Mutation Profiles Research Articles

Dissecting the Significance of Acid Phosphatase 1 Gene Alterations in Prostate Cancer.

The acid phosphatase 1 (ACP1) gene encodes low-molecular-weight protein tyrosine phosphatase, which is overexpressed in prostate cancer (PC) and a potential therapeutic target. We analyzed ACP1 expression in primary/metastatic PC and its association with molecular profiles and clinical outcomes. NextGen sequencing of DNA (592-gene/whole-exome sequencing)/RNA(whole-transcriptome sequencing) was performed for 5,028 specimens. ACP1-High/ACP1-Low expression was defined as quartile (Q4/1) of RNA transcripts per million (TPM). DNA mutational profiles were analyzed for ACP1-quartile-stratified samples. Gene set enrichment analysis was used for Hallmark collection of pathways. PD-L1+(≥2+, ≥5%; SP142) was tested by immunohistochemistry. Tumor microenvironment's (TME) immune cell fractions were estimated by RNA deconvolution/quanTIseq. Overall survival (OS) was assessed from initial diagnosis/treatment initiation to death/last follow-up. We included 3,058 (60.8%) samples from the prostate, 634 (12.6%) from lymph node metastases (LNMs), and 1,307 (26.0%) from distant metastases (DMs). ACP1 expression was higher in LNM/DM than prostate (49.8/47.9 v 44.1 TPM; P < .0001). TP53 mutations were enriched in ACP1-Q4 (37.9%[Q4] v 27.0%[Q1]; P < .001) among prostate samples. Pathways associated with cell cycle regulation and oxidative phosphorylation were enriched in ACP1-Q4, whereas epithelial-mesenchymal transition and tumor necrosis factor-alpha signaling via nuclear factor kappa-light-chain-enhancer of activated B-cell pathways were enriched in ACP1-Q1. Neuroendocrine and androgen receptor signaling was increased in ACP1-Q4. M2 macrophages and natural killer cell fractions were increased, whereas T cells and M1 macrophages were decreased in ACP1-Q4. While OS differences between ACP1-Q1/Q4 were not statistically significant, there was a trend for worse OS among ACP1-Q4 prostate samples (Q4 v Q1: hazard ratio [HR], 1.19 [95% CI, 0.99 to 1.42]; P = .06) and DM (HR, 1.12 [95% CI, 0.93 to 1.36]; P = .22) but not LNM (HR, 0.98 [95% CI, 0.74 to 1.29]; P = .87). ACP1-High tumors exhibit a distinct molecular profile and cold TME, highlighting ACP1's potential role in PC pathogenesis and novel therapeutic targeting.

A novel platform for mutation detection in colorectal cancer using a PNA-LNA molecular switch

Detection of KRAS mutation in colorectal cancer (CRC) is important in the prediction of response to target therapy. The study aims to develop a novel mutation detection platform called the “PNA-LNA molecular switch” for the detection of KRAS mutation in CRC. We employed the enhanced binding specificity of peptide nucleic acid (PNA) and locked nucleic acid (LNA) in conjunction with a loop-mediated isothermal amplification (LAMP) approach to identify the mutation status of KRAS oncogene codon 12 (c.35G>T/G12V and c.35G>A/G12D) using synthetic oligonucleotides and colon cancer cell lines (Caco-2 and SW480). This method specifically blocked the amplification of the wild-type sequences while substantially amplifying the mutated ones, which was visualized by both colorimetric and fluorescence assays. We then checked the mutation profile of KRAS codon 12 in the DNA derived from tumor tissue samples (number of samples, n = 30) and circulating tumor cells (n = 24) from CRC patients. Finally, we validated the results by comparing them with the data obtained from DNA sequencing of colon tumors (n = 21) of the same CRC patients. This method showed excellent sensitivity (1 DNA copy/μl), reproducibility [relative standard deviation (%RSD) < 5%, for n = 3], and linear dynamic range (1 ag/μl-10 pg/μl, R2 = 0.94). This platform is significantly faster, relatively cheaper, has superior sensitivity and specificity, and does not require any high-end equipment. To conclude, this method has the potential to be translated into clinical settings for the detection of mutations in diverse diseases and conditions.

Preliminary identification of somatic mutations profile in ACL injury

Anterior cruciate ligament (ACL) injury is a common orthopedic disease with a high incidence, long recovery time, and often requiring surgical treatment. However, the susceptibility factors for ACL injury are currently unclear, and there is a lack of analysis on the differences in the ligament itself. Previous studies have focused on germline mutations, with less research on somatic mutations. To determine the role of somatic mutations in ACL injuries, we recruited seven patients between the ages of 20 and 39 years diagnosed with ACL injuries, collected their peripheral blood, injured ligament ends, and healthy ligament ends tissues, and performed exome sequencing with gene function enrichment analysis. We detected multiple gene mutations and gene deletions, which were only present in some of the samples. Unfortunately, it was not possible to determine whether these somatic mutations are related to ligament structure or function, or are involved in ACL injury. However, this study provides valuable clues for future in-depth research.

