3,218 research outputs found
KCNQ potassium channels modulate Wnt activity in gastro-oesophageal adenocarcinomas
Voltage-sensitive potassium channels play an important role in controlling membrane potential and ionic homeostasis in the gut and have been implicated in gastrointestinal (GI) cancers. Through large-scale analysis of 897 patients with gastro-oesophageal adenocarcinomas (GOAs) coupled with in vitro models, we find KCNQ family genes are mutated in âŒ30% of patients, and play therapeutically targetable roles in GOA cancer growth. KCNQ1 and KCNQ3 mediate the WNT pathway and MYC to increase proliferation through resultant effects on cadherin junctions. This also highlights novel roles of KCNQ3 in non-excitable tissues. We also discover that activity of KCNQ3 sensitises cancer cells to existing potassium channel inhibitors and that inhibition of KCNQ activity reduces proliferation of GOA cancer cells. These findings reveal a novel and exploitable role of potassium channels in the advancement of human cancer, and highlight that supplemental treatments for GOAs may exist through KCNQ inhibitors
New advances in radiomics of gastrointestinal stromal tumors
Gastrointestinal stromal tumors (GISTs) are uncommon neoplasms of the gastrointestinal tract with peculiar clinical, genetic, and imaging characteristics. Preoperative knowledge of risk stratification and mutational status is crucial to guide the appropriate patientsâ treatment. Predicting the clinical behavior and biological aggressiveness of GISTs based on conventional computed tomography (CT) and magnetic resonance imaging (MRI) evaluation is challenging, unless the lesions have already metastasized at the time of diagnosis. Radiomics is emerging as a promising tool for the quantification of lesion heterogeneity on radiological images, extracting additional data that cannot be assessed by visual analysis. Radiomics applications have been explored for the differential diagnosis of GISTs from other gastrointestinal neoplasms, risk stratification and prediction of prognosis after surgical resection, and evaluation of mutational status in GISTs. The published researches on GISTs radiomics have obtained excellent performance of derived radiomics models on CT and MRI. However, lack of standardization and differences in study methodology challenge the application of radiomics in clinical practice. The purpose of this review is to describe the new advances of radiomics applied to CT and MRI for the evaluation of gastrointestinal stromal tumors, discuss the potential clinical applications that may impact patientsâ management, report limitations of current radiomics studies, and future directions
Artificial intelligence for predictive biomarker discovery in immuno-oncology: a systematic review
Background: The widespread use of immune checkpoint inhibitors (ICIs) has revolutionised treatment of multiple cancer types. However, selecting patients who may benefit from ICI remains challenging. Artificial intelligence (AI) approaches allow exploitation of high-dimension oncological data in research and development of precision immuno-oncology. Materials and methods: We conducted a systematic literature review of peer-reviewed original articles studying the ICI efficacy prediction in cancer patients across five data modalities: genomics (including genomics, transcriptomics, and epigenomics), radiomics, digital pathology (pathomics), and real-world and multimodality data. Results: A total of 90 studies were included in this systematic review, with 80% published in 2021-2022. Among them, 37 studies included genomic, 20 radiomic, 8 pathomic, 20 real-world, and 5 multimodal data. Standard machine learning (ML) methods were used in 72% of studies, deep learning (DL) methods in 22%, and both in 6%. The most frequently studied cancer type was non-small-cell lung cancer (36%), followed by melanoma (16%), while 25% included pan-cancer studies. No prospective study design incorporated AI-based methodologies from the outset; rather, all implemented AI as a post hoc analysis. Novel biomarkers for ICI in radiomics and pathomics were identified using AI approaches, and molecular biomarkers have expanded past genomics into transcriptomics and epigenomics. Finally, complex algorithms and new types of AI-based markers, such as meta-biomarkers, are emerging by integrating multimodal/multi-omics data. Conclusion: AI-based methods have expanded the horizon for biomarker discovery, demonstrating the power of integrating multimodal data from existing datasets to discover new meta-biomarkers. While most of the included studies showed promise for AI-based prediction of benefit from immunotherapy, none provided high-level evidence for immediate practice change. A priori planned prospective trial designs are needed to cover all lifecycle steps of these software biomarkers, from development and validation to integration into clinical practice
Divergent Microbial Profiles in Tumor and Adjacent Normal Tissue across Cancer Types
Ph.D.Ph.D. Thesis. University of HawaiÊ»i at MÄnoa 201
Disruption of DNA damage response pathways in tumorigenesis: investigating the role of ATM and BAP1 in hereditary cancers.
