TP53 Gene Mutations Research Articles

MGAT4A/Galectin9-Driven N-Glycosylation Aberration as a Promoting Mechanism for Poor Prognosis of Endometrial Cancer with TP53 Mutation.

Emerging evidence recognizes aberrant glycosylation as the malignant characteristics of cancer cells, but little is known about glycogenes' roles in endometrial carcinoma (EC), especially the most aggressive subtype carrying TP53 mutations. Using unsupervised hierarchical clustering, an 11-glycogene cluster is identified to distinguish an EC subtype associated with frequent TP53 mutation and worse prognosis. Among them, MGAT4A (alpha-1,3-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase A) emerges as the most consistently overexpressed glycogene, contributing to EC aggressiveness. In the presence of galectin-9, MGAT4A increases EC cell proliferation and invasion via promoting glucose metabolism. N-glycoproteomics further revealed GLUT1, a glucose transporter, as a glycoprotein modified by MGAT4A. Binding of galectin-9 to the MGAT4A-branched N-glycan on GLUT1 enhances its cell membrane distribution, leading to glucose uptake increase. In addition, oncogenic mutations of TP53 gene in EC cells upregulate MGAT4A expression by disrupting the regulatory oversight exerted by wild-type p53 on tumor-suppressive miRNAs, including miR-34a and miR-449a/b. The findings highlight a new molecular mechanism involving MGAT4A-regulated N-glycosylation on the key regulator of glucose metabolism in p53 mutants-driven EC aggressiveness, which may provide a strategic avenue to combat advanced EC.

Germline mutations of TP53 gene can be a key factor in prostate cancer genesis

Aim: The aim of this study is to investigate whether germline alterations of exon 5 of TP53 gene could be detected in the blood of known men with prostate cancer and to assess the potential association between the genomic alteration affecting this gene and clinicopathological characteristics of the patients. Methods: Forty-eight blood samples from men diagnosed with prostate cancer were analyzed for TP53 germline mutations and confirmed by Sanger sequencing. The frequency and distribution of high-frequency mutations were analyzed according to the pathological criteria of the patients and a computational study was performed to assess the effect of new mutations. Results: The Sanger sequencing revealed that 79% of the population studied carry mutations in TP53 gene. In summary, a total of 137 mutations have been identified in this gene, out of which 115 are new mutations. Frameshift mutations were the most frequent; the mutation c.392delA was recorded in fifteen cases (31%); the mutations c.383delC and c.432delG were observed at a frequency of 12.5% and 10% respectively. The most frequent missense mutation was the variant c.502C>A (p.His168Asn) identified in eleven patients (23%). One nonsense mutation was identified in one patient and resulted in a stop codon in position 126 (tyrosine). All codons affected by these alterations are part of the DNA binding domain of the protein TP53. Conclusions: The germline mutation frequency observed in prostate cancer patients, and the new mutations recorded in TP53 gene, could be in favor of a potential association of genomic alterations in this gene and prostate cancer genesis, thereby constituting a tool, similar to other genes in the DNA repair pathway such as BRCA1 and BRCA2. This could contribute to the advancement of diagnosis and therapeutic strategies for prostate cancer.

Multi-gene mutations in ultrasound-guided fine-needle aspiration specimens of thyroid micronodules and diagnostic value in thyroid microcarcinomas using next-generation sequencing