Molecular landscape of eyelid sebaceous gland carcinoma: A comprehensive review.

Eyelid sebaceous gland carcinoma (SGC) is an aggressive skin cancer characterized by a heightened risk of recurrence and metastasis. While surgical excision is the primary treatment, unraveling the molecular intricacies of SGC is imperative for advancing targeted therapeutic interventions and enhancing patient outcomes. This comprehensive review delves into the molecular landscape of eyelid SGC, emphasizing key genetic alterations, signaling pathways, epigenetic modifications, and potential therapeutic targets. Significant findings include aberrations in critical signaling pathways (β-catenin, lymphoid enhancer binding factor, hedgehog, epidermal growth factor receptor, P53, and P21WAF1) associated with SGC progression and poor prognosis. Notably, eyelid SGC manifests a distinctive mutational profile, lacking ultraviolet signature mutations in tumor protein 53 (TP53), indicating alternative mutagenic mechanisms. Next-generation sequencing identifies actionable mutations in genes such as phosphatase and tensin homolog (PTEN) and Erb-B2 receptor tyrosine kinase 2 (ERBB2), facilitating the emergence of personalized medicine approaches. Molecular chaperones, specifically X-linked inhibitor of apoptosis protein (XIAP) and BAG3, emerge as pivotal players in promoting tumor survival and proliferation. The review underscores the role of epithelial-mesenchymal transition, where regulators like E-cadherin, vimentin, and ZEB2 contribute to SGC aggressiveness. Epigenetic modifications, encompassing DNA methylation and microRNA dysregulation, further elucidate the molecular landscape. This review consolidates a comprehensive understanding of the molecular drivers of eyelid SGC, shedding light on potential therapeutic targets and providing a foundation for future investigations in diagnostic, prognostic, and personalized treatment strategies for this formidable malignancy.

CtDNA SNORD3F Hypermethylation is a Prognostic Indicator in EGFR-TKI-Treated Advanced Non-Small Cell Lung Cancer.

DNA methylation plays a regulatory role in the oncogenesis and tumor progression and is valuable in the diagnosis and prognosis of cancer. While circulating tumor DNA (ctDNA) is widely used in the detection of oncogenic mutations and the guidance of treatment in advanced non-small cell lung cancer (NSCLC), studies of ctDNA methylation remains insufficient. We aim to investigate the methylation profiles of ctDNA in patients with advanced NSCLC undergoing EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy and to discover novel biomarkers with predictive or prognostic value. We recruited 49 patients with EGFR-mutated advanced NSCLC undergoing EGFR-TKI as first-line treatment. Utilizing next-generation sequencing, we examined the somatic mutations and methylation signatures within the tumor-associated genomic regions of ctDNA from pre-treatment blood. Subsequently, we explored the association of these molecular features with the patients' response to therapy and their progression-free survival (PFS). Genomic mutation profiling revealed no significant association of PFS or best overall response (BOR) and ctDNA status. Evaluation of ctDNA methylation showed a negative correlation between the methylation of small nucleolar RNA (snoRNA) genes and PFS (R=-0.31, P=0.043). Furthermore, high-level methylation of SNORD3F was associated with poorer PFS (mPFS 346d vs 243d, HR 0.49, 95% CI 0.24-0.93, P=0.029). Our study explored the prognostic value of ctDNA methylation in patients with advanced NSCLC undergoing targeted therapies and first revealed the predictive role of SNORD3F.

Identification of a PANoptosis-related prognostic model in triple-negative breast cancer, from risk assessment, immunotherapy, to personalized treatment

BackgroundTriple-negative breast cancer is a breast cancer subtype characterized by its challenging prognosis, and establishing prognostic models aids its clinical treatment. PANoptosis, a recently identified type of programmed cell death, influences tumor growth and patient outcomes. Nonetheless, the precise impact of PANoptosis-related genes on the prognosis of triple-negative breast cancer has yet to be determined. MethodsClinical information for the triple-negative breast cancer samples was collected from the Gene Expression Omnibus and The Cancer Genome Atlas databases, while 19 PANoptosis-related genes were sourced from previous studies. We first categorized PANoptosis-related subtypes and determined the differentially expressed genes between them. Subsequently, we developed and validated a PANoptosis-associated predictive model using LASSO and Cox multivariate regression analyses. Statistical evaluations were conducted using R software, and the mRNA expression levels of the genes were quantified using real-time PCR. ResultsUsing consensus clustering analysis, we divided triple-negative breast cancer patients into two clusters based on PANoptosis-related genes and identified 1054 differentially expressed genes between these clusters. Prognostic-related genes were subsequently selected to re-cluster patients, validating their predictive ability. A prognostic model was then constructed based on four genes: BTN2A2, CACNA1H, PIGR, and S100B. The expression and enriched cell types of these genes were examined and the expression levels were validated in vitro. Furthermore, the model was validated, and a nomogram was created to enhance personalized risk assessment. The risk score, proven to be an independent prognostic indicator for triple-negative breast cancer, showed a positive correlation with both age and disease stage. Immune infiltration and drug sensitivity analyses suggested appropriate therapies for different risk groups. Mutation profiles and pathway enrichment were analyzed, providing insights into potential therapeutic targets. ConclusionA PANoptosis-related prognostic model was successfully developed for triple-negative breast cancer, offering a novel approach for predicting patient prognosis and guiding treatment strategies.

