Specific Types Of Mutations Research Articles

Dynamics of drug delivery determines course of evolution of antibiotic responses in bacteria.

To adjust to sudden shifts in conditions, microbes possess regulated genetic mechanisms that sense environmental challenges and induce the appropriate responses. The initial evolution of microbes in new environments is thought to be driven by regulatory mutations, but it is not clear how this evolution is affected by how quickly conditions change (i.e. dynamics). Here, we perform experimental evolution on continuous cultures of tetracycline resistant E. coli in different dynamical regimens of drug administration. We find that cultures evolved under gradually increasing drug concentrations acquire fine- tuning mutations adapting an alternative efflux pump to tetracycline. However, cultures that are instead periodically exposed to large drug doses evolve transposon insertions resulting in loss of regulation of the main mechanism of tetracycline resistance. A mathematical model shows that sudden drug exposures overwhelm regulated responses, which cannot induce resistance fast enough. These results help explain the frequent loss of regulation of resistance in clinical pathogens.

Efficacy of PARP inhibitors in advanced high-grade serous ovarian cancer according to BRCA domain mutations and mutation type.

Preclinical studies have emphasized the potential connection between BRCA specific domains defects and the activity of Poly ADP-ribose polymerase inhibitors (PARPi). Nevertheless, real-world evidence regarding the impact of BRCA domain defects and mutations on PARPi efficacy are limited. The aim of his study was to evaluate the efficacy of PARPi in terms of progression free survival (PFS) according to BRCA domains defects and mutation types. A retrospective analysis was performed among 79 BRCA mutated patients, diagnosed with advanced High-grade serous ovarian carcinoma (HGSOC) who received first- and second-line platinum- based chemotherapy followed by PARPi maintenance treatment. PFS was evaluated according to BRCA1 [Really Interesting Gene (RING), DNA Binding (DBD), Serine Cluster (SCD), BRCA1 C-terminal (BRCT)] and BRCA2 [RAD-51 Domain (RAD-51 BD), DBD] specific domain defects and mutation types [missense (MS), nonsense (NS), frameshift (FS), splicing (S), or large rearrangements (LR)]. After a median follow-up of 51 months, no significant difference in PFS was observed between the BRCA functional domains or mutation types in the BRCA1 and BRCA2 subgroups. Patients with BRCA2 DBD and RAD51-BD defects had the longest (39.8 months) and shortest (24.1 months) median PFS, respectively (p = 0.11). Additionally, patients with BRCA1 DBD defects had the greatest benefit (median PFS = 33.8 months) while those with BRCA1 RING domain mutations experienced the worst outcome (median PFS = 30.9 months (p = 0.43). The efficacy of maintenance treatment with PARPi is independent by BRCA domain defects or mutation types. Patients DBD domain defects experienced numerically longer median PFS compared to those with other BRCA1/2 alterations.

EGFR mutation based on lung laterality in adenocarcinoma type of non-small cell lung cancer

Targeted therapies have shown promise in improving survival rates for lung adenocarcinoma, a common and deadly malignancy. EGFR-targeting tyrosine kinase inhibitors (TKIs) are particularly effective among these therapies in cases with EGFR mutations. Detecting these mutations before TKI treatment is essential. Various radiological features have been linked to EGFR mutations. However, the relationship between tumor location and mutation types in Indonesian lung adenocarcinoma patients remains unexplored. This study aimed to identify the frequency of EGFR mutation in local lung adenocarcinoma cases based on the tumor location. Clinical data of lung adenocarcinoma patients (n = 272) diagnosed between 2018 and 2022 were retrospectively taken from the Department of Anatomical Pathology, Dr. Sardjito General Hospital, Yogyakarta. The qRT-PCR data of EGFR mutation status was obtained from the Department of Anatomical Pathology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta. Descriptive analysis was performed using STATA version 14.0. EGFR mutations were found in 60.7% of patients, with 58.2% having exon 19 mutations and 21.2% exhibiting exon 21 L858R mutations. Mutation status was found to be significantly different based on the patient's gender (p = 0.022) and age (p = 0.029) but not with lung laterality (p = 0.093). The proportion of exon 19, exon 21 L858R, and uncommon mutations in the right and left lung adenocarcinoma was similar across all samples. This study found no difference between specific EGFR mutation types and tumor location in lung adenocarcinoma.

Outcomes of EGFR, ALK, ROS1, BRAF, MET, and RET mutated non-small cell lung cancer with brain metastases (NSCLC BM).