Objective: To explore the detection of BRAF, RAS, TERT promoter, and TP53 gene mutations in solitary thyroid micronodule (TMN) specimens obtained by ultrasound-guided fine-needle aspiration (US-FNA) using next-generation sequencing (NGS) technology and assess its diagnostic value in thyroid microcarcinomas (TMC). Methods: On-site recruitment of 428 patients with single suspicious TMC who underwent thyroid ultrasound examination, US-FNA, and NGS from September 2018 to July 2021 at Beijing Tongren Hospital affiliated to Capital Medical University. A total of 147 patients were finally included. NGS was used to detect mutations in the BRAF, RAS, TERT promoter, and TP53 genes in the US-FNA specimens. Comparisons were made between patients with and without gene mutations in terms of age, gender, and the maximum diameter of nodules. The diagnostic efficiency of BRAF mutation for TMC was calculated using the receiver operating characteristic (ROC) curve, with postoperative pathology as the gold standard. Results: The age [M (Q1, Q3)] of the 147 patients was 43.0 (32.0, 51.0) years, and 37 were male (25.2%). Among the 147 US-FNA specimens, 97 (66.0%) were detected with BRAF gene mutations, all of which were p.V600E point mutation; 6 (4.1%) were detected with RAS gene mutation, and no TERT promoter or TP53 gene mutations were detected. Postoperative pathology confirmed that 136 cases were TMC, all of which were papillary thyroid microcarcinomas (PTMC); 11 cases (7.5%)were benign. Among 136 TMC samples, BRAF gene mutations were detected in 97 cases (71.3%). There were no statistically significant differences in age, gender, and maximum nodule diameter between patients with and without BRAF gene mutations (all P>0.05). The sensitivity and specificity of BRAF gene mutation in diagnosing TMC were 71.3% and 100.0%, respectively, with an area under the ROC curve (AUC) (95%CI) of 0.857 (0.789-0.925). For nodules classified as Bethesda Ⅲ-Ⅴ, the sensitivity and specificity were 63.0% and 100.0%, respectively, with an AUC (95%CI) of 0.815 (0.680-0.950). Conclusions: NGS technology can successfully detect multiple gene mutations in US-FNA specimens from TMN patients, especially BRAF gene mutation, and BRAF gene mutation has certain value in diagnosing TMC.

Pan-cancer analysis of TP53 mutations and their association with liver cancer and aristolochic acids

Liver cancer is a major global health concern, as its incidence continues to rise in numerous countries, making it a leading cause of cancer-related deaths. The TP53 gene, which encodes the p53 tumor suppressor protein, plays a crucial role in regulating cell growth and division. Mutations in TP53 have been implicated in increased risk for liver cancer development. In this study, we aim to conduct a pan-cancer analysis to further investigate the potential role of TP53 mutations in various cancer types and their relationship with liver cancer. Additionally, we will explore the interplay between TP53 gene mutations, liver cancer, and exposure to Aristolochic acids (AAs). To achieve these goals, we will utilize data from The Cancer Genome Atlas (TCGA) project and the Gene Expression Omnibus (GEO) databases, enabling a comprehensive analysis of TP53 in the context of multiple cancer types.

Electrochemical DNA Biosensors for the Detection of TP53 Gene Mutation Based on MWCNT and Gold Nanoparticles Embedded in Polypyrrole

Electrochemical DNA Biosensors for the Detection of TP53 Gene Mutation Based on MWCNT and Gold Nanoparticles Embedded in Polypyrrole

Roles of Mutant TP53 Gene in Cancer Development and Progression

TP53 is a tumor suppressor gene that is mutated in most cancer types and has been extensively studied in cancer research. p53 plays a critical role in regulating the expression of target genes and is involved in key processes such as apoptosis, cell cycle regulation, and genomic stability, earning it the title “guardian of the genome.” Numerous studies have demonstrated p53’s influence on and regulation of autophagy, ferroptosis, the tumor microenvironment, and cell metabolism, all of which contribute to tumor suppression. Alterations in p53, specifically mutant p53 (mutp53), not only impair its tumor-suppressing functions but also enhance oncogenic characteristics. Recent data indicate that mutp53 is strongly associated with poor prognosis and advanced cancers, making it an ideal target for the development of novel cancer therapies. This review summarizes the post-translational modifications of p53, the mechanisms of mutp53 accumulation, and its gain-of-function, based on previous findings. Additionally, this review discusses its impact on metabolic homeostasis, ferroptosis, genomic instability, the tumor microenvironment, and cancer stem cells, and highlights recent advancements in mutp53 research.