Population structure of the B0/W148 Mycobacterium tuberculosis subtype: Phylogenetic analysis and characteristics of genotypic drug resistance

Background. The B0/W148 subtype belongs to the L2phylogenetic lineage of Mycobacterium tuberculosis and is most common in the former Soviet Union. Test systems capable of detecting genetic variants of the pathogen are needed for effective epidemiological surveillance. Studying the genetic diversity of B0/W148 strains and finding molecular markers suitable for their genotyping are key steps in the development of such diagnostic tools.The aim of the work. To study the phylogenetic diversity of the B0/W148 subtype circulating in the territory of the Russian Federation and neighboring countries in order to identify unique clades and search for specific molecular markers suitable for their precise identification.Materials and methods. The study used DNA samples of B0/W148 strains (n = 34) isolated in different regions of the Russian Federation, as well as genomic data obtained from the SRA NCBI (Sequence Read Archive of the National Center for Biotechnology Information) (n = 419). Phylogenetic analysis and principal component analysis (PCA) of whole genome sequencing (WGS) data were used to analyze genetic diversity and to identify molecular markers. An evolutionary reconstruction of the age of the identified clades was carried out.Results. The analysis of the B0/W148 genomes (n = 453) revealed that they are divided into three phylogenetic clades: B – basal, M – minor and P – principal. It was found that specific mutations in the M and P clades allow for their differential diagnosis. The 4137219T&gt;G mutation is unique for the M clade, and the 2241091C&gt;T mutation is unique for the P clade. No characteristic mutations were found among the strains of B clade. In addition, unique mutation profiles in the genes responsible for drug resistance were identified for the clades.Conclusion. The study showed that B0/W148 strains represent a genetically heterogeneous population divided into B, M and P clades. M and P Clades have unique mutations that allow for their identification. It was also found that all clades are characterized by the presence of specific mutation profiles in drug resistance genes.

Identification of GPNMB in endometrial cancer based on pan-cancer analysis and in vitro validation

BackgroundGPNMB is a type I transmembrane protein, and emerging evidence supports the relationship between GPNMB and cancers.ObjectiveThrough a comprehensive pan-cancer analysis, we examined the expression levels, prognostic significance, and mutation profiles of GPNMB in different cancer types. Subsequently, utilizing in vitro experiments, we elucidated the impact of GPNMB in endometrial cancer (EC).MethodsTIMER2, GEPIA2, UALCAN and cBioPortal were used to analyze the expression pattern, prognostic values, and mutation status of GPNMB. HEC-1B and Ishikawa cells were used to conduct in vitro analyses of GPNMB overexpression. GeneMANIA and TIMER2 were used to evaluate the potential functions and correlations between GPNMB expression and tumor-infiltrating immune cells in EC.ResultsGPNMB was found to be highly expressed in multiple cancers, where it was associated with poor prognosis. Additionally, GPNMB was downregulated at both mRNA and protein levels in EC. Overexpression of GPNMB inhibited the proliferation, migration, and invasion of HEC-1B and Ishikawa cells. Functional analysis showed that GPNMB was enriched in pathways associated with regulation of plasma lipoprotein particle levels. The expression of GPNMB was positively connected with B cell, CD8+ T cell, CD4+ T cell, Macrophage, Neutrophil, and Dendritic cell levels.ConclusionThrough pan-cancer analysis, we identified the antitumor effect of GPNMB in EC and predicted the potential mechanisms between GPNMB expression and EC.

Large B-cell lymphomas with CCND1 rearrangement have different immunoglobulin gene breakpoints and genomic profile than mantle cell lymphoma

Mantle cell lymphoma (MCL) is genetically characterized by the IG::CCND1 translocation mediated by an aberrant V(D)J rearrangement. CCND1 translocations and overexpression have been identified in occasional aggressive B-cell lymphomas with unusual features for MCL. The mechanism generating CCND1 rearrangements in these tumors and their genomic profile are not known. We have reconstructed the IG::CCND1 translocations and the genomic profile of 13 SOX11-negative aggressive B-cell lymphomas using whole genome/exome and target sequencing. The mechanism behind the translocation was an aberrant V(D)J rearrangement in three tumors and by an anomalous IGH class-switch recombination (CSR) or somatic hypermutation (SHM) mechanism in ten. The tumors with a V(D)J-mediated translocation were two blastoid MCL and one high-grade B-cell lymphoma. None of them had a mutational profile suggestive of DLBCL. The ten tumors with CSR/SHM-mediated IGH::CCND1 were mainly large B-cell lymphomas, with mutated genes commonly seen in DLBCL and BCL6 rearrangements in 6. Two cases, which transformed from marginal zone lymphomas, carried mutations in KLF2, TNFAIP3 and KMT2D. These findings expand the spectrum of tumors carrying CCND1 rearrangement that may occur as a secondary event in DLBCL mediated by aberrant CSR/SHM and associated with a mutational profile different from that of MCL.

