'I Do It All Alone': The Burdens and Benefits of Being Diagnosed With, and Treated for, Colorectal Cancer During the Covid-19 Pandemic.

INTRODUCTION: The Covid-19 pandemic dramatically altered the way cancer care services were accessed and delivered, including for colorectal cancer (CRC). In the United Kingdom, patients were discouraged from presenting in primary care, many consultations took place remotely, investigative procedures and screening programmes were temporarily suspended, and fewer operations and treatments were delivered. People had to face the practical consequences of having cancer during a pandemic and navigate never before seen pathways, often alone. We examined the experience of being diagnosed and treated for CRC during the pandemic, and the implications of this on people's cancer journeys. METHODS: Semi-structured interviews were undertaken with people diagnosed with CRC during the Covid-19 pandemic (January 2020-May 2021), in the North East of England. An iterative topic guide was used during interviews, which took place remotely (telephone or Zoom), were audio recorded, pseudo-anonymised and transcribed. Initial transcripts were independently coded by two researchers, and a code 'bank' developed for application across transcripts. Development of themes and overarching analytical constructs was undertaken collaboratively by the research team. RESULTS: Interviews were conducted with 19 participants, analysed and four key themes identified: (1) The relative threats of Covid-19 and Cancer were not comparable, with cancer seen as posing a far greater risk than Covid-19; (2) Remote consultations were problematic, affecting patients' abilities to build rapport and trust with clinicians, assess nonverbal communication, and feel able to disclose, comprehend and retain information; (3) Stoma follow-up care was seen to be lacking, with long wait times for stoma reversal experienced by some; Finally, (4) Being alone during consultations negatively impacted some peoples' abilities to absorb information, and left them without the support of loved ones at an emotionally vulnerable time. However, some participants preferred being alone at certain points in their pathways, including receiving a diagnosis, and most frequently when receiving in-patient treatment. CONCLUSION: Being alone brought unexpected benefits, absolving people from undertaking emotions work for others, and instead focus on their recovery, however, remote consultations negatively impacted patients' experiences. This study highlights the complex benefits and burdens of pandemic-located cancer journeys, including how these shifted at different points across cancer pathways. PATIENT OR PUBLIC CONTRIBUTION: Lorraine Angell, a cancer survivor, has been central to this study from idea conception, contributing to: development of study focus and design; securing funding; production of patient-facing materials; development of interview topic guides; analysis and interpretation of data; and drafting of key findings and manuscripts.

A critical discourse analysis of the influence of organisational structures on inequality in head and neck cancer treatment in Denmark.

BACKGROUND: Concern is growing about inequality in cancer treatment, and a call has been made for more knowledge of the underlying causes of this inequality. Studies show that patients with low socioeconomic status in general face a greater risk of inequality than patients with a high socioeconomic status. AIM: The aim of the present study was to uncover how institutional factors may exacerbate inequality in cancer treatment for patients with low socioeconomic status exemplified by patients with head and neck cancer, most of whom have low socioeconomic status. METHOD: Inspired by Fairclough, we undertook a critical discourse analysis investigating the treatment pathway of patients with head and neck cancer on the basis of policy papers. RESULTS: These papers, which we conceived as formative instruments, harboured a discourse of efficiency and a discourse of participation, together carving out an effective cancer treatment pathway provided patients act in line with the recommendations. DISCUSSION: The discourses of efficiency and participation are not unfamiliar in health care, and prior research shows that they may pose difficulties for patients with low socioeconomic status. CONCLUSION: The discoursal framing of head and neck cancer treatment may exacerbate inequality because most patients with a low socioeconomic status fail to comprehend and act in accordance with these discourses.

In silico signaling modeling to understand cancer pathways and treatment responses.

Precision medicine has changed thinking in cancer therapy, highlighting a better understanding of the individual clinical interventions. But what role do the drivers and pathways identified from pan-cancer genome analysis play in the tumor? In this letter, we will highlight the importance of in silico modeling in precision medicine. In the current era of big data, tumor engines and pathways derived from pan-cancer analysis should be integrated into in silico models to understand the mutational tumor status and individual molecular pathway mechanism at a deeper level. This allows to pre-evaluate the potential therapy response and develop optimal patient-tailored treatment strategies which pave the way to support precision medicine in the clinic of the future.

