scholarly journals Comparative assessment of genes driving cancer and somatic evolution

2021 ◽  
Author(s):  
Lisa Dressler ◽  
Michele Bortolomeazzi ◽  
Mohamed Reda Keddar ◽  
Hrvoje Misetic ◽  
Giulia Sartini ◽  
...  
Keyword(s):  
Genetic Alterations ◽  
Comprehensive Overview ◽  
Somatic Evolution ◽  
Large Size ◽  
Somatic Alteration ◽  
Evolutionarily Conserved ◽  
Cancer Initiation ◽  
Germline Variation ◽  
Cancer Types ◽  
Genetic Events

ABSTRACTGenetic alterations of somatic cells can drive non-malignant clone formation and promote cancer initiation. However, the link between these processes remains unclear hampering our understanding of tissue homeostasis and cancer development. Here we collect a literature-based repertoire of 3355 well-known or predicted drivers of cancer and noncancer somatic evolution in 122 cancer types and 12 noncancer tissues. Mapping the alterations of these genes in 7953 pancancer samples reveals that, despite the large size, the known compendium of drivers is still incomplete and biased towards frequently occurring coding mutations. High overlap exists between drivers of cancer and noncancer somatic evolution, although significant differences emerge in their recurrence. We confirm and expand the unique properties of drivers and identify a core of evolutionarily conserved and essential genes whose germline variation is strongly counter-selected. Somatic alteration in even one of these genes is sufficient to drive clonal expansion but not malignant transformation. Our study offers a comprehensive overview of our current understanding of the genetic events initiating clone expansion and cancer revealing significant gaps and biases that still need to be addressed. The compendium of cancer and noncancer somatic drivers, their literature support and properties are accessible at http://www.network-cancer-genes.org/.

ctDNA analysis in patients with cancer of unknown primary and its value in guiding targeted treatment when combined with predicted cancer types by 90-gene reverse-transcription polymerase chain reaction assay.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18730-e18730
Author(s):  
Xin Liu ◽  
Shiyu Jiang ◽  
Xiaowei Zhang ◽  
Xiaoyan Zhou ◽  
Zhiguo Luo ◽  
...  
Keyword(s):  
Genetic Alterations ◽  
Cancer Of Unknown Primary ◽  
Primary Site ◽  
Targeted Treatment ◽  
Unknown Primary ◽  
Chain Reaction ◽  
Cdkn2a Mutation ◽  
Cancer Types ◽  
Polymerase Chain ◽  
Level 1

e18730 Background: No targeted agents except for drugs against NTRK fusion, dMMR/MSI-H or TMB-H are recommended for the treatment of cancer of unknown primary (CUP), despite of the occurrence of multiple actionable mutations identified by NGS. We aimed to explore the characteristics of circulating tumor DNA (ctDNA) and its value in guiding targeted treatment in combination with predicted cancer types by 90-gene reverse-transcription polymerase chain reaction assay for tissue origin. Methods: 172 treatment-naïve CUP patients with ctDNA testing were retrospectively included between April 2017 and Oct 2020. Of them, 98 patients had primary site predicted. Genetic alterations were reclassified based on their predicted primary site and the oncoKB scale. 153 patients treated with the first-line therapy and available survival data were used to explore prognostic value of detected genetic alterations in ctDNA. Results: We identified 82.6% (142/172) of patients had alterations detected, with the most commonly seen mutations of TP53 (51%), ARID1A (11%), KRAS (10%), RB1 (9%), APC (8%), PI3KCA (8%) and NFE2L2 (7%). The most commonly observed actionable mutations were PIK3CA (n=14, 9.8%), ERBB2 (n=7, 4.9%), BRAF (n=6, 4.2%), MET (n=6, 4.2%) and EGFR (n=5, 3.5%). After introducing predicted primary site in the 98 patients, 6.1% (n=6) of patients upgraded to a Level 1 alteration, 1.0% (n=1) to a Level 2 alteration (Table). In these 7 patients, only one patient with predicted lung cancer and EGFR 19 del received gefitinib with partial response for 5+ months. In multivariate analysis, NFE2L2 (hazard ratio [HR] = 2.96, 95%CI=1.32-6.61, P = .008) and CDKN2A mutation (HR = 2.50, 95%CI=1.26-4.96, P = .009) were independently associated with shorter PFS. Furthermore, NFE2L2 (HR = 4.96, 95%CI=1.98-12.43, P ＜ .001) and CDKN2A mutation (HR = 4.84, 95%CI=1.63-14.40, P = .005) were correlated with worse OS. Conclusions: This is the first attempt to integrate ctDNA sequencing and gene expression profiling for tissue of origin in OncoKB classification schema, resulting in 7.1% (7/98) of the genetic alterations reclassified to level 1 or 2, which might identify patients benefiting from corresponding targeted treatment. NFE2L2 and CDKN2A mutations in ctDNA were associated poor prognosis.[Table: see text]