201 Background: Non-small cell lung cancer (NSCLC) is a leading cause of brain metastases. Advances in gene-directed therapies have shifted the focus away from traditional platinum-based chemotherapies. Key targeted mutations in NSCLC include EGFR, ALK, BRAF, MET exon skipping, RET fusions, and ROS1 rearrangements. This retrospective study aims to explore overall survival (OS) and progression-free survival (PFS) in NSCLC BM patients with these gene mutations. Methods: In this retrospective study, conducted by the Department of Medical Oncology at Beijing Tiantan Hospital and the First Medical Center, PLA General Hospital, we reviewed 1526 patients with NSCLC brain metastasis from 2010 to 2022. Data collected included molecular marker status, systemic therapies, and dates of progression. The analysis focused on determining OS and PFS from the time of brain metastasis diagnosis to the last follow-up or death. Statistical analysis used the Cox proportional hazards model. Results: The study reviewed 1526 patients, identifying the following mutation distribution: EGFR mutations in 628 patients, ALK rearrangements in 207 patients, ROS1 rearrangements in 64 patients, BRAF mutations in 31 patients, MET exon skipping in 55 patients, and RET fusions in 42 patients. Significant variations in median OS (mOS) and median PFS (mPFS) were observed across these mutation groups. Patients with EGFR and ALK mutations demonstrated longer mOS and mPFS. Patients with RET and ROS1 mutations also showed better outcomes compared to those with BRAF and MET mutations. Conclusions: This study highlights the importance of molecular mutations in NSCLC BM as prognostic indicators and therapeutic targets. EGFR and ALK mutations were associated with more favorable outcomes, emphasizing the need for personalized medicine in managing NSCLC BM. The study suggests further research focused on specific mutation types is crucial to refine treatment strategies and improve patient care.

Targeted DNA sequencing of high-grade serous ovarian carcinoma reveals association of TP53 mutations with platinum resistance when combined with gene expression.

High-grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer and is among the most fatal gynecological malignancies worldwide, due to late diagnosis at advanced stages and frequent therapy resistance. In 47 HGSC patients, we assessed somatic and germline genetic variability of a custom panel of 144 known or suspected HGSC-related genes by high-coverage targeted DNA sequencing to identify the genetic determinants associated with resistance to platinum-based therapy. In the germline, the most mutated genes were DNAH14 (17%), RAD51B (17%), CFTR (13%), BRCA1 (11%), and RAD51 (11%). Somatically, the most mutated gene was TP53 (98%), followed by CSMD1/2/3 (19/19/36%), and CFTR (23%). Results were compared with those from whole exome sequencing of a similar set of 35 HGSC patients. Somatic variants in TP53 were also validated using GENIE data of 1287 HGSC samples. Our approach showed increased prevalence of high impact somatic and germline mutations, especially those affecting splice sites of TP53, compared to validation datasets. Furthermore, nonsense TP53 somatic mutations were negatively associated with patient survival. Elevated TP53 transcript levels were associated with platinum resistance and presence of TP53 missense mutations, while decreased TP53 levels were found in tumors carrying mutations with predicted high impact, which was confirmed in The Cancer Genome Atlas data (n = 260). Targeted DNA sequencing of TP53 combined with transcript quantification may contribute to the concept of precision oncology of HGSC. Future studies should explore targeting the p53 pathway based on specific mutation types and co-analyze the expression and mutational profiles of other key cancer genes.

Phenotypic variation of FXN compound heterozygotes in a Friedreich ataxia cohort.

Most individuals with Friedreich ataxia (FRDA) have homozygous GAA triplet repeat expansions in the FXN gene, correlating with a typical phenotype of ataxia and cardiomyopathy. A minority are compound heterozygotes carrying a GAA expansion on one allele and a mutation on the other. The study aim was to examine phenotypic variation among compound heterozygotes. Data on FXN mutations were obtained from the Friedreich Ataxia Clinical Outcome Measures Study (FA-COMS). We compared clinical features in a single-site FA-COMS cohort of 51 compound heterozygous and 358 homozygous patients, including quantitative measures of cardiac, neurologic, and visual disease progression. Non-GAA repeat mutations were associated with reduced cardiac disease, and patients with minimal/no function mutations otherwise had a typical FRDA phenotype but with significantly more severe progression. The partial function mutation group was characterized by relative sparing of bulbar and upper limb function, as well as particularly low cardiac involvement. Other clinical features in this group, including optic atrophy and diabetes mellitus, varied widely depending on the specific type of partial function mutation. These data support that the typical FRDA phenotype is driven by frataxin deficiency, especially severe in compound heterozygotes with minimal/no function mutations, whereas the heterogeneous presentations of those with partial function mutations may indicate other contributing factors to FRDA pathogenesis.

Efficacy of chemo-immunotherapy in metastatic BRAF-mutated lung cancer: a single-center retrospective data.