Multiomics and single‐cell sequencings reveal the specific biological characteristics of low Ki‐67 triple‐negative breast cancer

AbstractBackgroundTriple‐negative breast cancer (TNBC) displays high heterogeneity. The majority of TNBC cases are characterized by high Ki‐67 expression. TNBC with low Ki‐67 expression accounts for only a small fraction of cases and has been relatively less studied.MethodsThis study analyzed a large single‐center multiomics TNBC data set, combined with a single‐cell data set. The clinical, genomic, and metabolic characteristics of patients with low Ki‐67 TNBC were analyzed.ResultsThe clinical and pathological characteristics were analyzed in 2217 TNBC patients. Low Ki‐67 TNBC was associated with a higher patient age at diagnosis, a lower proportion of invasive ductal carcinoma, increased alterations in the PI3K‐AKT‐mTOR pathway, upregulated lipid metabolism pathways, and enhanced infiltration of M2 macrophages. High Ki‐67 TNBC exhibited a higher prevalence of TP53 gene mutations, elevated nucleotide metabolism, and increased infiltration of M1 macrophages.ConclusionsWe identified specific genomic and metabolic characteristics unique to low Ki‐67 TNBC, which have implications for the development of precision therapies and patient stratification strategies.

Prevalence of TP53 Gene Mutation in GBM Patients in Egyptian Population

Prevalence of TP53 Gene Mutation in GBM Patients in Egyptian Population

Molecular precision medicine: Multi-omics-based stratification model for acute myeloid leukemia

Acute myeloid leukemia (AML), as the most common malignancy of the hematopoietic system, poses challenges in treatment efficacy, relapse, and drug resistance. In this study, we have utilized 151 RNA sequencing datasets, 194 DNA methylation datasets, and 200 somatic mutation datasets from the AML cohort in the TCGA database to develop a multi-omics stratification model. This model enables comparison of prognosis, clinical features, gene mutations, immune microenvironment and drug sensitivity across subgroups. External validation datasets have been sourced from the GEO database, which includes 562 mRNA datasets and 136 miRNA datasets from 984 adult AML patients. Through multi-omics-based stratification model, we classified 126 AML patients into 4 clusters (CS). CS4 had the best prognosis, with the youngest age, highest M3 subtype proportion, fewest copy number alterations, and common mutations in WT1, FLT3, and KIT genes. It showed sensitivity to HDAC inhibitors and BCL-2 inhibitors. Both the M3 subtype and CS4 were identified as independent protective factors for survival. Conversely, CS3 had the worst prognosis due to older age, high copy number alterations, and frequent mutations in RUNX1, DNMT3A, and TP53 genes. Additionally, it showed higher proportions of cytotoxic cells and Tregs, suggesting potential sensitivity to mTOR inhibitors. CS1 had a better prognosis than CS2, with more copy number alterations, while CS2 had higher monocyte proportions. CS1 showed good sensitivity to cytarabine, while CS2 was sensitive to RXR agonists. Both CS1 and CS2, which predominantly featured mutations in FLT3, NPM1, and DNMT3A genes, benefited from FLT3 inhibitors. Using the Kappa test, our stratification model underwent robust validation in the miRNA and mRNA external validation datasets. With advancements in sequencing technology and machine learning algorithms, AML is poised to transition towards multi-omics precision medicine in the future. We aspire for our study to offer new perspectives on multi-drug combination clinical trials and multi-targeted precision medicine for AML.

Analysis of Factors Influencing Overall Survival and Prognosis of AML Patients Over 50 Years Old

To explore the overall survival and prognostic factors of patients over 50 years old with acute myeloid leukemia (AML). The clinical data of 222 AML patients aged over 50 years in our hospital from January 2016 and June 2021 were retrospectively analyzed. Kaplan-Meier method was used to evaluate the overall survival (OS) rate, and Cox regression model to evaluate the prognostic factors. The 1-year and 3-year OS rates of all patients were 46.8% and 28.8%, respectively. The recurrence rate of patients who achieved remission during follow-up time was 57%. Both univariate and multivariate analysis showed that advanced age, MLL family fusion gene, PHF6 gene mutation, TP53 gene mutation, intolerance to standard chemotherapy, incomplete remission, complex karyotype, +mar karyotype and inv(3) karyotype were significantly correlated with prognosis (all P <0.05). Negative fusion gene and positive AML- ETO fusion gene had no obvious survival advantage in this population. In patients with complete remission, there was no significant survival advantage in those who achieved minimal residual disease negative. AML patients aged over 50 years have a poor outcome and high recurrence rate. The prognosis is affected by multiple factors and has its own characteristics.