Sex Differences in Cancer Genomes: Much Learned, More Unknown

Endocrinology ◽  
2021 ◽  
Author(s):  
Chenghao Zhu ◽  
Paul C Boutros
Keyword(s):  
Sex Differences ◽  
Precision Medicine ◽  
Cause Of Death ◽  
Clinical Presentation ◽  
Response To Treatment ◽  
Critical Gap ◽  
Cancer Genomes ◽  
Cancer Initiation ◽  
Cancer Types ◽  
Key Resources

Abstract Cancer is a leading cause of death worldwide. Sex influences cancer in a bewildering variety of ways. In some cancer types it affects prevalence, in others genomic profiles, or response to treatment, or mortality. In some sex seems to have little or no influence. How and when sex influences cancer initiation and progression remain a critical gap in our understanding of cancer, with direct relevance to precision medicine. Here, we note several factors that complicate our understanding of sex differences: representativeness of large cohorts, confounding with features like ancestry, age and obesity, and variability in clinical presentation. We summarize the key resources available to study molecular sex differences, and suggest some likely directions for improving our understanding of how patient sex influences cancer behaviour.

scholarly journals Mismatch repair-deficient hormone receptor-positive breast cancers: Biology and pathological characterization

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Elham Sajjadi ◽  
Konstantinos Venetis ◽  
Roberto Piciotti ◽  
Marco Invernizzi ◽  
Elena Guerini-Rocco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mismatch Repair ◽  
Hormone Receptor ◽  
Therapy Resistance ◽  
Genetic Alterations ◽  
Diagnostic Tools ◽  
Breast Cancers ◽  
Comprehensive Overview ◽  
Hormone Receptor Positive ◽  
Status Assessment

AbstractThe clinical outcome of patients with a diagnosis of hormone receptor (HR)+ breast cancer has improved remarkably since the arrival of endocrine therapy. Yet, resistance to standard treatments is a major clinical challenge for breast cancer specialists and a life-threatening condition for the patients. In breast cancer, mismatch repair (MMR) status assessment has been demonstrated to be clinically relevant not only in terms of screening for inherited conditions such as Lynch syndrome, but also for prognostication, selection for immunotherapy, and early identification of therapy resistance. Peculiar traits characterize the MMR biology in HR+ breast cancers compared to other cancer types. In these tumors, MMR genetic alterations are relatively rare, occurring in ~3 % of cases. On the other hand, modifications at the protein level can be observed also in the absence of gene alterations and vice versa. In HR+ breast cancers, the prognostic role of MMR deficiency has been confirmed by several studies, but its predictive value remains a matter of controversy. The characterization of MMR status in these patients is troubled by the lack of tumor-specific guidelines and/or companion diagnostic tests. For this reason, precise identification of MMR-deficient breast cancers can be problematic. A deeper understanding of the MMR biology and clinical actionability in HR+ breast cancer may light the path to effective tumor-specific diagnostic tools. For a precise MMR status profiling, the specific strengths and limitations of the available technologies should be taken into consideration. This article aims at providing a comprehensive overview of the current state of knowledge of MMR alterations in HR+ breast cancer. The available armamentarium for MMR testing in these tumors is also examined along with possible strategies for a tailored pathological characterization.

