A Practical Approach to Tumor Heterogeneity in Clinical Research and Diagnostics

Stanta, Giorgio; Bonin, Serena

doi:10.1159/000477813

Cited by 13 publications

(10 citation statements)

References 83 publications

(96 reference statements)

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“…There is a risk of sampling bias with somatic mutations, given that PC is a very heterogeneous disease (51). This heterogeneity means that within a patient tumor there are multiple sub-tumors and normal tissues with different genotypes (different mutational profiles) or clones (52,53). For example, PC can have areas of moderately differentiated tumor and undifferentiated tumor, and each clone will have a different prognosis.…”

Section: Discussionmentioning

confidence: 99%

A systematic review of the prevalence of DNA damage response gene mutations in prostate cancer

et al. 2019

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Several ongoing international prostate cancer (PC) clinical trials are exploring therapies that target the DNA damage response (DDR) pathway. This systematic review summarizes the prevalence of DDR mutation carriers in the unselected (general) PC and familial PC populations. A total of 11 electronic databases, 10 conference proceedings, and grey literature sources were searched from their inception to December 2017. Studies reporting the prevalence of somatic and/or germline DDR mutations were summarized. Metastatic PC (mPC), castration-resistant PC (CRPC) and metastatic CRPC (mCRPC) subgroups were included. A total of 11,648 records were retrieved, and 80 studies (103 records) across all PC populations were included; 59 records were of unselected PC and 13 records of familial PC. Most data were available for DDR panels (n=12 studies), ataxia telangiectasia mutated ( ATM ; n=13), breast cancer susceptibility gene ( BRCA ) 1 (n=14) and BRCA2 (n=20). ATM , BRCA2 and partner and localizer of BRCA2 (PALB2) had the highest mutation rates (≥4%). Median prevalence rates for DDR germline mutations were 18.6% in PC (range, 17.2-19%; three studies, n=1,712), 11.6% in mPC (range, 11.4-11.8%; two studies, n=1,261) and 8.3% in mCRPC (range, 7.5-9.1%; two studies, n=738). Median prevalence rates for DDR somatic mutations were 10.7% in PC (range, 4.9-22%; three studies, n=680), 13.2% in mPC (range, 10-16.4%; two studies, n=105) and not reported (NR) in mCRPC. The prevalence of DDR germline and/or somatic mutations was 27% in PC (one study, n=221), 22.67% in mCRPC (one study, n=150) and NR in mPC. In familial PC, median mutation prevalence was 12.1% (range, 7.3-16.9%) for germline DDR (two studies, n=315) and 3.7% (range, 1.3-7.9%) for BRCA2 (six studies, n=945). In total, 88% of studies were at a high risk of bias. The prevalence of DDR gene mutations in PC varied widely within somatic subgroups depending on study size, genetic screening techniques, DDR mutation definition and PC diagnosis; somatic and/or germline DDR mutation prevalence was in the range of 23-27% in PC. These findings support DDR mutation testing for all patients with PC (including those with mCRPC). With the advent of the latest clinical practice PC guidelines highlighting the importance of DDR mutation screening, and ongoing mCRPC clinical trials evaluating DDR mutation-targeted drugs, future larger epidemiological studies are warranted to further quantify the international burden of DDR mutations in PC.

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Section: Discussionmentioning

confidence: 99%

A systematic review of the prevalence of DNA damage response gene mutations in prostate cancer

et al. 2019

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“…Most genes are not involved in clonal evolution, so it is possible to obtain reproducible quantitative analysis on the mRNA level comparing multiple samples of the same tumor taken from similar tumor areas, such as the infiltration sub-border. However, this is not the case, with an important difference in gene expression, if a specific microdissected area of the tumor is compared with the analysis of the entire tumor ( 12 ). To that purpose, accurate microdissection is required for analyses.…”

Section: Methods To Study Ithmentioning

confidence: 99%

“…Intra-tumor heterogeneity analysis is the key for more efficient treatments of cancer in our patients, but only if highly reproducible clinical research is performed. We should consider that different aspects of ITH could be themselves one of the major sources of research irreproducibility, together with preclinical conditions of the biological materials and standardization of the analytical methods ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

Overview on Clinical Relevance of Intra-Tumor Heterogeneity

2018

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Today, clinical evaluation of tumor heterogeneity is an emergent issue to improve clinical oncology. In particular, intra-tumor heterogeneity (ITH) is closely related to cancer progression, resistance to therapy, and recurrences. It is interconnected with complex molecular mechanisms including spatial and temporal phenomena, which are often peculiar for every single patient. This review tries to describe all the types of ITH including morphohistological ITH, and at the molecular level clonal ITH derived from genomic instability and nonclonal ITH derived from microenvironment interaction. It is important to consider the different types of ITH as a whole for any patient to investigate on cancer progression, prognosis, and treatment opportunities. From a practical point of view, analytical methods that are widely accessible today, or will be in the near future, are evaluated to investigate the complex pattern of ITH in a reproducible way for a clinical application.