Investigation of transcriptional and immunological disparities among patient groups with varied prognostic risk factors in cholangiocarcinoma.

This study explores molecular features associated with better prognosis in cholangiocarcinoma (CCA). The transcriptomic and whole-exome sequencing data obtained from paired tissues of 70 were analyzed, grouping them based on progression-free survival (PFS), differentiation degree, and lymph node metastasis. Among the 70 patients, the TP53 gene mutation frequency was the highest (53%), while FLG gene mutation occurred exclusively in the long PFS group. In the comparison between long and short survival groups, the short PFS group exhibited higher monocyte infiltration levels (p = 0.0287) and upregulation of genes associated with cancer-related transcriptional misregulation, chemokine signaling, and cytokine-cytokine receptor interactions. Differences in immune cell infiltration and gene expression were significant across differentiation and lymph node metastasis groups. Particularly noteworthy was the marked increase in CD8 T cell and NK cell infiltration (p = 0.0291, 0.0459) in the lymph node metastasis group, significantly influences prognosis. Additionally, genes related to platinum resistance, Th17 cell differentiation, and Th1 and Th2 cell differentiation pathways were overexpressed in this group. In summary, higher monocyte infiltration levels in the short PFS group, along with elevated expression of genes associated with cancer-related pathways, suggest a poorer prognosis. The significant increase in CD8 T cell and NK cell infiltration reflects an enhanced anti-tumor immune response, underscoring the relevance of immune infiltration levels and gene expression in predicting outcomes for CCA patients. In this study, we elucidated the pertinent molecular mechanisms and pathways that influence the prognosis of CCAs through comprehensive multi-omics analysis.

Influence of TP53 gene mutations and their allelic status in myelodysplastic syndromes with isolated 5q deletion

AbstractMutations in the TP53 gene, particularly multihit alterations, have been associated with unfavorable clinical features and prognosis in patients diagnosed with myelodysplastic syndrome (MDS). Despite this, the role of TP53 gene aberrations in MDS with isolated deletion of chromosome 5 [MDS-del(5q)] remains unclear. This study aimed to assess the impact of TP53 gene mutations and their allelic state in patients with MDS-del(5q). To that end, a comprehensive analysis of TP53 abnormalities, examining both TP53 mutations and allelic imbalances, in 682 patients diagnosed with MDS-del(5q) was conducted. Twenty-four percent of TP53-mutated patients exhibited multihit alterations, whereas the remaining patients displayed monoallelic mutations. TP53-multihit alterations were predictive of an increased risk of leukemic transformation. The impact of monoallelic alterations was dependent on the variant allele frequency (VAF); patients with TP53-monoallelic mutations and VAF <20% exhibited behavior similar to TP53 wild type, and those with TP53-monoallelic mutations and VAF ≥20% presented outcomes equivalent to TP53-multihit patients. This study underscores the importance of considering TP53 allelic state and VAF in the risk stratification and treatment decision-making process for patients with MDS-del(5q).

Identification and prognostic analysis of metabolic genes associated with TP53 mutation in multiple myeloma

ABSTRACT Background TP53 gene mutation is crucial in determining the prognosis of Multiple Myeloma (MM) patients. Understanding metabolic genes linked to TP53 mutation is vital for developing targeted therapies for these patients. Method We analyzed The Cancer Genome Atlas (TCGA) dataset to identify genes related to TP53 mutation and metabolism. Using univariate Cox regression and protein–protein interaction (PPI) analysis, we identified key genes. We categorized patients into high and low metabolism groups via non-negative matrix factorization (NMF) clustering, which led to the discovery of relevant differential genes. Integrating these with genes from the Gene Expression Omnibus (GEO) datasets and PPI interactions, we pinpointed crucial metabolic genes associated with TP53 mutation in MM. Additionally, we conducted prognostic analyses involving survival curves and receiver operating characteristic (ROC) charts. Results Our study reveals that the metabolic gene ribonucleotide reductase M2 (RRM2), linked to TP53 mutation, correlates positively with the International Staging System (ISS) stage in MM patients and is an independent prognostic risk factor. In the TCGA dataset, among the 767 patients, the 35 MM patients with TP53 mutation generally had poor survival outcomes. Specifically, the patients with both TP53 mutation and high RRM2 expression had a 2-year survival rate of only 38.87%, whereas those with normal TP53 function and low RRM2 expression had a 2-year survival rate of 86.31% (p < 0.001). Conclusion RRM2 significantly impacts MM prognosis and is associated with TP53 mutation, presenting itself as a potential therapeutic target and prognostic marker for MM.

