Prevalence Of Gene Mutations Research Articles

Gene-echocardiography: refining genotype-phenotype correlations in cardiomyopathy patients with restrictive phenotype

Abstract Background The restrictive phenotype, the least frequent and genetically complex form of cardiomyopathy, is the focus of this investigation. The aim is to clarify the association between restrictive phenotype and genetic variants in cardiomyopathy patient. Methods We utilized whole-exome sequencing in a cohort of 568 cardiomyopathy patients and performed echocardiographic evaluations to identify restrictive phenotypes. Comprehensive analysis of cardiac characteristics and functionality was also undertaken. Results Among the cohort, 33 patients exhibited a restrictive phenotype. These patients were distributed as follows: 7 within the restrictive cardiomyopathy group (RCM), 20 in the hypertrophic cardiomyopathy group (HRCM), and 6 in the dilated cardiomyopathy group (HDRCM). A notable prevalence of gene mutations, mainly in the MYBPC3 gene, was found in these individuals. We observed that mutation carriers, characterized by smaller aortic sinus dimension, demonstrated an association with the mutation and diminished myocardial work. Furthermore, MYBPC3 mutation carriers showed a thicker ventricular wall and a higher predisposition for septal hypertrophy. Both HRCM and HDRCM groups displayed consistent hypertrophic manifestations, with the latter demonstrating a higher frequency of interventricular septal hypertrophy. The 5-year survival rate was calculated at 54.5%, with gene mutations not significantly affecting longevity. Conclusion Genetic factors profoundly influence the restrictive phenotype of cardiomyopathy. There is a strong link between restrictive phenotype and genetic variants in cardiomyopathy, providing a foundation for more accurate genetic testing and personalized management of patients. The emerging "gene-echocardiography" concept may refine the accuracy and productivity of genetic counseling and testing in cardiomyopathy.

Prevalence and prognosis of hypoxia-inducible factor-2α (HIF-2α) pathway gene mutations across advanced solid tumors.

Hypoxia-inducible factor-2α (HIF-2α) modulates the hypoxic response pathway in tumors; however, mutations in pathways (including SDHA, SDHB, SDHC, SDHD, FH, and VHL genes) that are suspected to activate HIF-2α are poorly understood, with limited understanding of the prevalence and clinical prognosis. This retrospective observational study used a de-identified nationwide (US-based) clinico-genomic database (CGDB) across 15 available tumor types. Among the 9467 adult patients with advanced/metastatic solid tumors included in the analysis, any mutation at the above-mentioned six genes was observed in 1.8% (95% CI: 1.5-2.1) of patients. The mutation prevalence ranged from 0.05% of SDHD to 0.93% of VHL. When further stratified by tumor type, the prevalence of gene mutation in each tumor type was well below 1%, except for VHL with 44% in renal cell carcinomas (RCC). Excluding RCC, the prevalence of any HIF-2α gene mutations in the study population was 0.9% (95% CI: 0.8-1.2). The median overall survival (OS) from 1 and 2 L therapy among patients with any HIF-2α gene mutation was 14.5 (95% CI: 11.5-24.2) and 9.3 (95% CI: 6.0-18.1) months, respectively, compared with 13.4 (95% CI: 12.9-13.9) and 9.8 (95% CI: 9.3-10.4) months among patients without HIF-2α gene mutations. The prevalence of HIF-2α related gene mutations was generally low (<1%) across the 15 solid tumor types, except for VHL in RCC. No significant association between HIF-2α gene mutation status and OS was identified among patients evaluated in this study.

Abstract PO1-09-02: Universal genetic testing for women with newly diagnosed breast cancer identified many mutations, impacted clinical management and caused no psychological distress to patients