Ablation of the sperm-associated antigen 11A (SPAG11A) protein by active immunization promotes epididymal oncogenesis in the rat.

Incidence of cancer in the epididymis is very rare. It is proposed that proteins specific to this organ may contribute to this unique property. We previously demonstrated that siRNA-mediated knockdown of SPAG11A mRNA resulted in increased proliferation of epididymal epithelial cells, whereas overexpression of this gene caused reduced proliferation in immortalized cell lines. In this study, we evaluated the oncogenesis-related anatomical and transcriptome changes in the epididymis of SPAG11A-immunized rats challenged with a low dose of diethyl nitrosamine (DEN). DEN treatment or SPAG11A immunization alone did not cause any histopathological changes in the epididymis. Interestingly, indications of oncogenesis were observed in SPAG11A-immunized + DEN-treated rats. Using high throughput sequencing, we observed that 3549 transcripts that were differentially expressed in the caput epididymis of DEN only-treated rats displayed similar differential expression in the caput epididymis of SPAG11A-immunized rats, indicating that the microenvironment that contributes to oncogenesis sets in when SPAG11A protein is ablated. Differential expression of genes that are involved in 10 major cancer related pathways was also analyzed. Majority of the genes related to these pathways that were differentially expressed in the caput epididymis of DEN only-treated rats also showed similar pattern in the caput epididymis of SPAG11A-immunized rats. For the first time, results of our study demonstrate that ablation of SPAG11A by active immunization renders the epididymis susceptible to oncogenesis and that this protein may be one of the factors that contributes to the rarity of epididymal cancer.

QuaDMutNetEx: a method for detecting cancer driver genes with low mutation frequency.

BACKGROUND: Cancer is caused by genetic mutations, but not all somatic mutations in human DNA drive the emergence or growth of cancers. While many frequently-mutated cancer driver genes have already been identified and are being utilized for diagnostic, prognostic, or therapeutic purposes, identifying driver genes that harbor mutations occurring with low frequency in human cancers is an ongoing endeavor. Typically, mutations that do not confer growth advantage to tumors - passenger mutations - dominate the mutation landscape of tumor cell genome, making identification of low-frequency driver mutations a challenge. The leading approach for discovering new putative driver genes involves analyzing patterns of mutations in large cohorts of patients and using statistical methods to discriminate driver from passenger mutations. RESULTS: We propose a novel cancer driver gene detection method, QuaDMutNetEx. QuaDMutNetEx discovers cancer drivers with low mutation frequency by giving preference to genes encoding proteins that are connected in human protein-protein interaction networks, and that at the same time show low deviation from the mutual exclusivity pattern that characterizes driver mutations occurring in the same pathway or functional gene group across a cohort of cancer samples. CONCLUSIONS: Evaluation of QuaDMutNetEx on four different tumor sample datasets show that the proposed method finds biologically-connected sets of low-frequency driver genes, including many genes that are not found if the network connectivity information is not considered. Improved quality and interpretability of the discovered putative driver gene sets compared to existing methods shows that QuaDMutNetEx is a valuable new tool for detecting driver genes. QuaDMutNetEx is available for download from https://github.com/bokhariy/QuaDMutNetExunder the GNU GPLv3 license.

Transcriptomic analysis of marine endophytic fungi extract identifies highly enriched anti-fungal fractions targeting cancer pathways in HepG2 cell lines.