The correlation between KRAS and TP53 gene mutations and early growth of pulmonary nodules

PurposeThe purpose of this study is to investigate whether gene mutations can lead to the growth of malignant pulmonary nodules.MethodsRetrospective analysis was conducted on patients with pulmonary nodules at Hebei Provincial People’s Hospital, collecting basic clinical information such as gender, age, BMI, and hematological indicators. According to the inclusion and exclusion criteria, 85 patients with malignant pulmonary nodules were selected for screening, and gene mutation testing was performed on all patient tissues to explore the relationship between gene mutations and the growth of malignant pulmonary nodules.ResultsThere is a correlation between KRAS and TP53 gene mutations and the growth of pulmonary nodules (P < 0.05), while there is a correlation between KRAS and TP53 gene mutations and the growth of pulmonary nodules in the subgroup of invasive malignant pulmonary nodules (P < 0.05).ConclusionMutations in the TP53 gene can lead to the growth of malignant pulmonary nodules and are correlated with the degree of invasion of malignant pulmonary nodules.

Endometrial endometrioid adenocarcinoma with a malignant squamous component: is the unusual metastatic pattern unique of these tumors?

The FIGO scheme is currently applied for tumor grading of endometrioid adenocarcinoma. The current report presents a series of ten cases of endometrioid carcinomas that when applying the FIGO grading does not fully convey the true biological nature of the disease. The squamous component of these tumors is malignant; it constitutes the predominant invasive component, and it often metastasizes to unconventional sites. Half of the cohort developed distant disease recurrence within 2 years, even those with early-stage disease. Somatic mutations were analyzed, targeting 101 genes in all ten cases, and mutations in PTEN, MMR, PIK3CA, ATM, RB1, and TP53 genes were detected, often multiple mutations in the same case. None of the cases revealed unique molecular signatures or previously unreported gene mutations. Immunohistochemical staining for beta-catenin showed aberrant nuclear staining in eight of ten cases and remaining two showed cytoplasmic and membranous staining. Aggressive behavior and unusual sites of metastases are observed in this series even in low-grade tumor. The FIGO grading on smaller samples may be deceptive for these cases. Even if FIGO is applied, the pathology report should emphasize the malignant squamous component and its potential significance so that the gynecologic oncology team can formulate appropriate adjuvant treatment upfront. This case series argues that this histology should be regarded as a high-grade endometrioid carcinoma and can show unusual metastatic patterns. Further research is needed with more cases within this histologic subtype to guide recommendations on adjuvant therapies for this aggressive tumor type.

Molecular insights into TP53 mutation (p. Arg267Trp) and its connection to Choroid Plexus Carcinomas and Li-Fraumeni Syndrome.

Choroid plexus carcinomas (CPCs) are rare malignant tumors primarily affecting pediatric patients and often co-occur with Li-Fraumeni Syndrome (LFS), an inherited predisposition to early-onset malignancies in multiple organ systems. LFS is closely linked to TP53 mutations, with germline TP53 gene mutations present in approximately 75% of Li-Fraumeni syndrome families and 25% of Li-Fraumeni-like syndrome families. Individuals with TP53 mutations also have an elevated probability of carrying mutations in BRCA1 and BRCA2 genes. To investigate the structural and functional implications of the TP53: 799C > T, p. (Arg267Trp) missense mutation, initially identified in a Saudi family, and understand its impact on TP53 functionality and related intermolecular interactions. Computational analyses were conducted to examine the structural modifications resulting from the TP53: 799C > T, p. (Arg267Trp) mutation. These analyses focused on the mutation's impact on hydrogen bonding, ionic interactions, and the specific interaction with Cell Cycle and Apoptosis Regulator 2 (CCAR2), as annotated in UniProt. The study revealed that the native Arg267 residue is critical for a salt bridge interaction with glutamic acid at position 258. The mutation-induced charge alteration has the potential to disrupt this ionic bonding. Additionally, the mutation is located within an amino acid region crucial for interaction with CCAR2. The altered properties of the amino acid within this domain may affect its functionality and disrupt this interaction, thereby impacting the regulation of catalytic enzyme activity. Our findings highlight the intricate intermolecular interactions governing TP53 functionality. The TP53: 799C > T, p. (Arg267Trp) mutation causes structural modifications that potentially disrupt critical ionic bonds and protein interactions, offering valuable insights for the development of targeted mutants with distinct functional attributes. These insights could inform therapeutic strategies for conditions associated with TP53 mutations.