Abstract Background: For newly diagnosed breast cancer (BC) patients, identification of pathogenic germline mutations in hereditary breast cancer (HBC) genes can inform clinical management and risk mitigation strategies and identify patients who would benefit from targeted therapy and clinical trials. Offering germline testing based on NCCN or other guidelines fails to identify all patients with germline HBC gene mutations, potentially with adverse consequences for patients and their families. As an integral part of the study, we have explored the acceptance of universal testing among patients and clinicians. Methods: This is the largest Australian multi-centre prospective study exploring the prevalence of hereditary pathogenic variants in the Australian BC population. 650 newly diagnosed consecutive, consented patients with non-metastatic breast cancer or high-grade DCIS were recruited from May 2020 to March 2023 in 2 phases. Phase 1 (n=157) offered a combination of germline and somatic sequencing. Germline testing was performed by whole genome sequencing on DNA from blood or saliva, and the data analyzed for actionable HBC gene mutations, including large genomic rearrangements. Germline variants were interrogated for pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, BARD1, BRIP1, RAD51B, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2, CDH1, PTEN, STK11, TP53 and NTHL1.Tumour sequencing will be reported separately. Phase 2 (n=493) included germline exome sequencing with no somatic sequencing. The objectives were to assess the additional actionable HBC gene mutations identified by universal testing compared to algorithmic based (MANCHESTER and BOADICEA scores) and NCCN guidelines, the clinical impact of this identification and the prevalence of germline mutations in the general BC population. A 3-generation pedigree was constructed for every patient for accurate estimation of NCCN, MANCHESTER, and BOADICEA scores. Phase 1 patients completed surveys of perceptions of universal testing, psychological distress and cancer-specific worry pre- and post-testing. Results: 50 carriers of actionable germline mutations were identified: (7.7%). BRCA1 (n=10), BRCA2 (n=12), PALB2 (n=7), CHEK2 (n=10), ATM (n=4), PMS2 (n=2), MSH6 (n=1), RAD51C (n=2), and BARD1 (n=3). One carrier had both PALB2 and CHEK2 mutations. Updated NCCN guidelines (2023 version) identified 44/50 pathogenic germline variant carriers (88%). The BOADICEA and MANCHESTER scores only identified 22 carriers (44%). Immediate clinical management changed due to the discovery of HBC gene in 40/50 (80%). Among 105 participants, cancer-specific distress declined from pre- to post-testing. Anxiety, stress and depression did not change. 90/103 participants agreed that genetic testing should be routine, 100/104 reported their decision to undergo testing as correct. All (n=25) BC clinicians reported that genetic test results were helpful for important treatment decisions and none that testing was distressing to patients. Conclusion: HBC gene mutation prevalence was 7.7%. Universal germline HBC gene testing is the best method for detecting carriers. Current testing guidelines would have missed HBC genes which would have impacted clinical management. Updated NCCN guidelines were sensitive in the detection of HBC gene mutation, but more than half of HBC gene mutations were missed by Australian standards. Discovery of HBC gene mutations led to changed management in most cases. Universal testing is highly acceptable to clinicians and patients who reported no adverse impact on psychological distress or cancer-specific worry and no decision regret. Germline mutations identified and their impact on management Citation Format: Dilanka De Silva, Lesley Stafford, Anita Skandarajah, Michelle Sinclair, Lisa Devereux, Kirsten Hogg, Maira Kentwell, Allan Park, luxi Lal, Magnus Zethoven, Madawa Jayawardena, Fiona Chan, Paul James, Geoffrey Lindeman, Ian Campbell, Bruce Mann. Universal genetic testing for women with newly diagnosed breast cancer identified many mutations, impacted clinical management and caused no psychological distress to patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-09-02.

Prospective Study of Homologous Recombination Repair Gene Mutation Prevalence in Patients With Advanced Prostate Cancer From Latin America: Challenges and Future Approaches.

The prevalence of homologous recombination repair gene mutations (HRRm) in patients with metastatic castration-resistant prostate cancer (mCRPC) in Latin America and the Caribbean (LAC) is unknown. Prevalence of homologous Recombination repair (HRR) gene mutatiOns in patientS with metastatic castration resistant ProstatE Cancer in LaTin America (PROSPECT) aimed to determine this prevalence and to describe the demographic and clinical characteristics of the participants. This was a prospective, cross-sectional, multicenter study across 11 cancer centers in seven LAC countries. After informed consent, all eligible participants underwent genomic testing by provided blood samples for germline HRR testing; they also provided PC tissue blocks if available for somatic HRR testing. Between April 2021 and April 2022, 387 patients (median age, 70 years [49-89], 94.3% Eastern Cooperative Oncology Group 0-1) with mCRPC were enrolled in the study. Almost 40% of them had a family history of cancer, and the overall time from their initial PC and mCRPC diagnosis was 3 years and 1 year, respectively. The overall prevalence of germline HRRm was 4.2%. The mutations detected included the genes CHEK2 (n = 4, 1%), ATM (n = 3, 0.8%), BRCA2 (n = 3, 0.8%), BRIP1 (n = 2, 0.5%), RAD51B (n = 2, 0.5%), BRCA1 (n = 1, 0.3%), and MRE11 (n = 1, 0.3%). The prevalence of somatic HRRm could not be assessed because of high HRR testing failure rates (79%, 199/251) associated with insufficient DNA, absence of tumor cells, and poor-quality DNA. Despite the study's limitations, to our knowledge, PROSPECT was the first attempt to describe the prevalence of HRRm in patients with PC from LAC. Notably, the germline HRRm prevalence in this study was inferior to that observed in North American and European populations. The somatic HRR testing barriers identified are being addressed by several projects to improve access to HRR testing and biomarker-based therapies in LAC.

Whole Exome Sequencing of Patients with Adult-Onset Evans Syndrome: A Cohort of 80 Patients

