression profiles associated with response to chemotherapy in epithelial ovarian cancers. Gene expression profiles predict early relapse in ovarian cancer after platinum-paclitaxel chemotherapy. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Cancer Genome Atlas Research Network,. Integrated genomic analyses of ovarian carcinoma.

Prognostic and therapeutic relevance of molecular subtypes in high-grade serous ovarian cancer. Liu J and Matulonis UA: New Strategies in Ovarian Cancer: Translating the molecular complexity of ovarian cancer into treatment advances. The search for biomarkers to direct antiangiogenic treatment in epithelial ovarian cancer. Expression signature distinguishing two tumour transcriptome classes associated with progression-free survival among rare histological types of epithelial ovarian cancer.

Correlations with tumor progression and platinum resistance. Practical implications of gene-expression-based assays for breast oncologists. Nat Rev Clin Oncol. Structural rearrangements in DNA repair genes in breast cancer. University of Pittsburgh; Pittsburgh: Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. The Eyes Absent phosphatase-transactivator proteins promote proliferation, transformation, migration, and invasion of tumor cells. EYA1 phosphatase function is essential to drive breast cancer cell proliferation through Cyclin D1.

Fine mapping of human HOX gene clusters. HOX genes and their role in the development of human cancers. J Mol Med Berl. HOXB6 overexpression in murine bone marrow immortalizes a myelomonocytic precursor in vitro and causes hematopoietic stem cell expansion and acute myeloid leukemia in vivo.

Overexpression of HOXC11 homeobox gene in clear cell renal cell carcinoma induces cellular proliferation and is associated with poor prognosis. Shah N and Sukumar S: The Hox genes and their roles in oncogenesis. Biochem Biophys Res Commun. Differential expression of Hox genes in ovarian cancer. Serologic analysis of ovarian tumor antigens reveals a bias toward antigens encoded on 17q.

The prognostic significance of specific HOX gene expression patterns in ovarian cancer. CT45A1 acts as a new proto-oncogene to trigger tumorigenesis and cancer metastasis. Human colorectal carcinogenesis is associated with deregulation of homeobox gene expression. Potential candidates for the transcriptional control of the transformed and invasive phenotype.

New Perspectives on a Classic. Epidermal growth factor suppresses induction by progestin of the adhesion protein desmoplakin in T47D breast cancer cells.


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Desmoplakin expression and distribution in cultured rat bladder epithelial cells of varying tumorigenic potential. Immunohistochemical staining of desmosomal components in oral squamous cell carcinomas and its association with tumour behaviour. The immunohistochemical expression of desmoplakin and its role in vivo in the progression and metastasis of breast cancer. The RhoA-binding protein, Rhophilin-2, regulates actin cytoskeleton organization. Analyzing large-scale samples highlights significant association between rs polymorphism and colorectal cancer.

Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas. A vital regulator contributes to human tumorigenesis. F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous manner. Roles of F-box proteins in cancer. FBXW7 mutations in patients with advanced cancers: Welcker M and Clurman BE: A tumour suppressor at the crossroads of cell division, growth and differentiation.

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Estrogen receptor gene amplification occurs rarely in ovarian cancer. Involvement of Ras activation in human breast cancer cell signaling, invasion, and anoikis. Major oncogenes and tumor suppressor genes involved in epithelial ovarian cancer review. A genetically defined model for human ovarian cancer. Liao D and Dickson RB: Overexpression of cyclin D1 and c-Myc gene products in human primary epithelial ovarian cancer.

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Breast cancer biomarkers and molecular medicine: Expert Rev Mol Diagn. Combined analysis of p53 and RB pathways in epithelial ovarian cancer. July Volume 7 Issue 1. Sign up for eToc alerts. Home Submit Manuscript My Account. Molecular and Clinical Oncology. Molecular genetics complexity impeding research progress in breast and ovarian cancers Review Authors: This article is mentioned in: Breast and ovarian cancer are heterogeneous diseases. Various risk factors, including variable biological and clinical traits, are involved in the onset of breast and ovarian cancer.

Thus, elucidating the mechanisms underlying the pathology of these diseases is expected to improve their prevention, prognosis and management. The aim of the present study was to provide a comprehensive review and updated information on genomics and proteomics alterations associated with cancer pathogenesis, as reported by several research groups worldwide. Furthermore, molecular research in our laboratory, aimed at identifying new pathways involved in the pathogenesis of breast and ovarian cancer using microarray and chromatin immunoprecipitation ChIP , is discussed.