Frequency Of Gene Mutations Research Articles

Genetic Lesions in Russian CLL Patients with the Most Common Stereotyped Antigen Receptors.

Chronic lymphocytic leukemia (CLL) is one of the most common B-cell malignancies in Western countries. IGHV mutational status is the most important prognostic factor for this disease. CLL is characterized by an extreme narrowing of the IGHV genes repertoire and the existence of subgroups of quasi-identical stereotyped antigenic receptors (SAR). Some of these subgroups have already been identified as independent prognostic factors for CLL. Here, we report the frequencies of TP53, NOTCH1, and SF3B1 gene mutations and chromosomal aberrations assessed by NGS and FISH in 152 CLL patients with the most common SAR in Russia. We noted these lesions to be much more common in patients with certain SAR than average in CLL. The profile of these aberrations differs between the subgroups of SAR, despite the similarity of their structure. For most of these subgroups mutations prevailed in a single gene, except for CLL#5 with all three genes affected by mutations. It should be noted that our data concerning the mutation frequency in some SAR groups differ from that obtained previously, which could be due to the population differences between patient cohorts. The research in this area should be important for better understanding the pathogenesis of CLL and therapy optimization.

Elevated expression of TNFRSF4 impacts immune cell infiltration and gene mutation in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, which makes prognostic prediction challenging.We aimed to investigate association of TNFRSF4 expression with the immune infiltration and gene mutation in HCC. In this study, the expression profiles and corresponding clinical data of HCC patients were downloaded from the Cancer Genome Atlas (TCGA) database.Kaplan-Meier and Cox regression were used to evaluate the clinical value of TNFRSF4. ESTIMATE and CIBERSORT algorithms were applied to investigate the infiltration ratio of 22 immune cells. The WGCNA and LASSO COX algorithms were performed, establishing a prognostic risk model that was then validated by HCC samples from GEO. Finally, the effects on gene mutation occurring in HCC patients of TNFRSF4 expression and risk score were appraised. In HCC tissues, it was found the TNFRSF4 expression profile was significantly different with age, gender, tumor grade, disease stage, prominently affecting the survival outcome and prognosis of patients. Univariate and multivariate COX regression analysis suggested that TNFRSF4 was an independent prognostic marker. Samples of high/low expression of TNFRSF4 were screened for differential genes, and then the WGCNA and LASSO COX constructed a 13-gene signature, excellently dividing samples into hign/low risk groups. Compared with the low-risk group, the overall survival (OS) of high-risk group was markedly lower, with P< 0.0001. By ROC curve analysis, the predictive ability of the 13-gene signature was further confirmed. Both the high/low TNFRSF4 expression and the high/low risk score were demonstrated to exert effects on the frequency of gene mutation in HCC. As an independent prognostic marker of HCC, TNFRSF4 was found simultaneously to affect the immune infiltration of cells and the frequency of gene mutations.

GPX3 expression was down-regulated but positively correlated with poor outcome in human cancers.

Cancer is a crucial public health problem and one of the leading causes of death worldwide. Previous studies have suggested that GPX3 may be involved in cancer metastasis and chemotherapy resistance. However, how GPX3 affects cancer patients' outcomes and the underlying mechanism remains unclear. Sequencing data and clinical data from TCGA, GTEx, HPA, and CPTAC were used to explore the relationship between GPX3 expression and clinical features. Immunoinfiltration scores were used to assess the relationship between GPX3 and the tumor immune microenvironment. Functional enrichment analysis was used to predict the role of GPX3 in tumors. Gene mutation frequency, methylation level, and histone modification were used to predict the GPX3 expression regulation method. Breast, ovarian, colon, and gastric cancer cells were used to investigate the relationship between GPX3 expression and cancer cell metastasis, proliferation, and chemotherapy sensitivity. GPX3 is down-regulated in various tumor tissues, and GPX3 expression level can be used as a marker for cancer diagnosis. However, GPX3 expression is associated with higher stage and lymph node metastasis, as well as poorer prognosis. GPX3 is closely related to thyroid function and antioxidant function, and its expression may be regulated by epigenetic inheritance such as methylation modification or histone modification. In vitro experiments, GPX3 expression is associated with cancer cell sensitivity to oxidant and platinum-based chemotherapy and is involved in tumor metastasis in oxidative environments. We explored the relationship between GPX3 and clinical features, immune infiltration characteristics, migration and metastasis, and chemotherapy sensitivities of human cancers. We further investigated the potential genetic and epigenetic regulation of GPX3 in cancer. Our results suggested that GPX3 plays a complicated role in the tumor microenvironment, simultaneously promoting metastasis and chemotherapy resistance in human cancers.