The use of massive parallel sequencing techniques for genetic testing of hereditary cancer syndromes provides the possibility of analyzing multiple genes at the same time with limited costs. However, novel genes are being found in melanoma-prone families, but in many cases a causal relation has not been yet established. Moreover, the same gene is often found associated with multiple tumors, suggesting that spectrum of non-melanoma cancers in melanoma tumor syndromes could be broader than that currently known. This thesis describes the effort to tackle these issues, with a particular focus on two genes involved in DNA damage repair: the Ataxia-Telangiectasia Mutated (ATM) and BRCA1-associated protein 1 (BAP1) genes.
During the last year of my PhD I completed the first and carried out the second of the following two studies: \u201cGermline ATM variants predispose to cutaneous melanoma: a joint analysis across the genomel and melanostrum consortia\u201d, and \u201cBAP1-tumor predisposition syndrome and susceptibility to breast cancer\u201d.GERMLINE ATM VARIANTS PREDISPOSE TO CUTANEOUS MELANOMA: A JOINT ANALYSIS ACROSS THE GENOMEL AND MELANOSTRUM CONSORTIA.
ATM germline pathogenic variants predispose to several types of cancers, such as breast cancer and pancreatic cancer, and we recently found rare loss-of-function variants (LOF) in melanoma-prone families. However, considering that current literature on melanoma is non univocal, and that ATM is a large gene with a high number of variants of unknown significance (VUS), it is unclear whether ATM is a melanoma predisposition gene.
To assess if rare germline ATM variants are enriched in melanoma, we conducted and coordinated a multicentric study in collaboration with the GenoMel and MelaNostrum consortia. From 10 countries, we collected 261 multiple primary melanoma (MPM) cases, 941 apparently sporadic cases, and 734 melanoma-prone families probands who underwent ATM genotyping via panel, exome or whole genome sequencing. Nonsense, frameshift and canonical splice variants were considered LOF. Missense variants with an allele frequency (AF) above that expected of ataxia-telangiectasia heterozygous carriers (0.005), or found homozygous in more than two GnomAD individuals, were excluded, whereas the remaining missense variants were included as VUS. We then compared the (AF) of selected ATM variants in our cohort and in GnomAD non-Finnish Europeans (NFE).
We found 19 ATM LOF (18 unique) in 10 familial, 3 MPM and 6 sporadic cases, a frequency higher than that of the GnomAD NFE cohort (AF 0.005 vs 0.002, OR=2.68, p=0.0002), especially when restricting the analysis to familial+MPM cases (AF 0.006 vs 0.002, OR=3.66, p=0.0004). VUSs had a similar, albeit weaker association, both when assessing all (AF 0.05 vs 0.033, OR=1.53, p<0.001) and familial+MPM cases (AF 0.07 vs 0.033, OR=2.22, p<0.001). In 2 families with >1 genotyped cases, LOF co-segregated with melanoma, and one showed partial co-segregation. These results show that ATM variants are enriched in melanoma cases, suggesting that ATM is a melanoma-predisposition gene.BAP1-TUMOR PREDISPOSITION SYNDROME AND SUSCEPTIBILITY TO BREAST CANCER.
Germline LOF variants in the BAP1 gene underlie the BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), characterized by an increased susceptibility to melanoma (cutaneous and uveal) and other cancers, such as mesothelioma, clear cell renal cancer (CCRC), basal cell carcinoma, Melanocytic BAP1-associated intradermal tumor (MBAIT). However, the tumor spectrum of the BAP1-TPDS is not yet completely defined, as more types of cancers, including breast cancer, are being found associated with BAP1. The inclusion of a new type of cancer in the BAP1-TPDS is a complex task when it comes to cancers with a high incidence in the population, such as breast cancer. In fact, in the case of extremely rare syndromes such as BAP1-TPDS, it is difficult to determine if the occurrence of a high-incidence cancer is part of the syndrome or is merely due to chance.
During my research period at QIMR Berghofer (Brisbane, AU) from December 2018 to August 2019, we performed a study to assess if BAP1 is a breast cancer predisposition gene. First, we imputed and analyzed data from the BAP1 database of the recently established BAP1-Interest Group (BIG) Consortium, and we found an enrichment for breast cancer in 15% of families with BAP1 LOF variants.
To determine if germline BAP1 variants are enriched in breast cancer, we then assessed the frequency and type of BAP1 variants in 6088 BRCA1/2 negative high-risk breast cancer cases and 5847 healthy controls, who underwent germline testing via multi-gene panels.