BACKGROUND: Marine endophytic fungi (MEF) are good sources of structurally unique and biologically active secondary metabolites. Due to the increase in antimicrobial resistance, the secondary metabolites from MEF ought to be fully explored to identify candidates which could serve as lead compounds for novel drug development. These secondary metabolites might also be useful for development of new cancer drugs. In this study, ethyl acetate extracts from marine endophytic fungal cultures were tested for their antifungal activity and anticancer properties against C. albicans and the human liver cancer cell line HepG2, respectively. The highly enriched fractions were also analyzed by high performance liquid chromatography coupled with high resolution mass spectrometry (HPLC-HRMS) and their effect on the HepG2 cells was assessed via transcriptomics and with a proliferation assay. RESULTS: We demonstrated that the fractions could reduce proliferation in HepG2 cells. The detailed transcriptome analysis revealed regulation of several cancer- and metabolism-related pathways and gene ontologies. The down-regulated pathways included, cell cycle, p53 signaling, DNA replication, sphingolipid metabolism and drug metabolism by cytochrome P450. The upregulated pathways included HIF-1 signaling, focal adhesion, necroptosis and transcriptional mis-regulation of cancer. Furthermore, a protein interaction network was constructed based on the 26 proteins distinguishing the three treatment conditions from the untreated cells. This network was composed of central functional components associated with metabolism and cancer such as TNF, MAPK, TRIM21 and one component contained APP. CONCLUSIONS: The purified fractions from MEF investigated in this study showed antifungal activity against C. albicans and S. cerevisiae alone or both and reduced proliferation of the human liver cancer cell line HepG2 implicating regulation of several cancer- and metabolism-related pathways. The data from this study could be instrumental in identifying new pathways associated with liver cancer anti-proliferative processes which can be used for the development of novel antifungal and anti-cancer drugs.

Integrated analysis identifies a pathway-related competing endogenous RNA network in the progression of pancreatic cancer.

BACKGROUND: It is well acknowledged that cancer-related pathways play pivotal roles in the progression of pancreatic cancer (PC). Employing Integrated analysis, we aim to identify the pathway-related ceRNA network associated with PC progression. METHODS: We divided eight GEO datasets into three groups according to their platform, and combined TCGA and GTEx databases as a group. Additionally, we screened out the differentially expressed genes (DEGs) and performed functional enrichment analysis in each group, and recognized the top hub genes in the most enriched pathway. Furthermore, the upstream of miRNAs and lncRNAs were predicted and validated according to their expression and prognostic roles. Finally, the co-expression analysis was applied to identify a pathway-related ceRNA network in the progression of PC. RESULTS: A total of 51 significant pathways that common enriched in all groups were spotted. Enrichment analysis indicated that pathway in cancer was greatly linked with tumor formation and progression. Next, the top 20 hug genes in this pathway were recognized, and stepwise prediction and validation from mRNA to lncRNA, including 11 hub genes, 4 key miRNAs, and 2 key lncRNAs, were applied to identify a meaningful ceRNA network according to ceRNA rules. Ultimately, we identified the PVT1/miR-20b/CCND1 axis as a promising pathway-related ceRNA axis in the progression of PC. CONCLUSION: Overall, we elucidate the pathway-related ceRNA regulatory network of PVT1/miR-20b/CCND1 in the progression of PC, which can be considered as therapeutic targets and encouraging prognostic biomarkers for PC.

Molecular characterization and clinical relevance of m6A regulators across 33 cancer types.

The methylation of N6 adenosine (m6A) plays a critical role in diverse biological processes. However, knowledge regarding the reconstitution of m6A across cancer types is still lacking. Here, we systematically analyzed the molecular alterations and clinical relevance of m6A regulators across > 10,000 subjects representing 33 cancer types. We found that there are widespread genetic alterations to m6A regulators, and that their expression levels are significantly correlated with the activity of cancer hallmark-related pathways. Moreover, m6A regulators were found to be potentially useful for prognostic stratification, and we identified IGF2BP3 as a potential oncogene across multiple cancer types. Our results provide a valuable resource that will guide both mechanistic and therapeutic analyses of the role of m6A regulators in cancer.

Variation in the initial assessment and investigation for ovarian cancer in symptomatic women: a systematic review of international guidelines.