The effectiveness of combining immune checkpoint inhibitors (ICIs) with chemotherapy in treating non-small cell lung cancers (NSCLCs) with BRAF mutations has not been sufficiently explored. We compiled data from 306 NSCLC patients with identified BRAF mutations. We looked at efficacy by assessing the objective response rate (ORR) and disease control rate (DCR), as well as survival through measuring progression-free survival (PFS) and overall survival (OS). Out of the patient pool, 44 were treated with a regimen of immune-chemotherapy. Patients undergoing ICI in combination with chemotherapy had a median PFS of 4 months, and the median OS was recorded at 29 months. There was a notable increase in OS in patients receiving first-line treatment versus subsequent lines (29 vs 9.75 months, p=0.01); however, this was not the case with PFS (9 vs 4 months, p=0.46). The ORR for patients on ICIs was 36.3%. PFS and OS rates did not significantly differ between patients with the BRAF-V600E mutation and those with non-V600E mutations (p=0.75 and p=0.97, respectively). Additionally, we found a significant variation in PD-L1 expression between those who responded to treatment and those who didn't (p=0.04). Our findings indicate that chemo-immunotherapy as an initial treatment may lead to improved OS in patients with BRAF-mutated NSCLC when compared to its use in subsequent lines of therapy. Further studies are needed to validate these results and to delve deeper into how specific types of BRAF mutations and PD-L1 expression levels might predict a patient's response to treatments in NSCLC.

Real world treatment patterns, healthcare resource use and costs in patients with advanced or metastatic non-small cell lung cancer by EGFR mutation type

Aims This study described treatment patterns, healthcare resource utilization (HRU) and costs among advanced or metastatic non-small cell lung cancer (a/mNSCLC) patients with different epidermal growth factor receptor (EGFR) mutation types. Materials and methods This retrospective study leveraged NeoGenomics NeoNucleus linked with IQVIA PharMetrics Plus between 01 January 2016 to 30 April 2021 (study period). Patients with evidence of a/mNSCLC between 01 July 2016 to 31 March 2021 (selection window) with EGFR test results indicating exon 19 deletion (exon19del), exon 21 L858R (L858R), or exon 20 insertion (exon20i) mutations were included; date of first observed evidence of a/mNSCLC was the index date. Treatment patterns, all-cause HRU and costs during ≥1 month follow-up were reported for each cohort (exon19del, L858R, and exon20i). Results A total of 106 exon19del, 75 L858R, and 13 exon20i patients met the study criteria. The prevalence of hospitalization was highest in the exon20i cohort (76.9%), followed by L858R (62.7%) and exon19del (55.7%) cohorts. A higher proportion of patients had evidence of hospice/end-of-life care in the exon20i (30.8%) and L858R (29.3%) cohorts relative to the exon19del cohort (22.6%). The exon20i cohort had higher median total healthcare costs per patient per month ($27,069) relative to exon19del ($17,482) and L858R ($17,763). EGFR tyrosine kinase inhibitors (TKI) were the most frequently observed treatment type for exon19del and L858R cohorts, while chemotherapy was the most observed treatment in exon20i cohort. Limitations The sample size for the study cohorts was small, thus no statistical comparisons were conducted. Conclusions This is one of the first real-world studies to describe HRU and costs among a/mNSCLC patients by specific EGFR mutation type. HRU and costs varied between EGFR mutation types and were highest among exon20i cohort, potentially reflecting higher disease burden and unmet need among patients with this mutation.

Abstract A008: An in vivo screening platform based on Ba/F3 kinase-engineered cell lines for discovering next-generation kinase inhibitors

Abstract Tongtong Liu, Feng He, Xuyang Duan, Shuliang Li, Chang Liu, Jingying Ning, Feng Hao* KYinno Biotechnology (Beijing) Co., Ltd. No.3 Building, Yizhuang Biomedical Park, Beijing, China. Correspondence: Feng.hao@kyinno.com Protein kinases have become very popular targets in the treatment of cancer and other diseases, and since 2001, the FDA has approved more than 70 kinase inhibitor drugs. However, due to innate or acquired resistance in tumors, most of these small molecule inhibitors only delay tumor progression. The development of next-generation kinase inhibitors with better specificity and lower resistance is still ongoing. Ba/F3 is a mouse pro-B cell line whose survival and proliferation depend on IL-3. After transduction with driver genes such as kinase genes or their mutants, Ba/F3 cells switch from IL-3 dependence to driver gene dependence, making Ba/F3 cells a powerful tool for discovering new kinase inhibitors. Our group has constructed over 700 Ba/F3 engineered cell lines stably transfected with kinase gene mutants. These Ba/F3 kinase cell lines have been fully validated by sequencing, western blotting, and inhibitor testing, covering many popular kinases including EGFR (>150 cell lines), RAS (80 cell lines), FGFR (55 cell lines), ERBB2 (49 cell lines), MET (41 cell lines), RET (39 cell lines), BCR-ABL (37 cell lines), EML4-ALK (33 cell lines), and FLT3 (26 cell lines), etc. Most of these transformed Ba/F3 cell lines can be used for xenograft models in immunodeficient mice. Based on these Ba/F3 kinase cell line-derived xenograft models, we have established an in vivo screening platform to evaluate the efficacy and toxicity of candidate drugs against specific kinase mutation types, as well as their comparison with previous generation drugs. Overall, our data suggest that xenograft models derived from Ba/F3 kinase cell lines are powerful models for discovering next-generation kinase inhibitors. Citation Format: Stephanie Wang. An in vivo screening platform based on Ba/F3 kinase-engineered cell lines for discovering next-generation kinase inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A008.