LGG-08. DIFFUSE ASTROCYTOMA IN A PATIENT WITH POSSIBLE MBD4-ASSOCIATED NEOPLASIA SYNDROME (MANS)- EXPANDING THE SPECTRUM OF MANS-ASSOCIATED NEOPLASM

Abstract BACKGROUND MBD4-associated neoplasia syndrome (MANS) is a recently identified genetic syndrome characterized by the development of colorectal polyps, acute myeloid leukemia, and uveal melanoma, with an elevated mutation burden. MANS is attributed to bi-allelic germline variations in the MBD4 gene. METHOD We present a case of a pediatric patient with diffuse astrocytoma WHO-grade II and bi-allelic germline variations in the MBD4 gene. CASE REPORT A previously healthy 10-year-old female with a significant family history of high-grade IDH wild type-glioma in the deceased older brother presented with vague symptoms and was found to have abnormal brain MRI with multiple foci of subcortical FLAIR/T2 hyperintensity involving the right frontotemporal lobe, left frontal lobe, and left thalamus. She had intact neurologic exam findings and was followed with serial brain MRIs. Over the next 2 years, she continued to be asymptomatic, but her MRI showed an increase in the size of her brain lesions. Following a stereotactic biopsy of the right temporal lesion, a diagnosis of diffuse astrocytoma (WHO-grade II) was confirmed. Molecular analysis showed point mutations in IDH1, TP53, and PTEN genes, along with LOH at 17p (including TP53 gene), and outline gene expressions for NTRK2, OLIG2, GRM3, FGF1, SOX8, MBP, MGMT genes. Given the low grade of the tumor and the absence of tumor-related symptoms, a decision was made to continue monitoring with serial MRIs. Whole exome sequencing identified germline bi-allelic missense variations in the MBD4 gene, specifically C.1405A&amp;gt;G and C.1573A&amp;gt;C. Both parents were found to be heterozygous for one of these mutations. CONCLUSION The significance of MBD4 mutation remains unknown in our patient, but bi-allelic variations coupled with the presence of a brain tumor and positive family history raise concerns about MANS in our patient. Additional studies are needed to elucidate the potential association between brain tumors and MANS.

Bioinformatic Identification of TP53 Gene Mutation Hotspots in Colorectal Cancer

Mutations and inactivation of the TP53 gene are frequently observed in various types of malignancies. Precise knowledge of the genetic structure and detection of mutation hotspots are crucial, as these indicate a high probability of developing cancer. The aim of our study was to perform the bioinformatic detection of mutation hotspots in the TP53 gene in patients diagnosed with malignant colon neoplasms using self-developed software (version 1). We compared TP53 gene sequences from 50 healthy individuals with those from 50 patients diagnosed with colorectal carcinoma. Of the 50 samples from cancer patients, the most frequent mutations were observed in exons 5 and 8 (12 mutations per exon) and gene sequences of 12 samples, which differed from those of the 50 samples from healthy individuals. Based on our results, the distribution of mutations in the TP53 gene structure was not even across different exons. By comparing the gene sequences of healthy individuals with those of colon cancer samples, we conclude that structural changes occurring in similar gene regions are not associated with increases in susceptibility to malignancies in every case, namely, that the pathological mechanism is multifactorial.