Multi-omics analysis unravels the underlying mechanisms of poor prognosis and differential therapeutic responses of solid predominant lung adenocarcinoma.

Solid predominant adenocarcinoma (SPA) has been reported to be a subtype with poor prognosis and unsatisfactory response to chemotherapy and targeted therapy in lung adenocarcinoma (LUAD). However, the underlying mechanisms remain largely unknown and the suitability of immunotherapy for SPA has not been investigated. We conducted a multi-omics analysis of 1078 untreated LUAD patients with clinicopathologic, genomic, transcriptomic, and proteomic data from both public and internal cohorts to determine the underlying mechanisms of poor prognosis and differential therapeutic responses of SPA and to investigate the potential of immunotherapy for SPA. The suitability of immunotherapy for SPA was further confirmed in a cohort of LUAD patients who received neoadjuvant immunotherapy in our center. Along with its aggressive clinicopathologic behaviors, SPA had significantly higher tumor mutation burden (TMB) and number of pathways altered, lower TTF-1 and Napsin-A expression, higher proliferation score and a more immunoresistant microenvironment than non-solid predominant adenocarcinoma (Non-SPA), accounting for its worse prognosis. Additionally, SPA had significantly lower frequency of therapeutically targetable driver mutations and higher frequency of EGFR/TP53 co-mutation which was related to resistance to EGFR tyrosine kinase inhibitors, indicating a lower potential for targeted therapy. Meanwhile, SPA was enriched for molecular features associated with poor response to chemotherapy (higher chemoresistence signature score, lower chemotherapy response signature score, hypoxic microenvironment, and higher frequency of TP53 mutation). Instead, muti-omics profiling revealed that SPA had stronger immunogenicity and was enriched for positive biomarkers for immunotherapy (higher TMB and T cell receptor diversity; higher PD-L1 expression and more immune cell infiltration; higher frequency of gene mutations predicting efficacious immunotherapy, and elevated expression of immunotherapy-related gene signatures). Furthermore, in the cohort of LUAD patients who received neoadjuvant immunotherapy, SPA had higher pathological regression rates than Non-SPA and patients with major pathological response were enriched in SPA, confirming that SPA was more prone to respond to immunotherapy. Compared with Non-SPA, SPA was enriched for molecular features associated with poor prognosis, unsatisfactory response to chemotherapy and targeted therapy, and good response to immunotherapy, indicating more suitability for immunotherapy while less suitability for chemotherapy and targeted therapy.

An NGS based MRD evaluation from acute myeloid leukemia patients.

Measurable residual disease (MRD) is a prognostic factor for acute myeloid leukemia (AML). A next-generation sequencing (NGS) based MRD panel was developed and the results were validated. The NGS sequencing data was collected from 1003 Chinese AML patients. The sequencing data from 586 newly diagnosed AML patients showed that NRAS mutation was most common (20.8%), followed by NPM1 (19.4%), FLT3-ITD (18.5%), and DNMT3A (15.4%). NPM1 and FLT3-ITD mutations were less in Chinese than in Caucasian AML patients, and the result of KRAS mutation was opposite. A new panel named "AML NGS-MRD hot-spot panel" was designed, containing 178 hot-spot exons from 52 mutated genes and only 62.8 Kb in size. With this hot-spot panel, 92.5% newly diagnosed AML patients were found to carry ≥1 mutations. To verify the performance of this panel, additional 205 newly diagnosed AML patients and 212 post-treatment AML patients were evaluated, and the hot-spot panel achieved a similar detection rate (91.2% for newly diagnosed AML patients and 89.2% for post-treatment AML patients). Finally, this study found that the mutation frequencies of signaling pathway genes (e.g., KRAS, NRAS, FLT3-ITD, KIT) were significantly reduced in post-treatment AML. The "AML NGS-MRD hot-spot panel" detected the mutations from relapsed AML patients with minimal panel size, and was a reliable and cost-effective panel for AML patients.

Evolutionary route of nasopharyngeal carcinoma metastasis and its clinical significance

It is critical to understand factors associated with nasopharyngeal carcinoma (NPC) metastasis. To track the evolutionary route of metastasis, here we perform an integrative genomic analysis of 163 matched blood and primary, regional lymph node metastasis and distant metastasis tumour samples, combined with single-cell RNA-seq on 11 samples from two patients. The mutation burden, gene mutation frequency, mutation signature, and copy number frequency are similar between metastatic tumours and primary and regional lymph node tumours. There are two distinct evolutionary routes of metastasis, including metastases evolved from regional lymph nodes (lymphatic route, 61.5%, 8/13) and from primary tumours (hematogenous route, 38.5%, 5/13). The hematogenous route is characterised by higher IFN-γ response gene expression and a higher fraction of exhausted CD8+ T cells. Based on a radiomics model, we find that the hematogenous group has significantly better progression-free survival and PD-1 immunotherapy response, while the lymphatic group has a better response to locoregional radiotherapy.