We found four LOF in seven cases and one control, and 58 missense in 59 cases (0.9%) and 38 controls (0.6%). Five familial probands had the same c.783+2T>C splice site variant. We are currently performing a functional analysis to confirm that the variant affects splicing. Immunohistochemistry of tumor samples, only available for a small subset of patients, showed absence of BAP1 nuclear staining in three patients carrying the c.783+2T>C.
These data are in support of the hypothesis that BAP1 may be implicated in breast cancer predisposition. However, due to the scarcity of samples available for LOH assessment, and the fact that we don\u2019t have sufficient information to assess co-segregation in these families, there is still not enough supportive evidence to include breast cancer in the BAP1-TPDS.OTHER PROJECTS: CDKN2A AND SURVIVAL IN CUTANEOUS MELANOMA PATIENTS.
CDKN2A germline pathogenic variants have recently been associated with poor survival in melanoma patients. Despite the high mutation rate in melanoma patients from our centre (up to 10% in apparently sporadic patients), information on CDKN2A impact on survival in these patients is lacking. During the first year of my PhD course, I carried out a study to investigate whether poor survival associated with CDKN2A germline pathogenic variants recently observed in a Norwegian melanoma cohort could be confirmed in a high mutation prevalence Italian cohort of melanoma patients undergoing a mutation-based follow-up. Our study cohort consisred of one-thousand-two-hundred-thirty-nine cutaneous melanoma patients were tested for CDKN2A mutational status and then assigned to a follow-up scheme, according not only to family history but also to CDKN2A mutational status, as follow-up intervals were more frequent for CDKN2A mutation positive (MUT+) patients.
From this cohort, we selected 106 MUT+ patients (familial and apparently sporadic), and 199 CDKN2A mutation negative (MUT-) sporadic patients, matched by age and sex, and with similar tumor stage distribution. We found no difference in overall survival (Hazard Ratio (HR)=0.85, p=0.592, CI=0.48-1.52) and melanoma-specific survival (HR=0.86, p=0.718, CI=0.38-1.95) between MUT+ and MUT- patients. MUT+ patients were more likely to develop multiple melanomas and to undergo surgical excision of dysplastic nevi compared to MUT- patients.
These results show that CDKN2A pathogenic variants are not associated with survival in our cohort (project published: Dalmasso, Bruna, et al. "CDKN2A germline mutations are not associated with poor survival in an Italian cohort of melanoma patients." Journal of the American Academy of Dermatology 80.5 (2019): 1263-1271.)
The influence of BRAF and KRAS mutation status on the association between aspirin use and survival after colon cancer diagnosis
Background: Use of aspirin after diagnosis of colon cancer has been associated with improved survival. Identification of cancer subtypes that respond to aspirin treatment may help develop personalized treatment regimens. The aim of this study was to investigate the influence of BRAF and KRAS mutation status on the association between aspirin use and overall survival after colon cancer diagnosis. Methods: A random selection of 599 patients with colon cancer were analyzed, selected from the Eindhoven Cancer Registry, and BRAF and KRAS mutation status was determined. Data on aspirin use (80 mg) were obtained from the PHARMO Database Network. Parametric survival models with exponential (Poisson) distribution were used. Results: Aspirin use after colon cancer diagnosis was associated with improved overall survival in wild-type BRAF tumors, adjusted rate ratio (RR) of 0.60 (95% CI 0.44-0.83). In contrast, aspirin use in BRAF mutated tumors was not associated with an improved survival (RR 1.11, 95% CI 0.57-2.16). P-value for interaction was non-significant. KRAS mutational status did not differentiate in the association between aspirin use and survival. Conclusion: Low-dose aspirin use after colon cancer diagnosis was associated with improved survival in BRAF wild-type tumors only. However, the large confidence interval of the rate ratio for the use of aspirin in patients with BRAF mutation does not rule out a possible benefit. These results preclude BRAF and KRAS mutation status to be used as a marker for individualized treatment with aspirin, if aspirin becomes regular adjuvant treatment for colon cancer patients in the future
Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up
Gastrointestinal stromal tumours (GISTs) are malignant mesenchymal tumours with a variable clinical behaviour, marked by differentiation towards the interstitial cells of Cajal. GISTs belong to the family of soft tissue sarcomas (STSs) but are treated separately due to their peculiar histogenesis, clinical behaviour and specific therapy. This European Society for Medical Oncology (ESMO)âEuropean Reference Network for Rare Adult Solid Cancers (EURACAN)âEuropean Reference Network for Genetic Tumour Risk Syndromes (GENTURIS) Clinical Practice Guideline (CPG) will cover GISTs while other STSs are covered in the ESMOâEURACANâEuropean Reference Network for Paediatric Oncology (ERN PaedCan)âGENTURIS STS CPG
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