Molecular profiling of pre- and post- 5-azacytidine myelodysplastic syndrome samples identifies predictors of response.

Treatment with the hypomethylating agent 5-azacytidine (AZA) increases survival in high-risk (HR) myelodysplastic syndrome (MDS) patients, but predicting patient response and overall survival remains challenging. To address these issues, we analyzed mutational and transcriptional profiles in CD34+ hematopoietic stem/progenitor cells (HSPCs) before and following AZA therapy in MDS patients. AZA treatment led to a greater reduction in the mutational burden in both blast and hematological responders than non-responders. Blast and hematological responders showed transcriptional evidence of pre-treatment enrichment for pathways such as oxidative phosphorylation, MYC targets, and mTORC1 signaling. While blast non-response was associated with TNFa signaling and leukemia stem cell signature, hematological non-response was associated with cell-cycle related pathways. AZA induced similar transcriptional responses in MDS patients regardless of response type. Comparison of blast responders and non-responders to normal controls, allowed us to generate a transcriptional classifier that could predict AZA response and survival. This classifier outperformed a previously developed gene signature in a second MDS patient cohort, but signatures of hematological responses were unable to predict survival. Overall, these studies characterize the molecular consequences of AZA treatment in MDS HSPCs and identify a potential tool for predicting AZA therapy responses and overall survival prior to initiation of therapy.

Construction of a novel model based on PVT1-MYC duet-related genes for predicting survival and characterization of the tumor microenvironment in pancreatic cancer.

Pancreatic cancer is an extremely malignant tumor. PVT1 and MYC signaling has been considered as a therapeutic target recently. Nonetheless, the prognostic values and critical regulatory networks of PVT1-MYC duet in pancreatic cancer remain unclear. Firstly, we identified PVT1-MYC duet-related genes using public databases. Then we analyzed our Hi-C and ChIP-seq data to confirm PVT1-MYC duet. We performed LASSO regression and multivariate Cox regression analysis to build a prognostic model whose effectiveness and robustness were validated by Cox regression, ROC analysis, calibration curve, and nomogram. Besides, we conducted functional enrichment analyses, mutation profiles analyses and the immune features analyses to compare low- and high-risk group. Functional enrichment analyses revealed that several terms associated with cancer progression were enriched in the high-risk group. Mutation profile analysis showed that high-risk group had higher tumor mutation burden, and immune analysis demonstrated high-risk group had more immunosuppressive tumor microenvironment. Finally, we detected PVT1 expression in pancreatic cancer and paracancer tissues from the PUMCH cohort, which showed that PVT1 was significantly upregulated in pancreatic cancer and associated with invasion, metastasis, and poor prognosis. We further performed transwell and proliferation assays and found that PVT1, CDC6, and COL17A1 could promote migration or proliferation of PDAC cells. This study constructed a prognostic model based on three PVT1-MYC duet-related genes, which had a significant potential in predicting the prognosis and tumor microenvironment of pancreatic cancer. These results suggested that targeting PVT1-MYC duet or its regulatory processes could be a therapeutic option with great interests.

The RAS/BRAF genes status in patients with colorectal cancer (review)

Colorectal cancer (CRC) is the third in prevalence among oncological diseases worldwide and second in the structure of oncological mortality. Genetic assessment of CRC is a necessary stage during selecting further treatment for patients. Many studies demonstrate a diverse distribution of mutations in the KRAS, NRAS, and BRAF genes in CRC. A critical literature review was conducted in order to systematize data on the mutational profile and genetic heterogeneity of these driver mutations in Russian patients with CRC. Articles were searched for in open databases. Totally 17 Russian studies and 3 English meta-analyses were analyzed for comparison with Russian data. Mutations in the KRAS, NRAS, and BRAF genes, according to Russian and international studies, are found in 40 %, 4 %, and 7 % in CRC patients, respectively. The frequency and specific localization of mutations may depend on the geographical location and nationality of the cohort. High intertumoral and intratumoral heterogeneity in CRC, especially in KRAS gene mutations, significantly influences the choice of further therapy and underscores the need for more detailed study of the mutational profile of the primary tumor, affected lymph nodes, and distant metastases. In Russia, several molecular genetic methods are used to determine somatic mutations in CRC with different sensitivity and specificity, the most common is real-time PCR. More accurate diagnostic methods include digital droplet PCR, Sanger sequencing, and next-generation sequencing, but each method has its limitations that must be considered when planning diagnostics and research. The promising directions in personalized oncology is the study of gene copy number variations, which may contribute to the development of new methods for treating CRC in the future. Despite the large number of studies, some aspects of the mutational profile of CRC in Russian studies remain poorly understood, which is why further research is needed on patients with colorectal cancer in Russia.