Predicting Multi-Gene Mutation Based on Lung Cancer CT Images and Mut-SeResNet

Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (KRAS) are the most common driver genes in non-small cell lung cancer patients. However, frequent gene mutation testing raises a potential risk of cancer metastasis. In our paper, a Mut-SeResNet model based on the ResNet network that incorporated a residual block and attention mechanism was proposed to solve the performance degradation problem caused by a deepening of the network. We introduced a residual structure and extracted small differences between different levels to enhance the feature learning ability. The squeeze and excitation attention mechanism was adapted to fully extract the dependence between different channels of the feature image, and it calibrated the channel feature information. We used the dataset of 363 patients that were collected from collaborating hospitals to train our Mut-SeResNet model. The prediction accuracy for EGFR and KRAS mutations was 89.7% and 88.3%, respectively, with a loss accuracy of 6.4% and 9.2%, respectively. The results showed that the model provided a non-invasive and easy-to-use method to improve the accuracy and stability of clinical diagnosis.

Molecular profiling of gastric neuroendocrine carcinomas.

451 Background: Reports of comprehensive genetic analysis of gastric neuroendocrine carcinoma (G-NEC) are limited, and few have described the tumorigenesis of G-NEC. G-NEC usually has NEC and adenocarcinoma components and is considered to have a common origin in gastric adenocarcinoma because these two tumors share common pathogenic mutations and loss of heterozygosity. However, G-NEC without adenocarcinoma also exists, and it may have a different mechanism of tumorigenesis than that of G-NEC with adenocarcinoma. This study aimed to elucidate the tumorigenesis of G-NEC by focusing on the percentage of NEC component, using comprehensive genetic analysis. Methods: Of the 698 patients who had undergone gastrectomy for gastric cancer between January 2014 and March 2019, this study included 13 patients with G-NEC. Comprehensive genetic analysis using whole-exome sequencing, deep sequencing using a target gene panel, and microarray analysis were performed. NEC was classified according to the 2010 WHO classification. G-NEC without an adenocarcinoma component was defined as pure NEC. Results: There were six patients with mixed adeno-neuroendocrine carcinoma (MANEC), four patients with NEC, and three patients with pure NEC. TP53 was detected as the most frequent gene mutation, independent of classification (85%). RB1, ANKRD17, KMT2C, LTBP1, MAATS1, and RYR2 mutations were identified in two of three pure NEC patients but were not detected in other G-NEC patients. Gene expression analysis showed that six key transcripts of importance in NEC tumorigenesis were upregulated in two patients with pure NEC, while they were downregulated in all six MANEC patients. Conclusions: NEC and MANEC with adenocarcinoma components tend to share common pathogenic mutations, but Pure NEC has different genomic and transcriptomic characteristics than other NECs. This suggests that pure NEC has a different mechanism of tumorigenesis than other G-NECs with adenocarcinoma. This is the first study to present a comprehensive genetic analysis of G-NEC, classified by the percentage of NEC components.

22MO Homologous recombination gene mutations in uterine serous cancer: A phenotype of the hereditary breast and ovarian cancer syndrome?