Introduction Loss of tolerance toward several self-antigens suggests an underlying genetic predisposition. A previous study (1) conducted in children with Evans syndrome revealed a high prevalence of pathogenic mutations in genes involved in primary immunodeficiencies. Whether these findings are restricted to children is unknown. In this study, we assessed the prevalence of constitutional genetic variants in a cohort of patients with adult onset Evans syndrome. Patients and methods We consecutively included from November 2021 to June 2023 patients that had been diagnosed with adult onset (≥18 years) Evans syndrome (association of immune thrombocytopenia (ITP), warm autoimmune hemolytic anemia (wAIHA) and/or autoimmune neutropenia (AIN) according to international guidelines (2,3)), and identified in France throughout the network of the national reference center for adult' autoimmune cytopenia. We excluded patients with a systemic lupus (according to Systemic Lupus International Collaborating Clinics criteria (4)), and patients with indolent B cell malignancies at Evans syndrome onset. Clinical and biological data were retrospectively collected using a standardized form. Patients underwent whole-exome sequencing after written and informed consent was obtained. Gene variants already published and/or with in vitro confirmed consequences were considered as genetic diagnoses. Clinical interpretation of variants was performed according to the ACMG guidelines (5). A patient was classified as having a genetic diagnosis if carryinghemizygous/heterozygous pathogenic or likely pathogenic variant (for X-linked or autosomal dominant conditions), or 2 pathogenic or likely pathogenic variants in the same gene (for autosomal recessive conditions). Results We identified 80 patients (40% female, median age 31 years at Evans syndrome diagnosis [range 18-76]) with adult-onset Evans syndrome from 19 centers. Median age at first cytopenia was 28 years [range 1-73], and 13 patients (16%) were under 18 years at first cytopenia. 78 patients (96%) had ITP (chronic in 87%), 59 (73%) had wAIHA (with at least one relapse in 58%), and 38 (47%) had AIN (chronic in 74%). Median delay between first and second cytopenia was 18 months (range 0 - 329) and 28 patients (35%) had synchronous onset of cytopenia. Twenty-four patients (30%) had associated immune manifestation (involving endocrine system in 9%, lung in 9%, gastrointestinal tract in 6%, skin in 5%, central nervous system in 4%) and 28% had antinuclear antibody titers ≥ 1/160. Lymphoproliferation was found in 56%, including lymphadenopathy in 41% and splenomegaly in 35%. Nine patients (11%) had lymphoma or cancer history. Twenty patients (25%) had humoral immune defect, including 13 (16%) with a common variable immunodeficiency (CVID)-like phenotype. In the whole cohort, 9 patients (11.25%) had a genetic diagnosis that could be linked to Evans syndrome, with heterozygous variants in CTLA4, STAT3, NFKB1, CYBB, TNFAIP3, DDX41, MYH9 and homozygous variant in PIK3CG. Twenty (25%) patients had genetic testing prior to this study (targeted Sanger sequencing [N=3], or NGS panel [N=17]), resulting in 2 genetic diagnoses ( CYBB and TNFAIP3). A family history of immune manifestations in first-degree relatives was found in 56% of the patients with genetic diagnosis versus 20% of patients without (P=0.0308). However, the proportion of patients with CVID-like phenotype, associated immune disorder, lymphoproliferation, cancer/lymphoma, positive antinuclear antibodies, or pediatric onset of first cytopenia was not significantly increased in patients with genetic diagnosis. Discussion As expected, the proportion of genetic diagnoses in patients with adult onset Evans syndrome was lower that what was previously described in children, but led to a significant impact on clinical management in some patients. We did not find clinical or biological features associated with a genetic diagnosis, suggesting that genetic testing should be considered in every adult patient diagnosed with Evans syndrome in the absence of any obvious underlying cause or condition. References (1) Hadjadj J et al., Blood 2019; 134: 9-21. (2) Provan D et al., Blood Adv 2019; 3: 3780-817. (3) Jäger U et al., Blood Rev 2020; 41: 100648. (4) Petri M et al., Arthritis Rheum 2012; 64: 2677-86. (5) Richards S et al., Genet Med 2015; 17: 405-24.

Construction and validation of an efferocytosis-related prognostic signature in lung adenocarcinoma.

Accumulating evidence highlights the potential significance of efferocytosis in tumor progression. This study is directed towards the construction of a prognostic risk model for lung adenocarcinoma (LUAD), grounded on efferocytosis-related genes (ERGs). Employing LASSO-COX regression analysis, a risk-prognostic model was formulated, centered on seven ERGs. Concurrently, a nomogram was established that incorporated patient clinical features and risk scores. The predictive accuracy of the risk model and the nomogram was substantiated via external validation sets. The landscapes of immune infiltration and genetic mutation were evaluated for high- and low-risk groups, with the expression of seven key genes validated through RT-PCR. Our findings reveal that the high-risk group displayed considerably inferior survival outcomes in comparison to the low-risk group. A diminished abundance of immune cell infiltrates and a higher prevalence of gene mutations characterized the high-risk group. Genes with high expression were markedly enriched in pathways related to cell proliferation. The superior predictive performance of the risk model and nomogram was adequately substantiated by the external validation sets (GSE31210, GSE30219, and GSE50081). In addition, we discerned several potential therapeutic drugs demonstrating different sensitivities across patient risk groups. The differential expression of seven central genes was confirmed in A549, H1299, and BEAS-2B cell lines. The constructed risk model and nomogram display high accuracy in predicting the survival and immune landscape of LUAD patients, thus providing invaluable prognostic tools in clinical scenarios.

Isoniazid and Rifampicin Resistance-Conferring Mutations in Mycobacterium tuberculosis Isolates from South Africa.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), remains a significant global health issue, with high morbidity and mortality rates. The emergence of drug-resistant strains, particularly multidrug-resistant TB (MDR-TB), poses difficult challenges to TB control efforts. This comprehensive review and meta-analysis investigated the prevalence of and molecular insights into isoniazid (INH) and rifampicin (RIF) resistance-conferring mutations in M. tb isolates from South Africa. Through systematic search and analysis of 11 relevant studies, we determined the prevalence of gene mutations associated with RIF and INH resistance, such as rpoB, katG, and inhA. The findings demonstrated a high prevalence of specific mutations, including S450L in rpoB, and S315T, which are linked to resistance against RIF and INH, respectively. These results contribute to the understanding of drug resistance mechanisms and provide valuable insights for the development of targeted interventions against drug-resistant TB.