Abstract C102: Polyethnic-1000: Advancing cancer genomics by studying ethnically diverse, underserved patient populations in New York

Abstract Prompted by the considerable biases toward European ancestry cases in large cancer genomics repositories, the New York Genome Center initiated an effort to diversify the public datasets that are forming the foundations of current cancer research, in order to optimize the unbiased applications of modern genomically-driven discoveries to a larger population. Our effort was focused on 8 cancer types (breast, prostate, bladder, lung, pancreatic, colon and endometrial cancer, as well as multiple myeloma) and generated Illumina tumor-normal whole-genome sequencing and tumor transcriptome sequencing. The majority of the samples were retrospectively obtained in clinics and hospitals of the New York region and the analyses are conducted with collaborators in these institutions. Our dataset is currently composed of 851 tumor-normal WGS and 471 RNASeq, and is progressively being distributed to the scientific community in partnership with ICGC-ARGO. Overall, 75% of the cohort is predominantly of non-European ancestry, as estimated by genetic ancestry analysis using the 1000Genomes continental references.We analyzed the samples with NYGC’s somatic variant calling pipeline and will present results from the 8 cancer types related to germline and somatic variants (single-nucleotide variants, indels, copy-number alterations, complex structural variants) as well as mutational signatures, neoantigen prediction, fusion genes and expression profiles, in relation to genetic ancestry estimation and clinical features of the patients. We anticipate that the dataset will significantly diversify the genetic ancestry of tumor profiles in public databases, and serve to form hypotheses regarding the contribution of ancestry on cancer disparities. The experience of the Polyethnic-1000 project informs our contribution to the Cancer Grand Challenge SAMBAI, which focuses on breast, prostate and pancreatic cancers in the African Diaspora. SAMBAI will further investigate the causes of cancer disparity by combining genomic data with social determinants of health and exposomics information, deeper immune profiling and new genomics technologies such as long reads sequencing and the use of a pangenome reference. Citation Format: Nicolas Robine, Lara Winterkorn, Tim Chu, Zoe Goldstein, Will Hooper, Ali Oku, Heather M. Geiger, Melissa B. Davis, Onyinye Balogun. Polyethnic-1000: Advancing cancer genomics by studying ethnically diverse, underserved patient populations in New York [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C102.

Demographic Trends, Co-Alterations, and Imatinib Resistance across Genomic Variants in Gastrointestinal Stromal Tumors: An AACR Project GENIE Analysis

Introduction: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal tract, the treatment of which represents a significant breakthrough in targeted cancer therapy. Given its overall rare nature, genomic differences and clinical implications between demographic groups have not been previously investigated. Methods: Anonymized demographic, clinical, and genomic data from 1,559 GIST patients in the American Association for Cancer Research Project GENIE database were analyzed using cBioPortal and custom Python scripts. Data on patient demographics, genomic alterations, and co-occurrence genetic alerations were collected and classified according to clinical implications using the OncoKB database. χ2 tests for differences in genomic alterations were used across various demographic factors and mutual exclusivity analysis was employed to identify co-mutation patterns. Results: Male patients demonstrated higher incidence of PDGFRA mutation (14.56% vs. 8.05%; p < 0.001), while female patients had higher likelihood of NF1 mutations (7.46% vs. 3.23%; p = 0.001). Asian patients had higher alteration rates at KIT (85.59%; p = 0.002). Co-occurrence analysis revealed KIT alterations frequently co-occurred with CDKN2A (q < 0.001), MTAP (q = 0.045), and PTEN (q = 0.056), while there was mutual exclusivity with PDGFRA (q < 0.001), NF1 (q < 0.001), and BRAF (q = 0.015). CDKN2A alterations co-occurred with MTAP (q < 0.001) and PIK3CA (q = 0.015), while being mutually exclusive with TP53 (q = 0.002) and NF1 (q = 0.007). Trends were similar among patients who had received no prior medical treatment. Imatinib-resistant mutations were more common among male patients (25.6% vs. 18.9%; p = 0.0056) and individuals under 55 (27.3% vs. 20.9%; p = 0.0228). Among patients with imatinib-resistant mutations, 77.78% had sunitinib resistance, while 70.25% maintained sensitivity to ripretinib. Conclusion: Sex and race/ethnic differences in genomic alterations, as well as co-mutations, were prevalent among patients with GIST. Variations in mutational profiles highlight the importance of distinct genetic drivers that may be targeted to treat different patient populations.