BACKGROUND: Women with ovarian cancer can present with a variety of symptoms and signs, and an increasing range of tests are available for their investigation. A number of international guidelines provide advice for the initial assessment of possible ovarian cancer in symptomatic women. We systematically identified and reviewed the consistency and quality of these documents. METHODS: MEDLINE, Embase, guideline-specific databases and professional organisation websites were searched in March 2018 for relevant clinical guidelines, consensus statements and clinical pathways, produced by professional or governmental bodies. Two reviewers independently extracted data and appraised documents using the Appraisal for Guidelines and Research Evaluation 2 (AGREEII) tool. RESULTS: Eighteen documents from 11 countries in six languages met selection criteria. Methodological quality varied with two guidance documents achieving an AGREEII score ≥ 50% in all six domains and 10 documents scoring ≥50% for "Rigour of development" (range: 7-96%). All guidance documents provided advice on possible symptoms of ovarian cancer, although the number of symptoms included in documents ranged from four to 14 with only one symptom (bloating/abdominal distension/increased abdominal size) appearing in all documents. Fourteen documents provided advice on physical examinations but varied in both the examinations they recommended and the physical signs they included. Fifteen documents provided recommendations on initial investigations. Transabdominal/transvaginal ultrasound and the serum biomarker CA125 were the most widely advocated initial tests. Five distinct testing strategies were identified based on the number of tests and the order of testing advocated: 'single test', 'dual testing', 'sequential testing', 'multiple testing options' and 'no testing'. CONCLUSIONS: Recommendations on the initial assessment and investigation for ovarian cancer in symptomatic women vary considerably between international guidance documents. This variation could contribute to differences in the way symptomatic women are assessed and investigated between countries. Greater research is needed to evaluate the assessment and testing approaches advocated by different guidelines and their impact on ovarian cancer detection.

QuaDMutEx: quadratic driver mutation explorer.

BACKGROUND: Somatic mutations accumulate in human cells throughout life. Some may have no adverse consequences, but some of them may lead to cancer. A cancer genome is typically unstable, and thus more mutations can accumulate in the DNA of cancer cells. An ongoing problem is to figure out which mutations are drivers - play a role in oncogenesis, and which are passengers - do not play a role. One way of addressing this question is through inspection of somatic mutations in DNA of cancer samples from a cohort of patients and detection of patterns that differentiate driver from passenger mutations. RESULTS: We propose QuaDMutEx, a method that incorporates three novel elements: a new gene set penalty that includes non-linear penalization of multiple mutations in putative sets of driver genes, an ability to adjust the method to handle slow- and fast-evolving tumors, and a computationally efficient method for finding gene sets that minimize the penalty, through a combination of heuristic Monte Carlo optimization and exact binary quadratic programming. Compared to existing methods, the proposed algorithm finds sets of putative driver genes that show higher coverage and lower excess coverage in eight sets of cancer samples coming from brain, ovarian, lung, and breast tumors. CONCLUSIONS: Superior ability to improve on both coverage and excess coverage on different types of cancer shows that QuaDMutEx is a tool that should be part of a state-of-the-art toolbox in the driver gene discovery pipeline. It can detect genes harboring rare driver mutations that may be missed by existing methods. QuaDMutEx is available for download from https://github.com/bokhariy/QuaDMutEx under the GNU GPLv3 license.

Calcium role in human carcinogenesis: a comprehensive analysis and critical review of literature.

The central role played by calcium ion in biological systems has generated an interest for its potential implication in human malignancies. Thus, lines of research, on possible association of calcium metabolism regulation with tumorigenesis, implying disruptions and/or alterations of known molecular pathways, have been extensively researched in the recent decades. This paper is a critical synthesis of these findings, based on a functional approach of the calcium signaling toolkit. It provides strong support that this ubiquitous divalent cation is involved in cancer initiation, promotion, and progression. Different pathways have been outlined, involving equally different molecular and cellular structures. However, if the association between calcium and cancer can be described as constant, it is not always linear. We have identified several influencing factors among which the most relevant are (i) the changes in local or tissular concentrations of free calcium and (ii) the histological and physiological types of tissue involved. Such versatility at the molecular level may probably account for the conflicting findings reported by the epidemiological literature on calcium dietary intake and the risk to develop certain cancers such as the prostatic or mammary neoplasms. However, it also fuels the hypothesis that behind each cancer, a specific calcium pathway can be evidenced. Identifying such molecular interactions is probably a promising approach for further understanding and treatment options for the disease.

Whole-exome sequencing of duodenal adenocarcinoma identifies recurrent Wnt/ß-catenin signaling pathway mutations.