To determine the prevalence of somatic homologous recombination (HR) gene mutations in uterine serous cancer (USC) and compare these with rates among high-grade serous ovarian cancer (HGSOC). The American Association for Cancer Research’s (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database version 12.0 was queried via cBioPortal (http://genie.cbioportal.org). This is a publicly available, multi-institutional database of next-generation sequencing genomic profiles of tumor samples. Mutation frequencies for 8 homologous recombination deficiency (HRD) genes are reported and compared between uterine serous cancer (USC) and high-grade serous ovarian cancer (HGSOC) samples using chi-squared or Fisher's exact tests. The threshold used for statistical significance was a two-sided alpha of 0.05. Table: 22MOComparison of mutation frequencies of HR genes between tumor samples from uterine serous cancer and high-grade serous ovarian cancerMutation frequency among USCMutation frequency among HGSOCP-valueBRCA112/776, 1.5%313/3125, 10.0%p<0.001BRCA240/776, 5.2%218/3125, 7.0%p<0.001BRIP14/752, 0.5%57/2974, 1.9%p<0.01CHEK26/768, 0.8%19/3040, 0.6%0.82BARD112/664, 1.8%55/2615, 2.1%0.74RAD51C3/671, 0.4%27/2663, 1.0%0.25RAD51D4/671, 0.6%24/2658, 0.9%0.59PALB212/766, 1.6%37/3045, 1.2%0.58 Open table in a new tab Among 844 USC samples, the most prevalent somatic HR gene mutations were BRCA2 (5.2%), BARD1 (1.8%), PALB2 (1.6%) and BRCA1 (1.5%). When compared to 3304 HGSOC samples, higher HR gene mutation frequencies among HGSOC were only found for BRCA1 (10.0% vs 1.5%, p<0.001), BRCA2 (7.0% vs 5.2%, p<0.001) and BRIP1 (1.9% vs 0.5%, p<0.01); however, there was no difference between HGSOC and USC samples in mutation frequencies of BARD1, CHEK2, RAD51C, RAD51D or PALB2. Genomic profiling of USC tumor samples demonstrates a substantial rate of somatic gene mutations conferring HR deficiency, with rates for most HR gene mutations similar to those found among HGSOC samples. This demonstrates the need for genetically targeted clinical trials of poly-ADP ribose polymerase (PARP) inhibitors in patients with USC, and further research into the germline genetic profile of these patients to establish if this rare uterine cancer could be a phenotype of the hereditary breast and ovarian cancer syndrome.

Oxidative Stress Response Biomarkers of Ovarian Cancer Based on Single-Cell and Bulk RNA Sequencing.

The occurrence and development of ovarian cancer (OV) are significantly influenced by increased levels of oxidative stress (OS) byproducts and the lack of an antioxidant stress repair system. Hence, it is necessary to explore the markers related to OS in OV, which can aid in predicting the prognosis and immunotherapeutic response in patients with OV. The single-cell RNA-sequencing (scRNA-seq) dataset GSE146026 was retrieved from the Gene Expression Omnibus (GEO) database, and Bulk RNA-seq data were obtained from TCGA and GTEx databases. The Seurat R package and SingleR package were used to analyze scRNA-seq and to identify OS response-related clusters based on ROS markers. The "limma" R package was used to identify the differentially expressed genes (DEGs) between normal and ovarian samples. The risk model was constructed using the least absolute shrinkage and selection operator (LASSO) regression analysis. The immune cell infiltration, genomic mutation, and drug sensitivity of the model were analyzed using the CIBERSORT algorithm, the "maftools," and the "pRRophetic" R packages, respectively. Based on scRNA-seq data, we identified 12 clusters; OS response-related genes had the strongest specificity for cluster 12. A total of 151 genes were identified from 2928 DEGs to be significantly correlated with OS response. Finally, nine prognostic genes were used to construct the risk score (RS) model. The risk score model was an independent prognostic factor for OV. The gene mutation frequency and tumor immune microenvironment in the high- and low-risk score groups were significantly different. The value of the risk score model in predicting immunotherapeutic outcomes was confirmed. OS response-related RS model could predict the prognosis and immune responses in patients with OV and provide new strategies for cancer treatment.

Next-generation sequencing shows the genomic features of ovarian clear cell cancer and compares the genetic architectures of high-grade serous ovarian cancer and clear cell carcinoma in ovarian and endometrial tissues.

Ovarian clear cell carcinoma (OCCC) is a special histological type of epithelial ovarian cancer (EOC) that is not derived from epithelial cells of the ovarian or fallopian tube as the most common type of ovarian cancer, high-grade serous ovarian carcinoma (HGSOC), but is closely related to endometriosis and similar to endometrial clear cell carcinoma (ECCC) at morphologic and phenotypic features. However, limited data was shown in OCCC genomic features and compared with that in OCCC, HGSOC and ECCC. Herein, we utilized next-generation sequencing analysis of a panel of 1,021 genes to profile the mutational alterations in 34 OCCC and compared them to those from HGSOC (402 cases) and ECCC (30 cases). In result, the ARID1A and PIK3CA are high-frequency mutations of OCCC. Clonal architectures showed that all the mutations of genes occur in the later stage in the OCCC progress, whereas KRAS mutation is the earlier event compared with mutation of ARID1A or PIK3CA, which usually occurs in a group of ARID1A or PIK3CA mutations. The mutation frequency of main driver genes is similar between OCCC and ECCC, while TP53 is the main mutation in HGSOC and ECCC. Shared mutational signatures between OCCC and ECCC tissues with commonly observed a C>T change indicated a common carcinogens-exposed between these two carcinomas, but HGSOC and ECCC have common and distinct mutational signatures across cohorts respectively. In addition, we identified some novel CNV gains in NF1, ASXL1, TCF7L2, CREBBP and LRP1B and loss in ATM, FANCM, RB1 and FLT in OCCC. Our study offered a new perspective for OCCC tumorigenesis from two organs, the ovary and uterus, at genomic architectures and revealed novel CNV events for helping to provide theoretical support for OCCC treatment.