scholarly journals Analyzing cancer gene expression data through the lens of normal tissue-specificity

2021 ◽  
Author(s):  
H. Robert Frost
Keyword(s):  
Gene Expression ◽  
Normal Tissue ◽  
Tissue Specificity ◽  
Cancer Genomics ◽  
Expression Profiles ◽  
Genetic Alterations ◽  
Cancer Type ◽  
Tissue Specific ◽  
Normal Tissues ◽  
Cancer Types

AbstractThe genetic alterations that underlie cancer development are highly tissue-specific with the majority of driving alterations occurring in only a few cancer types and with alterations common to multiple cancer types often showing a tissue-specific functional impact. This tissue-specificity means that the biology of normal tissues carries important information regarding the pathophysiology of the associated cancers, information that can be leveraged to improve the power and accuracy of cancer genomic analyses. Research exploring the use of normal tissue data for the analysis of cancer genomics has primarily focused on the paired analysis of tumor and adjacent normal samples. Efforts to leverage the general characteristics of normal tissue for cancer analysis has received less attention with most investigations focusing on understanding the tissue-specific factors that lead to individual genomic alterations or dysregulated pathways within a single cancer type. To address this gap and support scenarios where adjacent normal tissue samples are not available, we explored the genome-wide association between the transcriptomes of 21 solid human cancers and their associated normal tissues as profiled in healthy individuals. While the average gene expression profiles of normal and cancerous tissue may appear distinct, with normal tissues more similar to other normal tissues than to the associated cancer types, when transformed into relative expression values, i.e., the ratio of expression in one tissue or cancer relative to the mean in other tissues or cancers, the close association between gene activity in normal tissues and related cancers is revealed. As we demonstrate through an analysis of tumor data from The Cancer Genome Atlas and normal tissue data from the Human Protein Atlas, this association between tissue-specific and cancer-specific expression values can be leveraged to improve the prognostic modeling of cancer, the comparative analysis of different cancer types, and the analysis of cancer and normal tissue pairs.

scholarly journals Widespread alteration of protein autoinhibition in human cancers

2018 ◽  
Author(s):  
Ashwani Jha ◽  
Jennifer M. Bui ◽  
Dokyun Na ◽  
Jörg Gsponer
Keyword(s):  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Signal Propagation ◽  
Genetic Alterations ◽  
Missense Mutations ◽  
Pathway Activation ◽  
Tumorigenic Potential ◽  
Significant Enrichment ◽  
Cancer Types ◽  
Cancer Drivers

ABSTRACTAutoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins as it prevents spurious pathway activation and primes for signal propagation only under appropriate inputs. Altered functioning of inhibitory allosteric switches underlies the tumorigenic potential of numerous cancer drivers. However, whether protein autoinhibition is altered generically in cancer cells remains elusive. Here, we reveal that cancer-associated missense mutations and fusion breakpoints are found with significant enrichment within inhibitory allosteric switches across all cancer types, which in the case of the fusion breakpoints is specific to cancer and not present in other diseases. Recurrently disrupted or mutated allosteric switches identify established and new cancer drivers. Cancer-specific mutations in allosteric switches are associated with distinct changes in signaling, and suggest molecular mechanisms for altered protein regulation, which in the case of ASK1, DAPK2 and EIF4G1 were supported by biophysical simulations. Our results demonstrate that autoinhibition-modulating genetic alterations are positively selected for by cancer cells, and that their study provides valuable insights into molecular mechanisms of cancer misregulation.

scholarly journals Genome-wide Identification and Expression Analysis of Autophagy-related Genes (ATGs) in Medicago Truncatula