Genomics of Breast Cancer Brain Metastases: A Meta-Analysis and Therapeutic Implications

Breast cancer brain metastases are a challenging daily practice, and the biological link between gene mutations and metastatic spread to the brain remains to be determined. Here, we performed a meta-analysis on genomic data obtained from primary tumors, extracerebral metastases and brain metastases, to identify gene alterations associated with metastatic processes in the brain. Articles with relevant findings were selected using Medline via PubMed, from January 1999 up to February 2022. A critical review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement (PRISMA). Fifty-seven publications were selected for this meta-analysis, including 37,218 patients in all, 11,906 primary tumor samples, 5541 extracerebral metastasis samples, and 1485 brain metastasis samples. We report the overall and sub-group prevalence of gene mutations, including comparisons between primary tumors, extracerebral metastases and brain metastases. In particular, we identified six genes with a higher mutation prevalence in brain metastases than in extracerebral metastases, with a potential role in metastatic processes in the brain: ESR1, ERBB2, EGFR, PTEN, BRCA2 and NOTCH1. We discuss here the therapeutic implications. Our results underline the added value of obtaining biopsies from brain metastases to fully explore their biology, in order to develop personalized treatments.

Genomic alterations in neuroendocrine prostate cancer: A systematic review and meta-analysis.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. We performed a systematic review and meta-analysis to evaluate the prevalence of genomic alterations in NEPC and better understand its molecular features to potentially inform precision medicine. EMBASE, PubMed, and Cochrane Central Register of Controlled Trials databases were searched for eligible studies until March 2022. Study qualities were assessed using the Q-genie tool. The prevalence of gene mutations and copy number alterations (CNAs) were extracted, and meta-analysis was performed using R Studio with meta package. A total of 14 studies with 449 NEPC patients were included in this meta-analysis. The most frequently mutated gene in NEPC was TP53 (49.8%), and the prevalence of deleterious mutations in ATM/BRCA was 16.8%. Common CNAs in NEPC included RB1 loss (58.3%), TP53 loss (42.8%), PTEN loss (37.0%), AURKA amplification (28.2%), and MYCN amplification (22.9%). RB1/TP53 alterations and concurrent RB1 and TP53 alterations were remarkably common in NEPC, with a prevalence of 83.8% and 43.9%, respectively. Comparative analyses indicated that the prevalence of (concurrent) RB1/TP53 alterations was significantly higher in de novo NEPC than in treatment-emergent NEPC (t-NEPC). This study presents the comprehensive prevalence of common genomic alterations and potentially actionable targets in NEPC and reveals the genomic differences between de novo NEPC and t-NEPC. Our findings highlight the importance of genomic testing in patients for precision medicine and provide insights into future studies exploring different NEPC subtypes.

THE PREVALENCE OF BETA-GLOBIN GENE MUTATION AND DISEASE TYPES IN BETA-THALASSEMIA PATIENTS AT KIEN GIANG GENERAL HOSPITAL

This study aimed to determine the prevalence of gene mutations and disease phenotypes in patients with β-thalassemia (β-Thal) treated at Kien Giang province general hospital. Blood samples were collected from 187 patients diagnosed with β-Thal disease in three departments. β-Globin gene sequencing was performed at the Center for Molecular Biology, University of Medicine and Pharmacy, Ho Chi Minh City, and dominant gene mutations were determined based on the sequencing results. The prevalence of β-Thal disease phenotypes was determined on the basis of Hb electrophoresis results along with β-globin gene mutations. The study found that most of the β-Thal patients belonged to the Kinh group and were under the age of 15. Among the 263 alleles, 10 β-globin gene mutations were detected, of which eight common alleles in Vietnam were detected at a rate of 97.7%. Six disease phenotypes were identified on the basis of Hb electrophoresis and β-globin gene mutations, with heterozygous HbE accounting for the highest percentage (39.0%) and homozygous β-Thal accounting for the lowest rate (0.5%). The rates of mutations and disease phenotypes varied among the Kinh, Hoa, and Khmer ethnic groups. β-Thal test for anemia patients is necessary, and prenatal carrier screening, genetic counseling, and diagnostics are recommended to prevent β-Thal homozygous or HbE/β-Thal heterozygosity from occurring in future generations. This study contributes to improving the quality of people's knowledge in Kien Giang province. Keywords: Gene Mutations, Kien Giang, β-Globin, β-Thal, β-Thalassemia DOI： https://doi.org/10.35741/issn.0258-2724.58.2.21

Spatiotemporal spread of Plasmodium falciparum mutations for resistance to sulfadoxine-pyrimethamine across Africa, 1990-2020.