A novel cuproptosis-related prognostic 2-lncRNAs signature in breast cancer.

Background: Cuproptosis, a newly defined regulated form of cell death, is mediated by the accumulation of copper ions in cells and related to protein lipoacylation. Seven genes have been reported as key genes of cuproptosis phenotype. Cuproptosis may be developed by subsequent research as a target to treat cancer, such as breast cancer. Long-noncoding RNA (lncRNA) has been proved to play a vital role in regulating the biological process of breast cancer. However, the role of lncRNAs in cuproptosis is poorly studied. Methods: Based on TCGA (The Cancer Genome Atlas) database and integrated several R packages, we screened out 153 cuproptosis-related lncRNAs and constructed a novel cuproptosis-related prognostic 2-lncRNAs signature (BCCuS) in breast cancer and then verified. By using pRRophetic package and machine learning, 72 anticancer drugs, significantly related to the model, were screened out. qPCR was used to detect the differentially expression of two model lncRNAs and seven cuproptosis genes between 10 pairs of breast cancer tissue samples and adjacent samples. Results: We constructed a novel cuproptosis-related prognostic 2-lncRNAs (USP2-AS1, NIFK-AS1) signature (BCCuS) in breast cancer. Univariate COX analysis (p < .001) and multivariate COX analysis (p < .001) validated that BCCuS was an independent prognostic factor for breast cancer. Overall survival Kaplan Meier-plotter, ROC curve and Risk Plot validated the prognostic value of BCCuS both in test set and verification set. Nomogram and C-index proved that BCCuS has strong correlation with clinical decision-making. BCCuS still maintain inspection efficiency when patients were splitting into Stage I-II (p = .024) and Stage III-IV (p = .003) breast cancer. BCCuS-high group and BCCuS-low group showed significant differences in gene mutation frequency, immune function, TIDE (tumor immune dysfunction and exclusion) score and other phenotypes. TMB (tumor mutation burden)-high along with BCCuS-high group had the lowest Survival probability (p = .005). 36 anticancer drugs whose sensitivity (IC50) was significantly related to the model were screened out using pRRophetic package. qPCR results showed that two model lncRNAs (USP2-AS1, NIFK-AS1) and three Cuproptosis genes (FDX1, PDHA1, DLAT) expressed differently between 10 pairs of breast cancer tissue samples and adjacent samples. Conclusion: The current study reveals that cuproptosis-related prognostic 2-lncRNAs signature (BCCuS) may be useful in predicting the prognosis, biological characteristics, and appropriate treatment of breast cancer patients.

Early epigenetic markers for precision medicine.

Changes in DNA methylation levels, changes in histones, and noncoding RNA functions (ncRNAs) are common among different diseases and epigenetic component mutations. The ability to distinguish between the roles of drivers and passengers in epigenetic changes will allow to identify diseases where epigenetics could influence diagnosis, prediction and treatment. In addition, by examining the interaction between epigenetic components and other pathways of disease, a combination intervention approach will be developed. A comprehensive study of the association of specific cancer types or the cancer genome atlas project has revealed frequent mutations in genes encoded by the epigenetic components. These include mutations in DNA methylase and demethylase, the cytoplasm and the change of cytoplasm, as well as genes involved in the restoration of chromatins and the structure of chromosomes, also, the metabolic genes isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) affect histone and DNA methylation, disrupting the architecture of the 3D genome, but also affect the metabolic genes IDH1 and IDH2. Repeated DNA elements also cause cancer. In the 21st century, epigenetic research has rapidly accelerated, causing legitimate excitement and hope, and causing a certain level of excitement. New epigenetic tools can be used as prevention, diagnosis and therapeutic markers. Drug development targets specific epigenetic mechanisms that regulate gene expression and promotes gene expression. The development and use of epigenetic tools is an appropriate and effective method for treating various diseases clinically.