2020 ◽  
Author(s):  
Mingkang Yang ◽  
Liping Wang ◽  
Xu Guo ◽  
Chuanglie Lin ◽  
Wei Huang ◽  
...  
Keyword(s):  
Medicago Truncatula ◽  
Expression Analysis ◽  
Interaction Network ◽  
Degradation Process ◽  
Abiotic Stress Response ◽  
Biotic And Abiotic Stress ◽  
Comprehensive Overview ◽  
Genome Wide ◽  
Evolutionarily Conserved ◽  
Gene Structures

Abstract Background: Autophagy is a highly conserved degradation process of cytoplasmic constituents in eukaryotes. Autophagy is known to be involved in the regulation of plant growth and development, as well as biotic and abiotic stress response. Although autophagy-related genes (ATGs) have been identified and characterized in many plant species, little is known about the autophagy process in Medicago truncatula. Results: In this study, 39 ATGs were identified in M. truncatula (MtATGs), and the gene structures and conserved domains of MtATGs were systematically characterized. In addition, many cis-elements which are related to hormone and stress responsiveness were identified in the promoters of MtATGs. Furthermore, phylogenetic analysis and interaction network analysis suggested that the function of MtATGs is evolutionarily conserved in Arabidopsis and M. truncatula. Gene expression analysis showed that most MtATGs were largely induced during seed development, but repressed by nodulation. Moreover, MtATGs were up-regulated in response to salt and drought stresses.Conclusion: These results provide a comprehensive overview of the MtATGs, which provided important clues for further functional analysis of autophagy in M. truncatula.

scholarly journals Microenvironmental variables need to effect intrinsic phenotypic parameters of cancer stem cells to affect tumourigenicity

2013 ◽  
Author(s):  
Jacob G Scott ◽  
Prakash Chinnaiyan ◽  
Alexander ARA Anderson ◽  
Anita Hjelmeland ◽  
David Basanta
Keyword(s):  
Stem Cell ◽  
Therapeutic Strategy ◽  
Tissue Growth ◽  
Genetic Mutations ◽  
Phenotypic Traits ◽  
Cell Behaviour ◽  
New Information ◽  
Cancer Initiation ◽  
Cancer Types ◽  
Direct Feedback

Since the discovery of tumour initiating cells (TICs) in solid tumours, studies focussing on their role in cancer initiation and progression have abounded. The biological interrogation of these cells continues to yield volumes of information on their pro-tumourigenic behaviour, but actionable generalised conclusions have been scarce. Further, new information suggesting a dependence of tumour composition and growth on the microenvironment has yet to be studied theoretically. To address this point, we created a hybrid, discrete/continuous computational cellular automaton model of a generalised stem-cell driven tissue with a simple microenvironment. Using the model we explored the phenotypic traits inherent to the tumour initiating cells and the effect of the microenvironment on tissue growth. We identify the regions in phenotype parameter space where TICs are able to cause a disruption in homeostasis, leading to tissue overgrowth and tumour maintenance. As our parameters and model are non- specific, they could apply to any tissue TIC and do not assume specific genetic mutations. Targeting these phenotypic traits could represent a generalizable therapeutic strategy across cancer types. Further, we find that the microenvironmental variable does not strongly effect the outcomes, suggesting a need for direct feedback from the microenvironment onto stem-cell behaviour in future modelling endeavours.

scholarly journals Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 114
Author(s):  
Lisa Linck-Paulus ◽  
Claus Hellerbrand ◽  
Anja K. Bosserhoff ◽  
Peter Dietrich
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Therapeutic Targets ◽  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
The Future ◽  
Associated Proteins ◽  
Cancer Types ◽  
Novel Therapeutic Strategies