BackgroundSulfadoxine-pyrimethamine (SP) is recommended in Africa in several antimalarial preventive regimens including Intermittent Preventive Treatment in pregnant women (IPTp), Intermittent Preventive Treatment in infants (IPTi) and Seasonal Malaria Chemoprevention (SMC). The effectiveness of SP-based preventive treatments are threatened in areas where Plasmodium falciparum resistance to SP is high. The prevalence of mutations in the dihydropteroate synthase gene (pfdhps) can be used to monitor SP effectiveness. IPTi-SP is recommended only in areas where the prevalence of the pfdhps540E mutation is below 50%. It has also been suggested that IPTp-SP does not have a protective effect in areas where the pfdhps581G mutation, exceeds 10%. However, pfdhps mutation prevalence data in Africa are extremely heterogenous and scattered, with data completely missing from many areas.Methods and findingsThe WWARN SP Molecular Surveyor database was designed to summarize dihydrofolate reductase (pfdhfr) and pfdhps gene mutation prevalence data. In this paper, pfdhps mutation prevalence data was used to generate continuous spatiotemporal surface maps of the estimated prevalence of the SP resistance markers pfdhps437G, pfdhps540E, and pfdhps581G in Africa from 1990 to 2020 using a geostatistical model, with a Bayesian inference framework to estimate uncertainty. The maps of estimated prevalence show an expansion of the pfdhps437G mutations across the entire continent over the last three decades. The pfdhps540E mutation emerged from limited foci in East Africa to currently exceeding 50% estimated prevalence in most of East and South East Africa. pfdhps540E distribution is expanding at low or moderate prevalence in central Africa and a predicted focus in West Africa. Although the pfdhps581G mutation spread from one focus in East Africa in 2000, to exceeding 10% estimated prevalence in several foci in 2010, the predicted distribution of the marker did not expand in 2020, however our analysis indicated high uncertainty in areas where pfdhps581G is present. Uncertainty was higher in spatial regions where the prevalence of a marker is intermediate or where prevalence is changing over time.ConclusionsThe WWARN SP Molecular Surveyor database and a set of continuous spatiotemporal surface maps were built to provide users with standardized, current information on resistance marker distribution and prevalence estimates. According to the maps, the high prevalence of pfdhps540E mutation was to date restricted to East and South East Africa, which is reassuring for continued use of IPTi and SMC in West Africa, but continuous monitoring is needed as the pfdhps540E distribution is expanding. Several foci where pfdhps581G prevalence exceeded 10% were identified. More data on the pfdhps581G distribution in these areas needs to be collected to guide IPTp-SP recommendations. Prevalence and uncertainty maps can be utilized together to strategically identify sites where increased surveillance can be most informative. This study combines a molecular marker database and predictive modelling to highlight areas of concern, which can be used to support decisions in public health, highlight knowledge gaps in certain regions, and guide future research.

A comprehensive literature review and meta-analysis of the prevalence of pan-cancer BRCA mutations, homologous recombination repair gene mutations, and homologous recombination deficiencies.

There is significant improvement in the outcomes following treatment with PARP inhibitors among patients with certain tumors that have BRCA mutations (BRCAm), homologous recombination repair (HRR) gene mutations, or homologous recombination deficiency (HRD) positivity. We performed a literature review and meta-analysis to evaluate the prevalence of BRCA1/2m, HRR gene mutations, and HRD positivity across multiple cancers. There were 265 publications on BRCA1/2 mutation prevalence, 189 on HRR gene mutation prevalence, and 7 on HRD positivity prevalence. The prevalences of germline BRCA1m and BRCA2m were 7.8% and 5.7% for breast cancer, 13.5% and 6.6% for ovarian cancer, 0.5% and 3.5% for prostate cancer, and 1.1% and 4.1% for pancreatic cancer, respectively. The prevalences of somatic BRCA1m and BRCA2m were 3.4% and 2.7% for breast cancer, 4.7% and 2.9% for ovarian cancer, 5.7% and 3.2% for prostate cancer, and 1.2% and 2.9% for pancreatic cancer, respectively. We identified 189 studies with over 418,649 samples across 25 tumor types that examined mutations in one or more HRR genes other than BRCA1/2. The prevalence of mutations among HRR genes remained low (less than 1%), with ATM (5.2%), CHEK2 (1.6%), and PALB2 (0.9%) exhibiting the highest prevalence. Seven studies evaluated HRD positivity in breast, ovarian, and prostate cancer patients. The prevalence of HRD positivity was 56% overall (95% CI=48%-64%). The understanding of biomarker prevalence across tumor types and standardization of biomarker assays could have important clinical implications.

Abstract 5103: Characterization of the genomic landscape and actionable mutations in Taiwanese prostate cancer patients