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“…The functional phenotypic events in tumors are strictly associated with the microenvironment. Immune-histochemical biomarkers have already shown a high phenotypic level of heterogeneity in several types of tumors, and this was recently confirmed by the introduction of immunotherapy biomarkers [22].…”

Section: Resultsmentioning

confidence: 86%

BIOFILM AND TUMOR: INTERPRETATION OF INTERACTION AND TREATMENT STRATEGIES. Review

Ivanenko

2021

Med. Sci. of Ukr.

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Relevance. Treatment of solid tumors and biofilm-derived infections face a common problem: drugs often fail to reach and kill cancer cells and microbial pathogens because of local microenvironment heterogeneities. There are remarkable challenges for current and prospective anticancer and antibiofilm agents to target and maintain activity in the microenvironments where cancer cells and microbial pathogens survive and cause the onset of disease. Bacterial infections in cancer formation will increase in the coming years. Collection of approaches such as ROS modulation in cells, the tumor is promoted by microbe’s inflammation can be a strategy to target cancer and bacteria. Besides that, bacteria may take the advantage of oxygen tension and permissive carbon sources, therefore the tumor microenvironment (TM) becomes a potential refuge for bacteria. It is noteworthy that the relationship between cancer and bacteria is intertwined. Objective: To analyze similarities between biofilm and tumor milieu that is produced against stress conditions and heterogeneous microenvironment for a combination of approaches the bacteriotherapy with chemotherapy which can help in defeating the tumor heterogeneity accompanied with malignancy, drug-resistance, and metastasis. Method: An analytical review of the literature on keywords from the scientometric databases PubMed, Wiley. Results: Bacteria evade antimicrobial treatment is mainly due to persistence that has become dormant during the stationary phase and tolerance. Drug-tolerant persisters and cellular dormancy are crucial in the development of cancer, especially in understanding the development of metastases as a late relapse. Bioﬁlms are formed by groups of cells in diﬀerent states, growing or non-growing and metabolically active or inactive in variable fractions, depending on maturity and on chemical gradients (O2 and nutrients) of the bioﬁlms producing physiological heterogeneity. Heterogeneity in the microenvironment of cancer can be described as a non-cell autonomous driver of cancer cell diversity; in a highly diverse microenvironment, different cellular phenotypes may be selected for or against in different regions of the tumor. Hypoxia, oxidative stress, and inflammation have been identified as positive regulators of metastatic potential, drug resistance, and tumorigenic properties in cancer. It is proven that, Escherichia coli (E. coli) and life-threatening infectious pathogens such as Staphylococcus aureus (SA) and Mycobacterium tuberculosis (Mtb) are noticeably sensitive to alterations in the intracellular oxidative environment. An alternative emerging paradigm is that many cancers may be promoted by commensal microbiota, either by translocation and adherence of microbes to cancer cells or by the distant release of inflammation-activating microbial metabolites. Microbial factors such as F. nucleatum, B. fragilis, and Enterobacteriaceae members may contribute to disease onset in patients with a hereditary form of colorectal cancer (CRC); familial adenomatous polyposis (FAP). These findings are linked with the creation of new biomarkers and therapy for identifying and treating biofilm-associated cancers. Currently, about 20% of neoplasms globally can be caused by infections, with approximately 1.2 million cases annually. Several antineoplastic drugs that exhibited activity against S. mutans, including tamoxifen, doxorubicin, and ponatinib, also possessed activity against other Gram-positive bacteria. Drug repurposing, also known as repositioning, has gained momentum, mostly due to its advantages over de novo drug discovery, including reduced risk to patients due to previously documented clinical trials, lower drug development costs, and faster benchtop-to-clinic transition. Although many bacteria are carcinogens and tumor promoters, some have shown great potential towards cancer therapy. Several species of bacteria have shown an impressive power to penetrate and colonize solid tumors, which has mainly led to neoplasm slower growth and tumor clearance. Different strains of Clostridia, Lactococcus, Bifidobacteria, Shigella, Vibrio, Listeria, Escherichia, and Salmonella have been evaluated against cancer in animal models. Conclusion. Cancer is a multifactorial disease and the use of bacteria for cancer therapy as an immunostimulatory agent or as a vector for carrying the therapeutic cargo is a promising treatment method. Therefore, the world has turned to an alternative solution, which is the use of genetically engineered microorganisms; thus, the use of living bacteria targeting cancerous cells is the unique option to overcome these challenges. Bacterial therapies, whether used alone or combination with chemotherapy, give a positive effect to treat multiple conditions of cancer.

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A Practical Approach to Tumor Heterogeneity in Clinical Research and Diagnostics

Cited by 13 publications

References 83 publications

A systematic review of the prevalence of DNA damage response gene mutations in prostate cancer

A systematic review of the prevalence of DNA damage response gene mutations in prostate cancer

Overview on Clinical Relevance of Intra-Tumor Heterogeneity

BIOFILM AND TUMOR: INTERPRETATION OF INTERACTION AND TREATMENT STRATEGIES. Review

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