Abstract C171: Identifying cancer driver mutation signatures in lung adenocarcinoma from Black/African American individuals: Addressing cancer health disparities

Abstract Lung cancer remains the leading cause of cancer-related mortality globally and continues to contribute significantly to cancer health disparities. Black/African American (B/AA) men exhibit a higher risk of lung cancer compared to White men; B/AA individuals also exhibit lower 5-year survival and stage-specific survival rates than White subjects. Biological factors, including genetic differences in cancer driver mutation, may influence this disparity. Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer across all ethnic groups, including B/AA individuals. Our study aims to characterize the main driver and co-mutation signatures of LUAD in B/AA individuals, who are significantly underrepresented in current mutational studies. We hypothesize that B/AA individuals will have a unique repertoire of cancer driver genes, which could contribute to genetic differences and response to targeted therapies compared to LUAD of White subjects. We are obtaining 100 de-identified archival formalin-fixed, paraffin-embedded (FFPE) LUAD samples from B/AA subjects from cancer registries in Florida and California. Extraction of DNA from the FFPE samples is in progress, and samples have been sent for whole exome sequencing (WES) and ancestry determination. This data will then be analyzed and compared with known LUAD mutation profiles from other ethnicities. Identification of cancer driver mutations will then inform the development of in vitro models for therapeutic testing. To date, the limited information on cancer driver genes in LUAD from B/AA subjects suggests that KRAS is the most common cancer driver gene, just like in LUAD from White subjects, and is found in ∼34% of cases. Therefore, we anticipate identifying KRAS mutations similar to this proportion based on the collection of previously published literature analyses. One key goal of this study is to obtain more information about the exact spectrum of KRAS mutations in LUAD from B/AA subjects. In addition, our work may unveil new variants of known cancer driver mutations such as KRAS, EGFR, BRAF, etc., and finally, “new” driver genes. Our efforts will address critical gaps in the understanding of lung cancer driver genes, a key step to developing personalized treatment of lung cancer and mitigating cancer health disparities between B/AA and White individuals. Supported by grants U54CA233396, U54CA233444, and U54CA233465 from the National Institutes of Health (NIH)/National Cancer Institute (NCI), the Norris Comprehensive Cancer Center core grant, award number P30CA014089 from the NIH/NCI, and by the Undergraduate Research Associates Program supported by the USC Provost. Citation Format: Davin Pan, Daniel J. Mullen, Colton Stensrud, Jose Aparicio, Christina M. Gobin, Sofia Lugo, Kweku Ofosu-Asante, Justin K. Mensah-Mamfo, Kyle R Phillips, Yong Huang, Nazarius S. Lamango, William D Wallace, Suhn K Rhie, Kristinanna M. Fredenburg, Ite A. Offringa. Identifying cancer driver mutation signatures in lung adenocarcinoma from Black/African American individuals: Addressing cancer health disparities [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C171.

Abstract C085: Somatic mutational profiles of breast tumors from Hispanic/Latino women

Abstract Background: Breast cancer is the leading cause of cancer mortality among Hispanic/Latina (H/L) women. Precision medicine holds promise for more effective treatments by targeting therapies based on somatic mutations, copy number changes, mutational signatures, and/or germline risk variants. However, there is a paucity of genomics data for H/L women with breast cancer leading to a disparity in the application of precision medicine. We have previously characterized mutational profiles of 146 breast tumors from 140 H/L women. Here, we analyze data from whole exome tumor/normal sequencing and tumor RNA sequencing from 430 self-reported H/L breast cancer cases and compare their profiles to 385 tumors from self-reported White breast cancer cases. Methods: All participants were treated at City of Hope and all sequencing data were generated using Ashion GEM ExTra (Exact Sciences). Tumor/germline sequence data were aligned to the human genome (Build37) and variants were called using the FreeBayes workflow. To determine significantly mutated genes, we used MutSigCV and dNdS. We used Fisher’s exact test to determine if the frequency of somatic mutations was significantly different among H/L women and White women and corrected for multiple hypothesis testing using Benjamini-Hochberg false discovery rate (FDR). Results: Seventeen genes and 19 genes had q-values &amp;lt; 0.05 in H/L and White samples, respectively. Of those, AKT1, CBFB, FOXA1, MAP2K4, MAP3K1, MLL3, PIK3CA, PTEN, RB1, RUNX1, TBX3, TP53, and ZFPM1 were significantly mutated in both. CTCF and HS6ST1 were significantly mutated only in tumors from H/L. ARID1A, CDKN1B, NCOR1, and PRRT2 were significantly mutated only in tumors from White women. There was a significantly higher frequency of TP53 mutations (FDR q-value = 0.007) and CTCF mutations (FDR q-value = 0.057) in tumors from H/L compared to tumors from Whites. Conclusions: We found TP53 and CTCF to be more commonly mutated in tumors from H/L women. CTCF mutations are seen in other tumor types, but our study is the first to demonstrate that this gene is significantly mutated in breast cancer in any population. Since CTCF is a broadly active transcriptional regulator, tumors with these mutations may be associated with broad dysregulation of gene expression. Citation Format: Yuan Chun Ding, Shu Tao, Allen Mao, Elad Ziv, Susan L. Neuhausen. Somatic mutational profiles of breast tumors from Hispanic/Latino women [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C085.