Abstract B097: Molecular disparities between cancer patients with normal weight and excessive body fat

Abstract Overweight and obesity, as measured by high body mass index (BMI), can have significant negative impacts on human health due to associated co-morbidities. Epidemiological data have demonstrated strong associations between overweight/obesity and 13 different types of cancer. However, the molecular features underlying the relationship between body weight and cancer remain poorly understood. In this study, we conducted a comprehensive analysis of molecular differences between patients with overweight/obesity and normal-weight patients across 14 different cancer types from The Cancer Genome Atlas (TCGA). By employing the propensity score weighting algorithm to balance confounding factors, we identified obesity-specific mutational features in multiple cancer types, such as a higher mutation burden in rectal cancer, biased mutational signatures, and overweight/obesity-specific significantly mutated genes in several cancer types. The biased mutation signatures are caused by the activity of AID/APOBEC family of cytidine deaminases and their contribution to DNA damage, ect, which suggest that obesity may contribute to the development of cancer by promoting the accumulation of specific types of mutations. Most of these biased genes have not been reported as significantly mutated genes in previous TCGA large cohort, implying these biased genes may be due to the environment of excessive body fat. We also found that differential expression genes (DEGs) and dysmethylated genes in overweight and obese tumors were predominantly upregulated and enriched in inflammatory and hormone-related pathways. These DEGs were significantly associated with survival rates in various cancer types, highlighting the impact of excessive body fat on gene expression profiles and clinical outcomes in cancer patients. Interestingly, while high BMI seemed to have a negative impact on most cancer types, it may be beneficial to endometrial cancers, as reflected by normal weight-biased mutational and gene expression patterns, suggesting the presence of an "obesity paradox" in this context. Moreover, our analysis revealed that excessive body fat significantly impacted the tumor microenvironment by altering immune cell infiltration, emphasizing the importance of understanding the complex interplay between obesity and immune response in cancer progression and treatment. Overall, our results provide the most comprehensive understanding of the molecular differences including mutational patterns, gene expression, and immune features between normal-weight and overweight/obese cancer patients. Such systematic understanding of the molecular basis for body weight disparities in multiple cancer types may provide critical insights into the future development of precision cancer therapy for cancer patients with overweight/obesity. Citation Format: Fengyuan Huang, Peng Xu, Zongliang Yue, Yuwei Song, Kaili Hu, Xinyang Zhao, Min Gao, Zechen Chong. Molecular disparities between cancer patients with normal weight and excessive body fat [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B097.

Clinical efficacy of avapritinib in gastrointestinal stromal tumors (GIST) with different KIT genotypes: Post hoc analysis of the phase 1 NAVIGATOR and phase 1/2 CS3007-101 trials.

11523 Background: Avapritinib, a novel KIT/platelet-derived growth factor receptor α (PDGFRA) kinase inhibitor, is approved in patients (pts) with GIST harboring PDGFRA activation loop (AL) exon 18 mutations, based on unprecedented clinical antitumor activity. Despite available treatments, there remains a great unmet medical need for pts with KIT-AL-mutant GIST receiving 2nd-line (2L) standard of care (SOC) sunitinib, and pts with primary KIT exon 9 ( KIT 9)-mutant GIST receiving 4th-line (4L) SOC ripretinib. This post hoc analysis assessed the clinical benefit of avapritinib in pts with KIT mutations, especially with AL exons 17 and 18, or primary KIT 9 mutations. Methods: Tumor tissue and liquid biopsy samples were collected and analyzed to determine baseline mutational status. KIT molecular subgroups and outcomes were determined in pts with primary KIT mutations treated with oral avapritinib 300 mg once daily (starting dose) enrolled in the phase 1 NAVIGATOR (NCT02508532) and phase 1/2 (China bridging) trials (NCT04254939, CS3007-101). Pts with PDGFRA mutations and PDGFRA- KIT co-mutations were excluded. Progression-free survival (PFS) and objective response rate (ORR) were compared using Cox and logistic regression, respectively. Results: A total of 160 pts with KIT-mutant GIST were evaluated (NAVIGATOR, n= 131; CS3007-101, n= 29). At data cutoff (NAVIGATOR: March 31, 2021; CS3007-101: June 30, 2021), median follow-up duration was 22.0 months (95% CI 18.3–27.4). KIT-AL mutations were more frequently detected (n = 74, 46.3%) than KIT ATP-binding pocket (ABP) mutations (n = 34, 21.3%). Sixty pts (37.5%) had KIT-AL mutations without KIT-ABP mutations (ALposABPneg group); the remaining 100 pts were designated as KIT OTHERS. Across all lines of therapy, the adjusted (inverse probability weighting of baseline characteristics) median PFS (mPFS) was longer for the ALposABPneg group than for the KIT OTHERS group (9.1 vs 3.4 months; HR 0.47, 95% CI 0.32–0.68; P< 0.0001), and the ORR was higher (31.4% vs 12.1%; odds ratio 3.31, 95% CI 1.44–7.58; P= 0.0047). mPFS and ORR in the KIT ALposABPneg group were 19.3 months and 38.5%, respectively, in the 2L setting (n = 13) and 11.0 months and 36.4%, respectively, in Chinese pts (3–9 lines, n = 11). In pts with KIT 9 mutations in the 4L (n = 14) and > 4L settings (n = 19), mPFS was 5.6 and 3.7 months, respectively. Conclusions: This post hoc analysis demonstrated significantly more robust avapritinib antitumor activity in pts with KIT ALposABPneg GIST versus pts with other KIT mutation profiles. The results suggest that avapritinib could confer meaningful clinical benefit in pts with GIST and specific KIT mutation types, especially KIT-AL or KIT 9 mutations. Avapritinib might be a potential 2L option for pts with KIT ALposABPneg GIST, and in later lines of therapy for pts with ALposABPneg or KIT 9 mutation profiles. Clinical trial information: NCT02508532 , NCT04254939 .