HEREDITARY CANCER MUTATIONS PREVALENCE AMONG BREAST CANCER PATIENTS ACCORDING TO NGS PANEL TESTING RESULTS, ITS IMPORTANCE IN CHOOSING THE EXTENT OF SURGICAL TREATMENT

Summary. Genetic testing for hereditary cancer gene mutations is important for breast cancer patients in many aspects (including the degree of risk determining the extent of surgical treatment) and helps the patient to choose the best option, both from the point of view of risk reducing, and from the point of view of the best aesthetic result and minimizing the consequences of treatment. Aim: to determine the spectrum of gene mutations in breast cancer patients who had at least one of the risk factors for heredity of the disease. Object and methods: the study included 160 breast cancer patients who had at least one of the risk factors for heredity of the disease according to the criteria defined in the NCCN version 2.2019 guideline. All patients underwent next-generation DNA sequencing (NGS) genetic testing for a panel of 30 hereditary cancer genes. Statistical analysis of the obtained results was carried out in the EXCEL. Results: among 160 patients, 90 mutations were detected in 72 patients (45.0%). Among them, 59 patients (81.9%) had one mutation, 13 patients (18.1%) had more than one mutation. 51 pathogenic or likely pathogenic mutations were detected in 45 patients. 39 VUS (variant of uncertain significance) mutations were detected in 31 patients. The rate of hereditary breast cancer among the studied patients was 27.5%. The most frequent gene mutations were: BRCA1 (47.1%), CHEK2 (17.6%), BRCA2 (17.6%), ATM (5.9%), PALB2 (3.9%), BRIP1 (2, 0%), others (5.9%). Among them, the most frequent mutation was 5382ins C of the BRCA1 gene. For 64.3% of patients, the results of genetic testing had the highest importance when choosing the extent of surgical intervention, and for only 5.1% of patients they were completely unimportant. Conclusion: genetic testing is important for patients in many aspects, from the choice of the scope of surgical treatment to the features of followup, preventive measures to reduce the risk of new events (multiple primary neoplasms), the feasibility of testing children, etc. It is relevant to continue studying the role of genetic testing for breast cancer patients in various aspects, in particular, in choosing the scope of surgical treatment.

Prevalence Study of Duchene Muscular Dystrophy and its Genetic Sequence in Southern India.

Duchene Muscular dystrophy (DMD) is the common X-linked heterogenous progressive muscular dystrophy characterized by mutations in the DMD gene. The frequency of dystrophin gene mutations is varied in different DMD population. A precise diagnosis can help to reduce the severity of DMD since it aids in planning of targeted medical treatment and required therapies. This study was aimed to investigate the mutation type, their rate and distribution of DMD'S in southern India. An observational study was conducted on 250 genetically confirmed DMD patients from March,2019 to March,2021. The distribution pattern and rate of mutations (deletion, duplication, nonsense mutations, minor mutations) were investigated. Mutation spectrum was studied on 250 DMD patients, of which 63% exon deletion pattern were reported. 16% deletions were detected in proximal hot region (exons 3-28). The duplications were found 21% in the proximal hotspot largest region (exon 3-25). 16% of the patients reported single deletion (45 exon), 10.7% reported deletions of exon 44. Point mutations detected in 6%, small mutations were detected in 1.2%, non-sense mutations were detected in 2% of study population respectively. Missense Mutations were detected in 0.8% of study population. This study estimates mutation spectrum of exon deletion pattern (63%) was predominantly identified in distal region; duplication was most frequent in proximal region. Point mutations, Nonsense mutations and small mutations have a least accountability. This study adds a real world evidence for developing research therapies in DMD.

Abstract C028: The differential burden of BRCA2 gene mutation in prevalent cancers in Nigeria: Any difference between Africa and the world?

Abstract Introduction: The high mortality rate among cancer patients in Africa has been attributed to the high rate of late-stage presentation, aggressiveness, and metastatic nature of the tumors. The manifestation of cancer has also been linked with mutation of DNA repair genes including BRCA1, evidenced by the lack of expression of the tumor suppressors in the affected tissue. However, in Africa, there is a paucity of studies on the frequency of BRCA2 gene mutation in prevalent cancers. This study determined the prevalence of BRCA2 mutation in common cancers in Nigeria in a bid to compare the disparity of the mutation between Africa and elsewhere. Methods: This retrospective study included 51, 54, 58, 48, and 55 viable formalin-fixed Paraffin-embedded tissues of the breast, colorectal, endometrial, ovarian, and prostate cancers, respectively diagnosed between 2017 and 2019 in two tertiary health care facilities in Southern Nigeria. Tissues were stained for BRCA2 protein using the immunohistochemical technique, scored based on staining intensity, and documented as 0, +1, +2, and +3. Tissues with scores of 0 and +1 were considered negative whereas those with scores of +2 and +3 were considered positive. Descriptive, Chi-square test and Pearson’s correlation were carried out and significance was set at ≤0.05. Results: The mean age of women diagnosed with endometrial cancer was lower (41.34 ± 9.16 years) compared with breast, colorectal, ovarian, and prostate cancers (51.00 ± 10.98 years, 47.34 ± 14.73 years, 50.15 ± 12.29 years, and 72.66 ± 8.67 years, respectively). The prevalence of BRCA2 mutation was higher in endometrial cancer (78.4%) than in breast, colorectal, ovarian, and prostate cancers (41.5%, 25%, 54.2%, and 65.1%, respectively) at p&amp;lt; 0.001. There was a direct relationship between age and BRCA2 mutation among women with endometrial cancer (p= 0.005). Conclusion: This study suggests that the prevalence of BRCA2 mutation is high in Southern Nigeria and could be linked with the poor survival rate observed among cancer patients in West Africa. Citation Format: Jude Ogechukwu Okoye, Chiemeka Michael Emeka, Okechi Obioma. The differential burden of BRCA2 gene mutation in prevalent cancers in Nigeria: Any difference between Africa and the world? [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C028.