Abstract C010: Integrating germline and somatic data to resolve variants of uncertain significance (VUS) in colorectal cancer (CRC) patients who self-identified as Hispanic/Latino

Abstract Germline and somatic genetic testing have become cornerstones for assessing patient risk and tailoring cancer treatment, respectively, relying on the ability to distinguish pathogenic from benign variants. Typically, clinical reporting from these tests is conducted independently, serving distinct clinical objectives and audiences. However, integrating the underlying genomic data from both germline and somatic tests can enhance interpretative clarity, particularly in resolving variants of unknown significance (VUS) that lack sufficient evidence to determine pathogenicity. This ambiguity is especially problematic for non-White populations and those of non-European ancestry, where VUSs are disproportionately found, thereby limiting the scope of precision medicine and perpetuating health disparities. To assess the potential utility of an integrated model, we examined a prospective cohort of 88 self-identified Hispanic patients with colorectal cancer (CRC), performing both germline and somatic genomic analyses. We found that at least one germline VUS was identified in 44% (39/88) of participants, compared to a frequently reported rate of below 15%. By integrating tumor transcriptome data, mutational signatures, and copy number variations with traditional germline testing, we aimed to clarify VUSs and identify driver mutations. Integrating data modalities of the tumor transcriptome, mutational signatures, and copy number variations alongside traditional germline testing can help clarify VUSs and identify driver mutations. We constructed a model whereby the assessment of VUSs was based on the putative functional impact on either the DNA mutational patterns or allelic expression observed in tumor RNA. Using our integrated model, we deemed the oncogene AXIN2 VUS of one participant was likely biologically significant due to mutant-allele specific expression observed in the tumor RNA. Furthermore, we showed that 26% (10/39) of participants harbored a VUS that was very likely benign based on the tumor mutational profile and RNA expression. These included variants associated with homologous recombination in PALB2 and BRCA2 as well as genes associated with DNA repair like MLH1, PMS2, POLE and POLD1. Among patients with VUSs in genes associated with homologous recombination deficiency (HRD), none exhibited HRD via copy number analyses. Conversely, of the six patients that did exhibit HRD, only one had a pathogenic variant in a gene associated with HRD (ATM). Additionally, we identified tumors with a DNA mismatch repair deficiency phenotype (high tumor mutational burden, high microsatellite instability, DNA mismatch repair deficiency mutational signature) but without a pathogenic variant in a Lynch syndrome-associated gene. Methylation analysis revealed hypermethylation of the MLH1 promoter in these cases, explaining the tumor phenotype. This finding indicates that our integrative method can accurately predict DNA mismatch repair deficiency even without a genetic alteration in a DNA mismatch repair gene. Citation Format: Jonathan Amzaleg, Julie O. Culve, Charité N. Ricker, Natalia Gutierrez, Yuxin Jin, Brigette Waldrup, Carmen Chaves, Lucia Enriquez, Joel Sanchez-Mendez, Daisy Hernandez, Bodour Salhia, Lourdes Baezconde-Garbanati, Mariana C. Stern, Enrique Velazquez Villarreal, John D. Carpten, Heinz-Joseph Lenz, David W. Craig. Integrating germline and somatic data to resolve variants of uncertain significance (VUS) in colorectal cancer (CRC) patients who self-identified as Hispanic/Latino [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C010.

Abstract C083: Meta-analysis reveals differences in somatic alterations by genetic ancestry across common cancers

Abstract Genetic similarity of populations (or genetic ancestry) contributes to cancer driving alterations. We performed a meta-analysis leveraging two real-world cohorts of targeted gene panel sequencing, comprising 275,605 tumor samples, to investigate ancestry-associated somatic alterations across 14 common cancers. We focused on five continental ancestries – European (EUR), African (AFR), East Asian (EAS), South Asian (SAS), and admixed American (AMR). Genetic ancestry was inferred using single nucleotide polymorphism markers from captured regions of gene panel sequencing in each cohort. The combined cohort from Memorial Sloan Kettering – Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) and Foundation Medicine (FMI) contains a substantial number (45,131) of non-EUR samples. Within each cohort, we performed multivariate logistic regression to test association of each cancer gene alteration with proportion of genetic ancestry as a continuous variable, controlling for relevant covariates (age, sex, gene panel version, and histological subtypes) for every combination of ancestry and cancer type. Our analysis focused on oncogenic or likely oncogenic alterations spanning mutations, copy number alterations, and structural rearrangements for each gene. We then aggregated the logistic regression results from the two cohorts using a fixed effects model of meta-analysis weighted by cohort sample size. We found 444 significant associations involving 116 unique genes with consistent logistic regression coefficients between cohorts and False Discovery Rate (FDR)-adjusted p-value &amp;lt; 0.1. These genes were involved in cancer-specific and cross-cancer associations. TP53, KRAS, and TERT were the top three recurrent ancestry-associated genes respectively. TERT promoter mutations were depleted in patients of AFR or EAS ancestry, but enriched in EUR ancestry in bladder urothelial carcinoma, glioblastoma, cutaneous melanoma, and hepatocellular carcinoma. Additionally, TP53 mutations were enriched in AFR and EAS ancestry across multiple cancers, consistent with previous reports, but depleted in prostate cancer in both AFR and EAS ancestries. Among the novel cancer-specific associations with FDA-approved targeted therapies, we found that CDK12 mutations in prostate adenocarcinoma were enriched in EAS ancestry while ERBB2 mutations in lung adenocarcinoma were enriched in AMR ancestry. We also found novel potential drug targets/biomarkers associated with AFR ancestry, such as enrichment of BAP1 mutations in head and neck squamous cell carcinoma and depletion of FGFR2 mutations in uterine endometrioid carcinoma. Overall, our work identified ancestry-associated somatic alteration differences of cancer genes in a combined cohort with a large number of non-European samples. This work underscores the value of studying under-represented populations to replicate or reveal new potential targets for precision oncology. Citation Format: Setor Amuzu, Amy Xie, Xuechun Bai, Kelly R. Pekala, David Ma, Tomin Perea-Chamblee, Kanika Aurora, Garrett Frampton, Michael Berger, Nikolaus Schultz, Justin Y. Newberg, Jian Carrot-Zhang. Meta-analysis reveals differences in somatic alterations by genetic ancestry across common cancers [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C083.