Safety and clinical efficacy of sintilimab in pediatric patients with advanced or recurrent malignancies in a phase I study.

e14601 Background: This is a first phase I study investigating the safety and efficacy of sintilimab in pediatric patients with advanced or recurrent malignancies. Methods: During dose escalation, patients received a single-dose intravenous infusion of sintilimab. The planned dosing groups were 1, 3 and 10 mg/kg. During dose expansion, patients received sintilimab every three weeks. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to sintilimab according to the Response Evaluation Criteria in Solid Tumours version 1.1. PD-L1 expression of tumor in subjects were identified by immunohistochemistry (DACO,22C3). Whole exome sequencing (WES) was performed in 15 patients to characterize the mutational landscape and CNV status. Results: 29 patients were enrolled, including 10 patients with Hodgkin lymphoma (HL), 19 patients with other tumor types. Some special pathological types, including thymoma, choroid plexus carcinoma, and NK-T cell lymphoma are included. Patients were pretreated with a median of 3 prior lines of systemic treatment. Sintilimab was well tolerated without dose-limiting toxicity. By the safety data cutoff date, all patients experienced treatment related adverse events (TRAE) with most adverse events being grade 1 or 2, and ≥ grade 3 TRAEs occurred in 10%. Among all 27 subjects evaluated, 4 confirmed complete response (2HL, 1 NK/T lymphoma, 1 anaplastic ependymoma), 7 confirmed partial responses (4 HL, 1 Ewing sarcoma, 1 diffuse large-B lymphoma and 1 thymoma), and 7 stable disease were observed, for an objective response rate of 40.7%, and a disease control rate of 66.7%. Subjects with PD-L1-positive expression benefited more from sintilimab treatment than PD-L1-negative subjects (66.7% ORR versus 33.3% ORR, p=0.314) although statistically insignificant. The genomic profiling of WES indicatedpatients with a specific genomic mutation type predict the response of PD-1 therapy. Conclusions: Sintilimab was well tolerated and demonstrated promising anti-tumor activity in pediatric HL. The completion of the current phase I study has led to the initiation of the first prospective anti-PD-1 registration trial in Asia focusing on pediatric patients and serve as the basis for its potential study in combinatorial regimens for childhood cancer. Clinical trial information: NCT04400851 . [Table: see text]

Abstract 4255: Concurrent KRAS and TP53 mutations in pancreatic cancer real-world data (RWD) highlight convergent tumor evolutionary patterns