BACKGROUND: Genomic alterations of small bowel cancers remain poorly understood due to the rarity of these diseases. In the current study, the authors report the identification of somatic mutations from patients with duodenal adenocarcinoma by whole-exome sequencing. METHODS: Whole-exome sequencing and follow-up analysis were conducted in 12 matched tumor-normal tissue duodenal adenocarcinoma tissue pairs to examine the genetic characteristics of this disease. Somatic mutations (single-nucleotide variants and short insertion/deletions) were obtained and filtered and then searched for recurrently mutated genes and pathways. RESULTS: An excess of C-to-T transitions at the CpG dinucleotide was observed in the substitution of bases. The authors identified recurrent mutations in tumor protein p53 (TP53), KRAS, catenin (cadherin-associated protein) ß-1 (CTNNB1), AT-rich interactive domain 2 (ARID2), adenomatous polyposis coli (APC), erb-b2 receptor tyrosine kinase 2 (ERBB2), ARID1A, cadherin-related family member 1 (CDHR1), NRAS, Bcl-2-related ovarian killer (BOK), radial spoke head 14 homolog (chlamydomonas) (RTDR1), cell division cycle 27 (CDC27), catalytic subunit of phosphoinositide-3-kinase (PIK3CA), and SMAD family member 4 (SMAD4). Pathway scan indicated that the Wnt signaling pathway, regulation of the actin cytoskeleton pathway, ErbB signaling pathway, and the pathway of focal adhesion were the most extensively affected pathways. CONCLUSIONS: This genomic characterization of duodenal adenocarcinoma provides researchers with insight into its somatic landscape and highlights the vital role of the Wnt/ß-catenin signaling pathway. The study data also indicate that duodenal adenocarcinomas have a genetic resemblance to gastric and colorectal cancers. These discoveries may benefit the future development of molecular diagnosis and personalized therapies. Cancer 2016;122:1689-96. © 2016 American Cancer Society.

Impact of smoking on lung cancer treatment effectiveness: a review.

Tobacco smoke contains more than 4000 detectable substances, such as polycyclic aromatic hydrocarbons, nicotine, carbon monoxide and heavy metals, which are considered powerful enzymatic inducers that have notable influence on the efficacy and tolerability of many medications through complex pharmacokinetic and pharmacodynamic interactions. As a result, adjustments of drug dosages are required in smokers, both if they continue to smoke or if they quit after smoking cessation treatment. The purpose of this review is to examine the main drug interactions with tobacco smoke clinically relevant, with a closer look on patients developing oncologic diseases.

Identification of novel mutations by exome sequencing in African American colorectal cancer patients.

BACKGROUND: The purpose of this study was to identify genome-wide single nucleotide variants and mutations in African American patients with colorectal cancer (CRC). There is a need of such studies in African Americans, because they display a higher incidence of aggressive CRC tumors. METHODS: We performed whole exome sequencing (WES) on DNA from 12 normal/tumor pairs of African American CRC patient tissues. Data analysis was performed using the software package GATK (Genome Analysis Tool Kit). Normative population databases (eg, 1000 Genomes SNP database, dbSNP, and HapMap) were used for comparison. Variants were annotated using analysis of variance and were validated via Sanger sequencing. RESULTS: We identified somatic mutations in genes that are known targets in CRC such as APC, BRAF, KRAS, and PIK3CA. We detected novel alterations in the Wnt pathway gene, APC, within its exon 15, of which mutations are highly associated with CRC. CONCLUSIONS: This WES study in African American patients with CRC provides insight into the identification of novel somatic mutations in APC. Our data suggest an association between specific mutations in the Wnt signaling pathway and an increased risk of CRC. The analysis of the pathogenicity of these novel variants may shed light on the aggressive nature of CRC in African Americans.

Prospective cohort study assessing patient satisfaction and diagnostic accuracy in channeled endoscope local anesthetic biopsy in the investigation of head and neck cancer.