Abstract Background: Prostate Cancer (PCa) is the second most common male cancer worldwide and the most common cancer in males over 65 years old. PCa is the sixth most common cancer in Taiwan, and its incidence rate has increased gradually over the past 30 years. PAPR inhibitors are the only type of targeted drug approved by the FDA to treat advanced castration-resistant prostate cancer (CRPC) that has grown after the hormone therapy drugs. This study aimed to characterize the genomic profile of Taiwanese PCa and explore whether there are potential treatment guidances derived. Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissues from 99 patients diagnosed with PCa and collected at Chi-Mei Medical Center (CMMC) were subject to next-generation sequencing using ACTOnco® CGP panel that cover coding regions of 440 cancer-related genes. Genomic alterations (GAs) and signatures, including single nucleotide variations (SNVs), short insertions and deletions (InDels), copy-number variations (CNVs), fusion genes, tumor mutations burden (TMB), and microsatellite instability (MSI) status were retrieved. The gene mutation prevalence was compared with the Western population using the TCGA prostate cancer dataset. Results: A total of 1558 variants was identified, including 215 SNVs, 22 InDels, 1178 CN gain and 135 homozygous deletions. Similar to the Western population, the most frequently mutated genes were SPOP (21.2%), KMT2C (10.1%), MUC16 (8.1%), TP53 (6.1%), ARID2 (5.1%), IDH1 (5.1%), PTGS2 (5.1%). Further analysis showed that 12 patients harbored deleterious/likely deleterious mutations in genes implicated in homologous recombination (HRR) DNA repair pathway, including three BRCA2, two CDK12, BRAD1 and ARID1A, respectively, and one ATR, ATM and PALB2, respectively. All BRCA2 mutations were predicted to be germline origin and only one-third of 12 HRR mutants had a biallelic gene loss. Median TMB calculated from NGS data is 0.6 muts/Mb (range 0 to 4.5) and all samples are microsatellite-stable (MSS). Therapeutically actionable gene and pathway analysis revealed that up to 24.2% of patients harbored at least one aberration against FDA-approved targeted drugs, such as MET copy number (CN) gain (11.1%), mTOR pathway aberration (6.1%), HRR gene biallelic loss (4%), BRAF activating mutation (4%), IDH1 activating mutations (4%), EGFR CN gain (3.0%), FGFR1 CN gain (2.0%), MET fusion (1.0%) and BRAF fusion (1%). Conclusion: This CGP study unraveled the genomic profile of Taiwanese prostate cancers, and the results showed that GAs identified could serve as a potential biomarker to guide personalized, targeted therapies in one-fourth of patients. Citation Format: Kien Thiam Tan, Chia-Ling Wu, Yen-Jung Lu, Ka-Po Tse, Chien-Feng L Li. Characterization of the genomic landscape and actionable mutations in Taiwanese prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5103.

Patterns and prevalence of pathogenic germline mutations using multi-gene panel testing in patients with ovarian cancer: The Jordanian Exploratory Cancer Genetics (Jo-ECAG) Ovarian Study.

e17593 Background: Ovarian cancer is one of the most common gynecological malignancies. Because of the absence of effective screening methods, ovarian cancer is usually diagnosed at late stages contributing to high mortality rates. Patients with BRCA1 and BRCA2 pathogenic germline variants (PGVs) harbor elevated risk of developing both ovarian and breast cancer. Identifying PGVs may help optimize management options and improve outcomes. The worldwide prevalence of gene mutations is variable. Multiple series have demonstrated differences in PGVs according to ethnicity and geographic area. Data about prevalence of the aforementioned PGVs among Arab patients with ovarian cancer is not well understood. Methods: Patients with epithelial ovarian, fallopian tube or primary peritoneal carcinomatosis were referred for 20 or 84-multi-gene panel testing (MGPT). All patients had their diagnosis, treatment and follow up at a single cancer center. Following detailed counselling, MGPT was performed at no-cost to all patients at two reference laboratories. Descriptive statistics were performed, groups outcome was determined by two-tailed Fisher’s exact test and unpaired t-test. The study was approved by the Institutional Review Board (IRB) at King Hussein Cancer Center and all patients signed informed consent. Results: During the study period, 152 patients, median age (range): 50 (18-79) years were tested. Two patients had fallopian tube cancer, while all others had epithelial ovarian cancer. The majority (n = 100, 65.8%) had high-grade serous carcinoma, and 106 patients (69.7%) had metastatic disease on presentation. In total, 38 (25.0%) had PGVs while 47 (30.9%) others had variants of uncertain significance (VUS). PGVs were mostly in BRCA1 (n = 21, 13.8%) and in BRCA2 (n = 12, 7.9%), while only 5 (3.3%) had PGVs in non- BRCA1/2 genes ( CHECK2, MUTYH, PMS2, RAD51D, and RB1) . Age (&lt; 50 versus ≥50) at diagnosis, histological tumor subtype, and disease stage had no impact on pathogenic variant rates. However, PGVt rates were significantly higher (60.0%, p = 0.022) among patients with positive family history of ovarian cancer and 40.4% (p = 0.017) among patients with positive family history of breast cancer. The two patients with fallopian tube cancer were both positive for BRCA1 PGVs. Only one patient underwent prophylactic bilateral mastectomies. Conclusions: PGVs in patients with ovarian cancer are common among Arabs and mostly in BRCA1/2 and rates are significantly higher among patients with family history of ovarian or breast cancers.