Mutations in Helicobacter pylori infected patients with chronic gastritis, intestinal type of gastric cancer and familial gastric cancer

BackgroundDevelopment of sequential changes of mucous leading to gastric cancer and familial cases of gastric cancer of intestinal type is widely connected with Helicobacter pylori infections. In this study we analysed variants of genes involved in cancerogenesis and inflammatory processes of intestines in patients infected with H.pylori. Our goal was to test whether mutations in these genes predestinate to development of gastric cancer, and whether there is a genetic factor that makes it more likely for infections with H.pylori to cause gastric cancer. As infections with H. pylori are relatively common, discovering such genetic predispositions could be used for establishing risk-groups and for planning treatments.MethodsOur studies cover analysis of variants in genes involved in cancerogenesis: TP53 (rs11540652, rs587782329, COSM10771), MSH2 (rs193922376), MLH1 (rs63750217), and inflammatory processes of intestine: NOD2 (rs2066847, rs2066842), IL1A (rs1800587) and IL1B (rs1143634) from H.pylori-infected patients.ResultsMutations were more common in the group of patients with gastric cancer of intestinal type and familial cases of gastric cancer in comparison with patients with chronic gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia or gastric cancer (p-value = 0.00824), with the prevalence of p53 mutations in patients with familial gastric cancer vs. patients with other changes of mucosa (p-value = 0.000049). Additionally, gastric cancer patients have mainly genotype TT or CT of the rs2066842 variant of the NOD2 gene.ConclusionsThe lack of statistically significant changes of other interleukin genes involved in inflammatory processes may suggest the presence of H.pylori infection as a potential trigger for the development of the inflammatory process of the mucosa, leading through microbiota dysbiosis to the development of enteric gastric cancer. Mutations in analysed genes correlated with more severe mucosal changes, with a much more frequent presence of TP53 gene mutations, with a limited presence of other mutations in the familial history of gastric cancer.

Incorporating precision oncology in everyday clinical practice: First two years of comprehensive genomic profiling (CGP) testing experience in Croatia.

11151 Background: Despite increased availability of modern technologies and evolution of tailored treatment, which has already significantly changed the outcomes in some cancer types, applicability of precision medicine in everyday clinical practice is still emerging and is one of the hot topics. Croatia is among first ones in the World to have entered into force a country-level based project of precision oncology throughout the CGP analysis in everyday clinical work, fully covered by Croatian health insurance. Hence, here we would like to present our data from everyday clinical practice and analyze the penetration of CGP given the opportunity and challenges we had. Methods: The study was observational and retrospective in nature, conducted on a country level among all patients on whose tumor specimens CGP was performed between January 1, 2020 and December 31, 2021. Eligible patients for the CGP analysis were those with metastatic disease, with at least 6-12 months of life-expectancy, with ECOG performance status ≤ 2, and after the recommendation from the multidisciplinary team. The analysis was performed in accredited laboratory (Foundation Medicine Inc., Cambridge, MA, USA), through FoundationOneCDx for solid tumors, FoundationOne Liquid in case of insufficient tissue or FoundationOneHeme for sarcomas. Results: There was total of 481 patients with CGP results. Median age was 61 years (IQR 49-69) and 58% of patients were women, while 42% were men. Most commonly tested were gastrointestinal (29.1%) and reproductive tumors (28.9%) with colorectal (19.1%) and uterine cancer (11.2%) as the most prevalent. At least one clinically relevant genomic alteration was found in 48.7% of patients. The most frequent mutations were those of KRAS (27.2%), PIK3CA (12.9%), AR (10.6%), NRAS (10.4%) and PTEN (9.1%) genes. Currently clinically not relevant mutations were found in 51.8% of patients with TP53 gene mutation as the most common (42.8%). According to the Croatian cancer registry, there was around 26 000 cancer related deaths during the investigated period defining population of at least more than 10 000 potentially eligible patients for the CGP analysis. Conclusions: Our results have shown that almost 50% of tested patients could have potential treatment benefit based on the detection of clinically relevant genomic alteration. Unfortunately, taking into consideration country level insurance eligibility criteria for CGP testing and number of potentially eligible cancer patients, we could say that only less than 5% of patients with metastatic disease were tested within first two years and that penetration of CGP is rather low, resulting with a significant number of patients underserved.