BACKGROUND: There are delays in the head and neck Urgent Suspicion of Cancer (USOC) pathway. Local anesthetic (LA) biopsy with channeled endoscopes in outpatients can reduce time to diagnosis. METHODS: Questionnaire-based prospective study of LA or general anesthetic (GA) biopsy for investigation of cancer from September 2021 to July 2022. RESULTS: 100% (n = 48) were very satisfied or satisfied with their overall experience. 71% (n = 20) of LA patients reported they would prefer to have a biopsy under LA. LA biopsy was 68% sensitive and 100% specific for cancer diagnosis. 28.6% (8) and 10% (2) of LA and GA patients had palliative MDT outcomes. Median time to diagnosis was 44.5 and 49.0 days for LA and GA biopsy, respectively. CONCLUSION: LA biopsy had a high satisfaction rate and is sensitive for diagnosing cancer. LA biopsy can expedite treatment pathways. LA biopsy should be considered as an option for first line investigation.

Cat-E: A comprehensive web tool for exploring cancer targeting strategies.

Identifying potential cancer-associated genes and drug targets from omics data is challenging due to its diverse sources and analyses, requiring advanced skills and large amounts of time. To facilitate such analysis, we developed Cat-E (Cancer Target Explorer), a novel R/Shiny web tool designed for comprehensive analysis with evaluation according to cancer-related omics data. Cat-E is accessible at https://cat-e.bioinfo-wuerz.eu/. Cat-E compiles information on oncolytic viruses, cell lines, gene markers, and clinical studies by integrating molecular datasets from key databases such as OvirusTB, TCGA, DrugBANK, and PubChem. Users can use all datasets and upload their data to perform multiple analyses, such as differential gene expression analysis, metabolic pathway exploration, metabolic flux analysis, GO and KEGG enrichment analysis, survival analysis, immune signature analysis, single nucleotide variation analysis, dynamic analysis of gene expression changes and gene regulatory network changes, and protein structure prediction. Cancer target evaluation by Cat-E is demonstrated here on lung adenocarcinoma (LUAD) datasets. By offering a user-friendly interface and detailed user manual, Cat-E eliminates the need for advanced computational expertise, making it accessible to experimental biologists, undergraduate and graduate students, and oncology clinicians. It serves as a valuable tool for investigating genetic variations across diverse cancer types, facilitating the identification of novel diagnostic markers and potential therapeutic targets.

Time intervals to care and health service use experiences of uninsured cancer patients treated under public financing in Mexico City.

BACKGROUND: The present study assesses the time intervals from symptom discovery to treatment start and describes the health service use experiences of uninsured patients with cancer of the breast, cervix uteri, testicle, and prostate before their arrival to the cancer hospital. METHODS: This cross-sectional study included 1468 patients who were diagnosed between June 2016 and May 2017 and received treatment for the selected cancers in two of the largest public cancer hospitals in Mexico City, financed through Seguro Popular. Data was collected through a survey administered via face-to-face interviews with patients and a review of their medical files. RESULTS: The median time between detection (symptom discovery or first abnormal screening test) and treatment start was 6.6 months. For all types of cancer, the longest interval was the diagnostic interval -between the first use of healthcare services and the confirmation of cancer. Less than 20% cancer patients were diagnosed in the earliest stages that are associated with the best chances of long-term survival. The participants described a high use of private services for their first consultation, the use of several different types of health services and multiple consultations before arrival to the cancer centers, and 35% perceived being misdiagnosed by the first doctor they consulted. CONCLUSIONS: Most cancer patients treated in the two largest public institutions available for the uninsured faced long delays to get diagnosed and started treatment at advanced stages. Strengthening quality and access for effective early cancer diagnosis and treatment is key to improve patient outcomes in low and middle-income settings.

Reduction of daily-use parabens and phthalates reverses accumulation of cancer-associated phenotypes within disease-free breast tissue of study subjects.