T241 Prevalence of gene mutation in congenital thrombophilia for Serbian population

T241 Prevalence of gene mutation in congenital thrombophilia for Serbian population

P53 Gene Mutation Associated With Worse Clinicopathological Characteristic in Breast Cancer

Background: P53 is a tumour suppresor gene. In breast cancer, p53 gene mutation were noted with frequency of about 30% (range 15 to 71%) and associated with poor prognosis. This study was performed to determine p53 mutation association with clinicopathological characteristic in breast cancer and to assess the suitability of patients’ serum to detect p53 autoantibody. Methods: This study conducted in Hospital Seberang Jaya and Institut Perubatan dan Pergigian Termaju, Universiti Sains Malaysia. Sixty-four breast cancer patients with available fresh breast cancer tissue that been kept under -80°C and with complete clinicopathological, data involve in this study. These fresh breast tissues DNA extracted and 10sampels sent for DNA sequencing. The remaining 54samples proceeded with Polymerase Chains Reaction analysis based on the result from DNA sequencing. The serum of these patients was also taken for p53 autoantibody study using ELISA method. Results: The mean age of the patients in this study was 52.45±9.51 yrs. Most of the patients were Malay with 67.2% followed by Indian and Chinese with 17.2% and 15.6% respectively. 51.6%, of these patients undergone CT scan staging and 14.1% has distant metastases. p53 gene mutation prevalence showed rs1042522 only has 15.7% mutation. There was 54.7% Deletion A and 45.3% Wild Type A detected in rs59758982, 87.5% Deletion A and 12.5% Wild Type A in rs35069695 and 92.2 % recorded for Deletion GAA in rs376546152. There was no significant result between these mutation with breast cancer molecular classification and breast cancer aggressiveness except for rs59758982 shows significant result with p value 0.04 (p &lt;0.05). In regards on for p53 serum autoantibodies, 20.3% of the patients noted to be positive but it has no significant association with p53 gene mutations. Conclusion: In this study, tissue p53 genetic mutation has no significant association with clinicopathological characteristic of breast cancer and the use of serum p53 autoantibody as biomarkers is inconclusive.

Germline Variants Identified in Patients with Early-onset Renal Cell Carcinoma Referred for Germline Genetic Testing

BackgroundDespite guidelines recommending genetic counseling for patients with early-onset renal cell carcinoma (RCC), studies interrogating the spectrum of germline mutations and clinical associations in patients with early-onset RCC are lacking. ObjectiveTo define the germline genetic spectrum and clinical associations for patients with early-onset RCC diagnosed at age ≤46 yr who underwent genetic testing. Design, setting, and participantsWe retrospectively identified patients with early-onset RCC who underwent germline testing at our institution from February 2003 to June 2020. Outcome measurement and statistical analysisThe frequency and spectrum of pathogenic/likely pathogenic (P/LP) variants were determined. Clinical characteristics associated with mutation status were analyzed using two-sample comparison (Fisher’s exact or χ2 test). Results and limitationsOf 232 patients with early-onset RCC, 50% had non–clear-cell histology, including unclassified RCC (12.1%), chromophobe RCC (9.7%), FH-deficient RCC (7.0%), papillary RCC (6.6%), and translocation-associated RCC (4.3%). Overall, 43.5% had metastatic disease. Germline P/LP variants were identified in 41 patients (17.7%), of which 21 (9.1%) were in an RCC-associated gene and 20 (8.6%) in a non–RCC-associated gene, including 17 (7.3%) in DNA damage repair genes such as BRCA1/2, ATM, and CHEK2. Factors associated with RCC P/LP variants include bilateral/multifocal renal tumors, non–clear-cell histology, and additional extrarenal primary malignancies. In patients with only a solitary clear-cell RCC, the prevalence of P/LP variants in RCC-associated and non–RCC-associated genes was 0% and 9.9%, respectively. ConclusionsPatients with early-onset RCC had high frequencies of germline P/LP variants in genes associated with both hereditary RCC and other cancer predispositions. Germline RCC panel testing has the highest yield when patients have clinical phenotypes suggestive of underlying RCC gene mutations. Patients with early-onset RCC should undergo comprehensive assessment of personal and family history to guide appropriate genetic testing. Patient summaryIn this study of 232 patients with early-onset kidney cancer who underwent genetic testing, we found a high prevalence of mutations in genes that increase the risk of cancer in both kidneys and other organs for patients and their at-risk family members. Our study suggests that patients with early-onset kidney cancer should undergo comprehensive genetic risk assessment.

Spectrum mutations of PRF1, UNC13D, STX11, and STXBP2 genes in Vietnamese patients with hemophagocytic lymphohistiocytosis.

The prevalence of gene mutations in hemophagocytic lymphohistiocytosis (HLH) varied between studies. Thus far, data on the genetic background of HLH in Vietnamese patients are limited. We recruited 94 HLH patients and analyzed for the 4genes using Sanger sequencing technology. Pathogenic variants were observed in 36 (38.29%) patients, including 27 in UNC13D, 5 in STXBP2, 3 in PRF1, and 2 in STX11 (one patient with digenic variants in both UNC13D and STX11). Monoallelic variants accounted for 77.8% of all cases with mutation. A total of 23 different types of pathogenic variants were documented in the 4genes tested, including 15 in UNC13D, 3 in PRF1, 3 in STXBP2, and 2 in STX11. Interestingly, the novel splicing variant c.3151G>A in UNC13D was recurrently identified in 8 unrelated patients. Vietnamese patients with HLH showed a distinct genetic variant spectrum, in which UNC13D is the predominant genetic lesion associated with HLH.