The Prevalence of CHEK1 and CHEK2 Mutations in Prostate Cancer: a Retrospective Cohort Study.

Prostate cancer (PCa) is one of the most common types of cancer among men. Mutations and accumulation of chromosomal deviations are correlated with the development and aggressiveness of PCa. Cell cycle checkpoint pathways and DNA repair mechanisms are reported to deviate in cancers. Mammalian checkpoint kinase 1/2 (CHEK1/CHEK2) genes act as key signal transducers inside the genomic integrity checkpoints. CHEK1 and CHEK2 gene mutations were reported in a few different types of cancers. In PCa, CHEK2 mutations were studied, but CHEK1 gene variations were not well investigated. This study aimed to investigate the occurrence of variations in the CHEK1 and CHEK2 genes in PCa in the Jordanian population. Formalin-fixed paraffin-embedded PCa specimens of radical prostatectomy surgical procedures from 74 Jordanian patients were subjected to DNA extraction, polymerase chain reactions and Sanger sequencing to screen the mutations in selected exons of CHEK1 and CHEK2 tumor suppressor genes. The presence of F281L (T/C) (1.4%) homologous missense point mutation in the kinase domain of the CHEK2 gene and P188P (1.4%) silent point mutation in the kinase domain of the CHEK1 gene. In addition, the 1100delC mutation was not detected in the studied PCa specimens. In line with previous reports, the presence of CHEK2 mutation with a frequency of 1.4% supported the possible role of genetic variants of this gene in the development of PCa. No 1100delC mutation was detected in this study. No association was found in this study between CHEK1 mutations and the development of PCa. Further studies are needed with larger cohorts along with a screening of more exons in order to shed more light on the frequency of CHEK2 gene mutations and their role in the development of PCa in Jordan.

Abstract P040: Mutational heterogeneity of colorectal cancers across ancestries and its implications for cancer early detection

Abstract Introduction: Early cancer detection with liquid biopsies has the potential to reduce mortality rates by improving screening strategies, adoption, and adherence. Towards this, a deeper understanding of the cancer genomic landscape among patients of different ethnicities is critical to ensure comparable performance across a broad population. In this study, we sought to understand how the mutational landscape of patients with colorectal cancer (CRC) varies across ethnicities. Methods: A total of 20,845 de-identified patients with stage I-IV CRC, who had undergone commercial personalized and tumor-informed ctDNA testing (SignateraTM) as of April 14, 2022, were eligible for inclusion in the study. We performed ancestry inference using Principal Component Analysis on single nucleotide polymorphisms (SNPs) and validated the predictions in a subset of 2,032 patients with whole exome sequencing data available along with self-reported ethnicity. Individuals were assigned to one of four major ethnic groups: African (AFR), European (EUR), East Asian (EAS) and South Asian (SAS). Results: Our cohort consisted of 69.1% EUR, 9.6% AFR, 20% EAS, and 1.3% SAS patients. On comparing the somatic driver mutations across ancestry groups, we observed APC mutations in 71% of EUR, 79% of AFR, 80% of EAS and 69% of SAS (p&amp;lt;0.0001), KRAS mutations in 39% of EUR, 50% of AFR, 40% of EAS and 38% of SAS (p&amp;lt;0.0001), and TP53 mutations in 64% in EUR, 64% in AFR, 74% in EAS and 69% in SAS (p&amp;lt;0.0001) patients, respectively. The microsatellite instability (MSI) rates similarly varied across ancestral groups, with EUR ancestry (12.3%) having a significantly higher rate of MSI than AFR (8.9%) and EAS (7.5%) (p&amp;lt;0.0001). Comparing the mutational patterns in left vs. right colon across 712 patients with available tumor location information, we found 64% of tumors in EAS to be left sided vs. 49% in EUR (p=0.0002). Left-sided tumors were enriched for MSI and RAS mutations and right-sided tumors were enriched for APC and TP53 mutations, confirming known differences in left- vs. right-sided colorectal tumors. Among left sided tumors, we also observed TP53 mutations in 79% of EAS as compared to 64% of EUR (p=0.001), APC mutations in 84% of EAS as compared to 70% of EUR (p=0.002) and RNF43 mutations in 1% of EAS as compared to 7% in EUR (p=0.002) suggesting differences in mechanisms of WNT pathway inactivation across ethnicities. Finally, we looked at the predicted performance of a cancer screening panel which is based on large and heterogeneous data and maximizes recurrent mutation coverage while minimizing panel size. Despite the differences in individual driver gene mutation frequency, we found that the mean number of mutations covered by the panel in AFR, EAS and SAS individuals relative to EUR was 1.07, 1.1 and 1.02, respectively. Conclusions: Our results demonstrate that the expected performance of a theoretical cancer screening panel was similar across the different ancestry groups despite differences in their somatic landscape. Citation Format: Preethi Srinivasan, Boris Gutman, Vasily Aushev, Shruti Sharma, Taly Arbel, Hsin-Ta Wu, Meenakshi Malhotra, Raheleh Salari, Bernhard Zimmermann, Ryan Swenerton, Trupti Kawli, Breeana Mitchell, Matthew Rabinowitz, Alexey Aleshin, Johannes G. Reiter. Mutational heterogeneity of colorectal cancers across ancestries and its implications for cancer early detection. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P040.