Estrogenic overstimulation is carcinogenic to the human breast. Personal care products (PCPs) commonly contain xenoestrogens (XE), such as parabens and phthalates. Here, we identified the adverse effects of persistent exposure to such PCPs directly within human estrogen responsive breast tissue of subjects enrolled in a regimen of reduced XE use (REDUXE). Pre- and post-intervention fine needle aspirates (FNAs) of the breast were collected from healthy volunteers who discontinued the use of paraben and phthalate containing PCPs over a 28 d period. Based on high-dimensional gene expression data of matched FNA pairs of study subjects, we demonstrate a striking reversal of cancer-associated phenotypes, including the PI3K-AKT/mTOR pathway, autophagy, and apoptotic signaling networks within breast cells of REDUXE compliant subjects. These, and other altered phenotypes were detected together with a significant reduction in urinary parabens and phthalate metabolites. Moreover, in vitro treatment of paired FNAs with 17ß-estradiol (E2), displayed a 'normalizing' impact of REDUXE on gene expression within known E2-modulated pathways, and on functional endpoints, including estrogen receptor alpha: beta ratio, and S-phase fraction of the cell cycle. In a paradigm shifting approach facilitated by community-based participatory research, REDUXE reveals unfavorable consequences from exposure to XEs from daily-use PCPs. Our findings illustrate the potential for REDUXE to suppress pro-carcinogenic phenotypes at the cellular level towards the goal of breast cancer prevention.

Widespread transcriptomic alterations of transient receptor potential channel genes in cancer.

Ion channels, in particular transient-receptor potential (TRP) channels, are essential genes that play important roles in many physiological processes. Emerging evidence has demonstrated that TRP genes are involved in a number of diseases, including various cancer types. However, we still lack knowledge about the expression alterations landscape of TRP genes across cancer types. In this review, we comprehensively reviewed and summarised the transcriptomes from more than 10 000 samples in 33 cancer types. We found that TRP genes were widespreadly transcriptomic dysregulated in cancer, which was associated with clinical survival of cancer patients. Perturbations of TRP genes were associated with a number of cancer pathways across cancer types. Moreover, we reviewed the functions of TRP family gene alterations in a number of diseases reported in recent studies. Taken together, our study comprehensively reviewed TRP genes with extensive transcriptomic alterations and their functions will directly contribute to cancer therapy and precision medicine.

Early contribution of germline and nevi genetic alterations to a rapidly-progressing cutaneous melanoma patient: a case report.

BACKGROUND: Cutaneous melanoma is the skin cancer with the highest mutational burden and metastatic rate. Early genetic alterations and biomarkers of distant progression are a point of interest. In addition to germline-susceptibility loci, almost 30% of melanomas arise from precursor benign nevi lesions, providing a source for malignant transformation. CASE PRESENTATION: Patient#009 developed a cutaneous melanoma over a nevus, followed by progression to regional and distant metastases in months, unresponsive to targeted therapy. To search for the genetic contribution to this rapid progression, a longitudinal analysis was performed through WES of germline, nevi, primary tumor, and a metastatic lymph node. Differential SNP/INDEL and CNV gene alterations, with functional impact on key pathways and cancer hallmarks in each step of evolution, were discerned. Tumor-associated nevus was, for the first time, split into two sections, distant and adjacent to the primary tumor, to study its heterogeneity. Shared SNP alterations, with stable allele fraction from germline to metastasis were detected, mainly affecting DNA repair genes and promoting genome instability. Early somatic alterations, shared by nevi and primary and metastatic tumors, included BRAFV600E and focal copy-loss of several genes, acquiring additional cancer hallmarks. Phylogenetic analyses revealed that these common somatic alterations would provide a "bridge", allowing progression from a benign to a malignant state. Distant and adjacent nevi were rich in alterations, presenting differential SNP and CNV alterations. Upon tumor transformation, a marked increase in CNV over SNP alterations was determined. Both the number of SNP and CNV-affected genes, including known driver genes, increased throughout progression, although TMB levels remained lower than expected for melanoma. Typical alterations in BRAFV600E tumors related to intrinsic resistance to targeted therapy were found, including BRAF amplification and loss of PTEN, CDKN2A/B, and TP53 surveillance genes. Finally, numerous metastatic alterations were detected, further promoting tumor progression. CONCLUSIONS: In this patient, longitudinal WES analysis revealed a sequential and cumulative pattern of genetic alterations, where germline and nevi somatic events contributed early to its rapid clinical progression. In this case report, we found tumor-associated nevi as genetically heterogeneous precursor entities, in which potential prognostic biomarkers should be studied prospectively.