Abstract Pancreatic cancer is one of the most fatal of all cancers. Pancreatic adenocarcinomas have been historically difficult to treat, in part due to lack of early detection, and due to their resistance to conventional chemotherapy. There has recently been an improved understanding of the biologic processes driving pancreatic tumorigenesis, and an increase in clinical trial options available to patients, especially in the context of KRAS mutation positive pancreatic ductal adenocarcinoma (PDAC). KRAS is a known driver of pancreatic cancer initiation, with concurrent loss of TP53 in many cases. Among all mutated genes in pancreatic cancer, KRAS, TP53, CDKN2A, and SMAD4 are most frequently reported, followed by CDKN2B and ARID1A among others. Mutations in TP53 commonly found in pancreatic cancer are either missense or truncating. The specific type of mutation may be important to note since point mutations may produce dysfunctional proteins that acquire gain of functions that are tumor-promoting, although the most well-agreed upon effects of TP53 mutations stem from the absence or decrease of its normal physiologic functions including cell cycle arrest, apoptosis promotion, DNA damage response triggering, maintenance of cell polarity, and maintenance of genomic stability. Here we present an in-depth multi-dimensional analysis of 29 pancreatic adenocarcinoma patients, consisting of 11 patients with KRAS G12D mutations, 5 patients with KRAS G12V mutations, 3 patients with non-canonical KRAS mutations, and 10 patients with no KRAS mutations identified in their tumors. Individual TP53 mutations were highlighted in the context of associated KRAS mutations and tumor genomic landscape at the time of testing. Real-world data was collected with patient consent through community embedded Oncology Clinical Team (ceOCT) facilitated engagement. Tumor evolution prediction rules were constructed based on mutational landscapes of the 29 patients and evidence published in peer-reviewed journals. Pancreatic cancer patient data from the AACR GENIE Cohort v12.0-public database and the cBioportal for Cancer Genomics public site was subsequently used for testing predicted tumor evolutionary trajectories. Here we describe multiple independent combinations of KRAS and TP53 mutations leading to convergent functional outcomes for tumor cells, in the context of patient-specific gene mutation landscapes. Recurrent patterns of paired mutations with common cellular function dysregulation outcomes highlight core underlying mechanisms of pancreatic tumor evolution. Citation Format: Kaumudi Bhawe, Adrienne Nugent, Deb Christensen, Lauren Levine, Emma Shtivelman. Concurrent KRAS and TP53 mutations in pancreatic cancer real-world data (RWD) highlight convergent tumor evolutionary patterns. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4255.

Correlations between Molecular Alterations, Histopathological Characteristics, and Poor Prognosis in Esophageal Adenocarcinoma

Esophageal adenocarcinoma (EAC) is a severe malignancy with increasing incidence, poorly understood pathogenesis, and low survival rates. We sequenced 164 EAC samples of naïve patients (without chemo-radiotherapy) with high coverage using next-generation sequencing technologies. A total of 337 variants were identified across the whole cohort, with TP53 as the most frequently altered gene (67.27%). Missense mutations in TP53 correlated with worse cancer-specific survival (log-rank p = 0.001). In seven cases, we found disruptive mutations in HNF1alpha associated with other gene alterations. Moreover, we detected gene fusions through massive parallel sequencing of RNA, indicating that it is not a rare event in EAC. In conclusion, we report that a specific type of TP53 mutation (missense changes) negatively affected cancer-specific survival in EAC. HNF1alpha was identified as a new EAC-mutated gene.

Ovarian cancer onset across different BRCA mutation types: a view to a more tailored approach for BRCA mutated patients

ObjectiveTo evaluate the role of different specific types of germline breast cancer susceptibility BRCA mutations on the age of onset of high grade serous ovarian cancer.MethodsThis was a multicenter, international,...

Specific Nucleotide Substitutions and Stressors Erode Highly Conserved Genomic Regions in Acute Myelogenous Leukemia

Background: "Leukemia stressors” refer to extrinsic factors that may facilitate clonal progression. We previously reported that smoking initiates unique leukemogenic signatures in acute myelogenous leukemia (AML) characterized by a higher proportion of C>A and G>A single base substitutions (SBS) [Hoang. ASH. 2021]. These G>A SBS are known to be particularly prevalent in CpG islands due to cytosine methylation. However, toxic smoking metabolites could potentially induce specific genomic signatures in patients with AML that resemble COSMIC SBS4 in lung cancer [i.e. enrichment in C>A transversion], and spontaneous C>T SBS1 signatures within specific genomic clusters or nodes. In this study, we investigate how these SBS1/SBS4 signatures distribute within hot-spot regions and evaluate whether G>A mutations (mut), commonly observed in methylated CpG islands, are differentially expressed in AML patients who are older and/or are smokers. In our study, these hot-spot regions or nodes were referenced as a genomic pool 1 (GP1). Methods: After IRB approval, the incidence of specific SBS densities were investigated in vulnerable hot-spot regions affected by exogenous [SBS4] and endogenous [SBS1] mutagenesis. Next generation sequencing (NGS) was used in patients to obtain data regarding specific mutation types and locations. In known gene exons, we examined genomic coordinates corresponding to individual mut. COSMIC browser allowed genomic coordinate examination to "aggregate” mut within putative "vulnerable exon neighborhoods". "Hot-spot neighborhoods” were described as genomic pool 1 (GP1). Descriptive and inferential statistics were used to analyze data, which was obtained from a single institution. Results: 80 patients (pt) diagnosed with hematopoietic malignancies with available next generation sequencing (NGS) were selected for analysis. 73/80 (91%) were AML pt. The median age was 63 years (y) (range, 22-88). 42% and 64% of pt were smokers and older than 63 y, respectively. With respect to specific hot spots or nodes, AML pt showed increased G>A mutagenicity in GP1 cluster 1 (Fig 1). Specifically, for G>A, smoking increased the rate from 18.4% to 37.5% (p=0.01) (Fig 1 A and B). Age > 63 y led to an increased mutagenicity rate of 17.1% to 30.5% (p=0.03) (Fig 1 C and D). A synergistic effect in mutagenicity was observed when combining age > 63 y plus smoking (10.3% to 41.9%, p=0.01) (Fig 1. E and F). In regards to hotspots in specific genes, smoking has the ability to increase NRAS (G>A), P53 (G>A) and SRSF2 (C>A) frequencies within GP1. Interestingly, smoking increased C>A mutagenicity in the SRSF2 gene in GP1 from 50% vs 82%. Conclusions: Our data suggests that aging and smoking globally and locally erode the AML genome by potentially accelerating cytosine methylation and thus G>A mutagenicity, most likely in CpG islands within genes like NRAS and P53. These genes likely contain hot spots aggregated in GP1 that, when mutated, can de-stabilize the genome and increase the risk of AML. Importantly, we observed similar COSMIC SBS4 substitutions seen in lung cancer associated with C>A transversions in older AML pt who had a history of smoking, which is specifically found in the SRSF2 gene. Overall, our data advances our understanding on how risk factors for AML affect the human AML genome. These have strong implications for AML prevention, pathogenesis and therapy. Future studies should be aimed at identifying other intrinsic and extrinsic risk factors for AML seeking to explore their specific mutational patterns and locations within the human genome. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Matrix metalloproteinase gene mutations and bioinformatics of telocytes in hepatocellular carcinoma.