Liquid Biopsy for the Identification of Intravascular Large B-Cell Lymphoma

[Backgrounds] Intravascular large B cell lymphoma (IVLBCL) is a rare subtype of extranodal diffuse large B-cell lymphoma (DLBCL) that features lymphoma cells lodged in lumina of small vessels. Because of the lack of mass formation, diagnosis by tumor biopsy is often difficult, and thus, cell-free DNA (cfDNA) analysis might be useful for assisting diagnosis of IVLBCL. In this study, we first aimed at investigating the prevalence of mutations in genes involved in the B-cell receptor, Toll-like receptor/interleukin-1 receptor, and nuclear factor kappa B pathways. We then evaluated the liquid biopsies for detection of hot-spot mutations by droplet digital polymerase chain reaction (ddPCR).[Patients and Methods] Twenty-seven IVLBCL patients whose archived samples were available were included in this study. The patients were diagnosed as IVLBCL from January 2005 to May 2017 in University of Tsukuba Hospital, JA Toride Medical Center, and Kameda Medical Center. The study was approved by the review board in each institution, and conducted according to the Declaration of Helsinki. Tissue-derived DNA (tdDNA) was extracted from formalin-fixed paraffin-embedded specimens and/or cryo-preserved bone marrow samples, in which the lymphoma cell infiltration had been pathologically confirmed. cfDNA was extracted from 1 ml of serum or plasma obtained prior to chemotherapy. We performed targeted sequence for 8 genes (B2M, BTG2, CARD11, CD79B, MYD88, PIM1, PRDM1, and TNFAIP3) in paired tdDNA and cfDNA from 9 IVLBCL subjects by Ion Torrent Personal Genome Machine (Thermo Fisher Scientific). MYD88 L265P (c.794T>C) mutational analysis was performed by ddPCR assays (BioRad) for 46 samples in total collected from 27 subjects. Statistical analysis was performed with EZR version 1.3.2. Paired t-test was used to compare variant allele frequencies (VAFs) in paired samples.[Results] All cases were categorized as the non-GCB by Hans classification. Random skin biopsies (RSB) and bone marrow biopsies (BMB) were performed in 21 and 27 patients. The diagnostic yield of RSB was 81.0% (17 of 21). Initial BMB detected lymphoma cells in 48.1% (13/27) patients, but repeated BMB increased successful detection up to 66.7% (18/27). tdDNA was available in 26 out of 27 subjects, and in 9 of which paired cfDNA was also available (Figure 1). In one subject, only cfDNA but not tdDNA was available. Targeted sequencing for 8 genes demonstrated at least one mutation in CD79B, MYD88, PIM1, or PRDM1 in both tdDNA and cfDNA, or only in cfDNA, in 8 of 9 subjects (Figure 2). We identified 3 missense CD79B mutations in 6 (66.7%; Y196C in 2, Y196H in 3, and L199P in 1). All MYD88 mutations were L265P, which were found in 5 of 9 (55.6%). Together, either Y196 CD79B or L265P MYD88 mutation was found in 7 of 9 (77.8%). PIM1 mutations and PRDM1 mutations were seen each in 3 (33.3%). VAFs were higher in cfDNA than in tdDNA (mean, 45.6% vs. 3.7%; P=0.0006, Figure 3). Four mutations in 3 patients were detected only in cfDNA. On the other hand, all variants detected in tdDNA were confirmed in cfDNA. ddPCR assay for the L265P MYD88 mutation with all 46 samples including tdDNA and cfDNA revealed the L265P MYD88 mutation in 24/46 (52.2%) samples from 16/27 (59.3%) IVLBCL patients. Furthermore, sequential analysis of cfDNA was performed in one of the MYD88 -mutated patients. The L265P MYD88 mutation was detected (VAF=30%) in cfDNA collected 17 weeks before the diagnosis of IVLBCL, whereas the mutation was not detected in DNA derived from the bone marrow sample that was collected at the same timing and resulted in the negative pathological finding.[Conclusion] Mutations in MYD88 and CD79B are frequent in IVLBCL . Targeted sequencing suggested that tumor cell-derived DNA is abundant in serum/plasma. Liquid biopsy to detect L265P MYD88 and Y196 CD79B may provide a powerful tool for approaching diagnosis of IVLBCL. [Display omitted] DisclosuresChiba:Nippon Shinyaku: Honoraria, Research Funding.

The conserved alternative splicing factor caper regulates neuromuscular phenotypes during development and aging

RNA-binding proteins play an important role in the regulation of post-transcriptional gene expression throughout the nervous system. This is underscored by the prevalence of mutations in genes encoding RNA splicing factors and other RNA-binding proteins in a number of neurodegenerative and neurodevelopmental disorders. The highly conserved alternative splicing factor Caper is widely expressed throughout the developing embryo and functions in the development of various sensory neural subtypes in the Drosophila peripheral nervous system. Here we find that caper dysfunction leads to aberrant neuromuscular junction morphogenesis, as well as aberrant locomotor behavior during larval and adult stages. Despite its widespread expression, our results indicate that caper function is required to a greater extent within the nervous system, as opposed to muscle, for neuromuscular junction development and for the regulation of adult locomotor behavior. Moreover, we find that Caper interacts with the RNA-binding protein Fmrp to regulate adult locomotor behavior. Finally, we show that caper dysfunction leads to various phenotypes that have both a sex and age bias, both of which are commonly seen in neurodegenerative disorders in humans.