In this review, we summarize the current knowledge on miRNAs as therapeutic targets in two cancer types that were frequently described to be driven by miRNAs—melanoma and hepatocellular carcinoma (HCC). By focusing on common microRNAs and associated pathways in these—at first sight—dissimilar cancer types, we aim at revealing similar molecular mechanisms that are evolved in microRNA-biology to drive cancer progression. Thereby, we also want to outlay potential novel therapeutic strategies. After providing a brief introduction to general miRNA biology and basic information about HCC and melanoma, this review depicts prominent examples of potent oncomiRs and tumor-suppressor miRNAs, which have been proven to drive diverse cancer types including melanoma and HCC. To develop and apply miRNA-based therapeutics for cancer treatment in the future, it is essential to understand how miRNA dysregulation evolves during malignant transformation. Therefore, we highlight important aspects such as genetic alterations, miRNA editing and transcriptional regulation based on concrete examples. Furthermore, we expand our illustration by focusing on miRNA-associated proteins as well as other regulators of miRNAs which could also provide therapeutic targets. Finally, design and delivery strategies of miRNA-associated therapeutic agents as well as potential drawbacks are discussed to address the question of how miRNAs might contribute to cancer therapy in the future.

scholarly journals Genetic Engineering of Zebrafish in Cancer Research

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2168
Author(s):  
Ludivine Raby ◽  
Pamela Völkel ◽  
Xuefen Le Bourhis ◽  
Pierre-Olivier Angrand
Keyword(s):  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
Molecular Signatures ◽  
Reverse Genetic ◽  
Human Cancers ◽  
Oncogenic Mutations ◽  
Cancer Models ◽  
Conditional Expression ◽  
Cancer Initiation

Zebrafish (Danio rerio) is an excellent model to study a wide diversity of human cancers. In this review, we provide an overview of the genetic and reverse genetic toolbox allowing the generation of zebrafish lines that develop tumors. The large spectrum of genetic tools enables the engineering of zebrafish lines harboring precise genetic alterations found in human patients, the generation of zebrafish carrying somatic or germline inheritable mutations or zebrafish showing conditional expression of the oncogenic mutations. Comparative transcriptomics demonstrate that many of the zebrafish tumors share molecular signatures similar to those found in human cancers. Thus, zebrafish cancer models provide a unique in vivo platform to investigate cancer initiation and progression at the molecular and cellular levels, to identify novel genes involved in tumorigenesis as well as to contemplate new therapeutic strategies.

scholarly journals High Expression of Pd-1 in Circulating Cells of Patients With Advanced Colorectal Cancer Receiving Adjuvant Therapy

2020 ◽  
Vol 19 ◽  
pp. 153303382096944
Author(s):  
Muhammed A. Bakhrebah ◽  
Mohammad Nasrullah ◽  
Wesam H. Abdulaal ◽  
Mohammed A. Hassan ◽  
Halima Siddiqui ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
Adjuvant Therapy ◽  
Tumor Cells ◽  
Immune Cells ◽  
Human Leukocyte ◽  
Genetic Alterations ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Cancer Types

Among all cancer types, colorectal cancer is the third most common in men and the second most common in women globally. Generally, the risk of colorectal cancer increases with age, and colorectal cancer is modulated by various genetic alterations. Alterations in the immune response serve a significant role in the development of colorectal cancer. In primary cancer types, immune cells express a variety of inhibitory molecules that dampen the immune response against tumor cells. Additionally, few reports have demonstrated that classical chemotherapy promotes the immunosuppressive microenvironment in both tissues and immune cells. This study assessed the expression levels of genes using RT-qPCR associated with the immune system, including interferon-γ, programmed death-1, β2-microglobulin, human leukocyte antigen-A, CD3e, CD28 and intracellular adhesion molecule 1, in patients with colorectal cancer, as these genes are known to serve important roles in immune regulation during cancer incidence. Gene expression analysis was performed with the whole blood cells of patients with colorectal cancer and healthy volunteers. Compared with the normal controls, programmed death-1was highly expressed in patients with advanced-stage colorectal cancer. Furthermore, the expression of programmed death-1 was higher in patients receiving adjuvant therapy, which suggests the therapy dampened the immune response against tumor cells. The results of the present study indicate that classical adjuvant therapies, which are currently used for patients with colorectal cancer, should be modulated, and a combination of classical therapy with anti-programmed death-1 antibody should be conducted for improved management of patients with colorectal cancer.

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