Cuproptosis-related lncRNA signatures predict prognosis and immune relevance of kidney renal papillary cell carcinoma.

Kidney renal papillary cell carcinoma (KIRP) has a high mortality rate and a poor prognosis. Cu concentrations differed significantly between renal cancer tissues and adjacent normal tissues. Cuproptosis is a newly identified cell death. Long non-coding RNAs (lncRNAs) play a crucial role in the progression of KIRP. In this study, we focused on constructing and validating cuproptosis-related lncRNA signatures to predict the prognosis of KIRP patients and their immune correlation. We created prognosis models using Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) algorithm. We found that patients in the high-risk group had poorer overall survival (OS) and progression-free survival (PFS) and higher mortality. Risk score and stage are prognosis factors independent of other clinical features. Kaplan-Meier analysis, receiver operating characteristic (ROC) curves, and C-index curves showed that cuproptosis-related lncRNA signatures could more accurately predict the prognosis of patients. Functional enrichment analysis suggests that the function of differentially expressed genes (DEGs) is associated with KIRP development and immunity. In immune-related function analysis, we found a significant difference in parainflammation responses between high-risk and low-risk groups. The mutation frequencies of TTN, MET, KMT2C, PKHD1, SETD2, and KMT2D genes in the high-risk group were higher than those in the low-risk group, but the mutation frequencies of MUC16, KIAA109, CUBN, USH2A, DNAH8 and HERC2 genes were significantly lower than those in the low-risk group. Survival analysis of tumor mutation burden (TMB) and combined TMB-risk showed better OS in patients with high TMB. Immune infiltration and immune checkpoint analysis assessed the immune association of six high mutation frequency genes (TTN, MET, KMT2C, PKHD1, SETD2, and KMT2D) with KIRP. Finally, we performed a drug sensitivity analysis and screened 15 potential drugs that differed between high-risk and low-risk patients. In this study, we constructed and validated cuproptosis-related lncRNA signatures that can more accurately predict the prognosis of KIRP patients and provide new potential therapeutic targets and prognosis markers for KIRP patients.

Mutation of the TP53 Gene in Placental Chorangiomatosis

Objective: We explored the frequency of TP53 gene mutations in chorangiomas (CA) and chorangiomatosis (CM). Materials and ­methods: By Sanger sequencing, we evaluated mutations in exons 4-6 of the TP53 gene in CM and CA regions of placentas. Results: In total, 7/11(63.6%) CAs and 24/26 (92.3%) CMs had TP53 mutations, with a significantly higher frequency in the latter. Mutations in both groups predominately involved exon 4, most commonly at the 119th C. The mutation types at the 119th C were C/G and G/G. Among the patients with exon 4 mutations at the 119th C, C/G mutations, the most common type, were observed more frequently in the CM group (63.16%, 12/19) than in the CA group (14.29%, 1/7), and the difference was significant. Conclusion: It is suggested that both CM and CA are tumors rather than tumor-like lesions. Although they are histologically similar, they have a different TP53 profile.