Telocytes (TCs) have crucial functions to promote the metastasis of hepatocellular carcinoma (HCC) by over-expressing matrix metalloproteinases (MMPs), but the mechanism by which TCs secrete MMPs in the genome is still unknown. We first cultured and isolated primary TCs from distinct liver cancer tissues and hepatic hemangioma surrounding tissues (Control group). Their whole exon genes were tested by Illumina HiSeq family of platforms and by high-throughput sequencing as well as variant mutations. Moreover, immunohistochemistry, Western blot, and quantitative reverse transcription-polymerase chain reactionassays were utilized to assess the expression of MMPs. The perniciousness of signal-nucleotide polymorphism (SNP) mutations of proteins were predicted by the Polyphen-2 database. Divergent expression and overall survival (OS) of MMPs was screened by StarBase-Pan Cancer plate; and MMPs associated signaling pathways were found by Kyoto Encyclopedia Genes andGenomes. The "competing endogenous RNA(ceRNA)" network was constructed by Cytoscape software. We found that 12 specific types of SNP mutations related to 5 types of MMPs occurred in TCs of liver malignant tumors as a potential result of MMP1, MMP9, and MMP17 overexpression. High levels of MMP1, MMP7, and MMP9 represented poor OS in HCC, and an interactive network of MMPs is shown. Allele shifts of C/T (rs20544) and G/C (rs2250889) in MMP9 were risk factors for TCs in HCC by the prediction of the Polyphen-2 Database. (MMP9(-3 C/T)) mutation might be a genetic mechanism of upregulating MMP9 in TCs.

Atypical clinical manifestations and genotype-phenotype correlations of neurofibromatosis type 1

Purpose of the study: Analysis of available data on geno-phenotypic correlations and atypical forms of neurofibromatosis type 1. Material and methods. We searched for relevant sources in the Scopus, Web of Science, PubMed systems, including publications from May 1993 to October 2021. Of the 318 studies we identified, 59 were used to write a systematic review. Results. We found studies describing atypical forms of neurofibromatosis type 1 with an erased course without manifestation of a tumor syndrome, which are caused by specific mutations in the NF1 gene (causing substitutions of amino acids in neurofibromin: p.Arg1038, p.Met1149, p.Arg1809, or deletion of amino acids: p.Met990del, p.Met992del). NF1 patients with microdeletions are characterized by more severe disease symptoms (more often facial dysmorphism, skeletal and cardiovascular abnormalities, learning difficulties, and symptomatic spinal neurofibromas). mutations of splicing sites and extended deletions of the NF1 gene are associated with early manifestation of tumors, mutations at the 5’-end of the gene, causing a shortening of the protein product, are associated with optic nerve gliomas. the mutation c.3721C>T (p.R1241*) correlated with structural brain damage, and c.6855C>A (p.Y2285*) with endocrine disorders. the manifestations of NF1, similar to lipomatosis and Jaffe-Campanacci syndrome, not associated with a specific type of mutation are described. Conclusion. In spite of pronounced clinical variability of the disease, even among members of the same family, several studies have described genotype-phenotype correlations. Therefore, the role of modifier genes and epigenetic factors in the pathogenesis of NF1 is assumed, since the neurofibromin protein has a complex structure with several functional domains. It has been shown that the severity of the tumor syndrome is influenced by the methylation characteristics of NF1 gene and adjacent areas. in addition, NF1 gene is associated with a variety of microRNAs. therefore, targeted therapy aimed at specific non-coding RNAs to restore normal expression of NF1 gene can become a promising treatment for NF1.