Intraparenchymal low-grade B-cell lymphomas of the central nervous system: Clinicopathologic and molecular analysis of three cases and a review of the literature

Primary central nervous system (CNS) lymphomas represent 1 % of all non-Hodgkin lymphomas, with diffuse large B-cell lymphomas as the prevailing subtype. Low-grade B-cell lymphomas are exceptional with only 24 marginal zone B-cell lymphomas (EMZL) and 1 follicular lymphoma (FL) previously reported so far. While their molecular profiles are studied elsewhere, data on primary intraparenchymal CNS cases remain limited. The objective of the present study is to contribute new cases of primary intraprenchymal low-grade B-cell lymphomas in the CNS and characterize their mutational profile. We conducted a comprehensive review of cases and a literature review to identify similar instances. Clinical, imaging, histological, immunohistochemical, and molecular characteristics were analyzed. Diagnoses were established according to established criteria. We present three novel cases of intraparenchymal CNS low-grade B-cell lymphomas. One case of intraparenchymal EMZL exhibited plasmacytic differentiation, while another lacked a plasma cell component. The third case was diagnosed as FL. The L265P mutation of MYD88 was absent in all cases. Next generation sequencing revealed pathogenic mutations in SPEN (Glu1970ValfsTer64) and ARID1A (Pro1355LeufsTer118) genes in one EMZL case. In conclusion, intraparenchymal CNS low-grade B-cell lymphomas are rare, with few reported cases. Our findings expand knowledge on their clinical and molecular features. We present the first molecular profile of primary CNS intraparenchymal EMZL, underscoring the need for further research to understand their biology and optimize treatment strategies.

Customised design of antisense oligonucleotides targeting EGFR driver mutants for personalised treatment of non-small cell lung cancer

Tyrosine kinase inhibitors (TKIs) are currently the standard therapy for patients with non-small cell lung cancer (NSCLC) bearing mutations in epidermal growth factor receptor (EGFR). Unfortunately, drug-acquired resistance is inevitable due to the emergence of new mutations in EGFR. Moreover, the TKI treatment is associated with severe toxicities due to the unspecific inhibition of wild-type (WT) EGFR. Thus, treatment that is customised to an individual's genetic alterations in EGFR may offer greater therapeutic benefits for patients with NSCLC. In this study, we demonstrate a new therapeutic strategy utilising customised antisense oligonucleotides (ASOs) to selectively target activating mutations in the EGFR gene in an individualised manner that can overcome drug-resistant mutations. We use extracellular vesicles (EVs) as a vehicle to deliver ASOs to NSCLC cells. Specifically guided by the mutational profile identified in NSCLC patients, we have successfully developed ASOs that selectively inhibit point mutations in the EGFR gene, including L858R and T790M, while sparing the WT EGFR. Delivery of the EGFR-targeting ASOs by EVs significantly reduced tumour growth in xenograft models of EGFR-L858R/T790M-driven NSCLC. Importantly, we have also shown that EGFR-targeting ASOs exhibit more potent anti-cancer effect than TKIs in NSCLC with EGFR mutations, effectively suppressing a patient-derived TKI-resistant NSCLC tumour. Overall, by harnessing the specificity and efficacy of ASOs, we present an effective and adaptable therapeutic platform for NSCLC treatment. This study was funded by Singapore's Ministry of Health (NMRC/OFIRG/MOH-000643-00, OFIRG21nov-0068, NMRC/OFLCG/002-2018, OFYIRG22jul-0034), National Research Foundation (NRF-NRFI08-2022, NRF-CRP22-2019-0003, NRF-CRP23-2019-0004), A∗STAR, and Ministry of Education.