Molecular imaging biomarkers in familial frontotemporal lobar degeneration: Progress and prospects

Familial frontotemporal lobar degeneration (FTLD) is a pathologically heterogeneous group of neurodegenerative diseases with diverse genotypes and clinical phenotypes. Three major mutations were reported in patients with familial FTLD, namely, progranulin (GRN), microtubule-associated protein tau (MAPT), and the chromosome 9 open reading frame 72 (C9orf72) repeat expansion, which could cause neurodegenerative pathological changes years before symptom onset. Noninvasive quantitative molecular imaging with PET or single-photon emission CT (SPECT) allows for selective visualization of the molecular targets in vivo to investigate brain metabolism, perfusion, neuroinflammation, and pathophysiological changes. There was increasing evidence that several molecular imaging biomarkers tend to serve as biomarkers to reveal the early brain abnormalities in familial FTLD. Tau-PET with 18F-flortaucipir and 11C-PBB3 demonstrated the elevated tau position in patients with FTLD and also showed the ability to differentiate patterns among the different subtypes of the mutations in familial FTLD. Furthermore, dopamine transporter imaging with the 11C-DOPA and 11C-CFT in PET and the 123I-FP-CIT in SPECT revealed the loss of dopaminergic neurons in the asymptomatic and symptomatic patients of familial FTLD. In addition, PET imaging with the 11C-MP4A has demonstrated reduced acetylcholinesterase (AChE) activity in patients with FTLD, while PET with the 11C-DAA1106 and 11C-PK11195 revealed an increased level of microglial activation associated with neuroinflammation even before the onset of symptoms in familial FTLD. 18F-fluorodeoxyglucose (FDG)-PET indicated hypometabolism in FTLD with different mutations preceded the atrophy on MRI. Identifying molecular imaging biomarkers for familial FTLD is important for the in-vivo assessment of underlying pathophysiological changes with disease progression and future disease-modifying therapy. We review the recent progress of molecular imaging in familial FTLD with focused on the possible implication of these techniques and their prospects in specific mutation types.

The devil you know: A population-level analysis of tumor-based next-generation sequencing of high-grade epithelial ovarian cancer (151)

<b>Objectives:</b> Clinical use of tumor-based next-generation sequencing (tbNGS) is expanding, but the indications and implications remain vague. We aimed to assess the clinical relevance of tbNGS data in a large cohort of patients with high-grade epithelial ovarian cancer. <b>Methods:</b> Electronic medical records (both internal notes and external scanned documents) of 905 patients with high-grade serous or endometrioid ovarian cancer were queried for tbNGS data using optical character recognition (OCR) and natural language processing (NLP) technologies. Identified results and clinical-demographic information were entered into an institutional database. Data were analyzed with descriptive statistics and log-rank tests comparing selected genetic alterations to progression-free survival (PFS). <b>Results:</b> Three hundred and twelve (34.4%) patients had their tbNGS results identified. Tests used had variable breadth, ranging from 46 genes to whole-exome sequencing. The most common was an institutional panel that evaluated 146 genes. Nearly all (99.7%) patients had their genomic alterations (mutations or copy number variations) identified. On average, each tumor had 2.38 (±2.46) aberrations. Two hundred and fifty-two (80.8%) patients had actionable alterations, defined as relaying eligibility for targeted treatment or clinical trial, according to the Precision Oncology Decision Support System (PODSS) database. Twenty-seven (10.7% of those with actionable abnormalities) enrolled in relevant clinical trials. In total, 630 mutations were detected in the population, with half of these (58.6%) considered actionable. The most common type of abnormality encountered was missense substitution (52.9%), followed by amplification (14.7%) and a frameshift mutation (9.72%). The most frequently mutated genes were <i>TP53</i> (93.0%), <i>PIK3CA</i> (9.35%), <i>BRCA1/2</i> (8.30%), <i>NF1</i> (4.90%), and <i>KRAS</i> (4.52%). Among these, only <i>BRCA1/2</i> was associated with a significant improvement in PFS (20.1 vs 14.1 months, p=0.046). <i>CCNE1</i> amplification, the most prevalent copy number variant, was present in 9.4% of those tested. Specific mutation types or copy number variations were not correlated with PFS. <b>Conclusions:</b> Clinical use of tbNGS is prevalent in ovarian cancer. Of patients undergoing tbNGS at our institution, four out of five gained the opportunity for an FDA-approved treatment or genotypically relevant clinical trial. Description of population-level tumor genomics could help identify therapeutic targets and guide the development of clinical decision support tools.