Somatic Driver Mutations Research Articles

Large-scale multi-omic analysis identifies noncoding somatic driver mutations and nominates ZFP36L2 as a driver gene for pancreatic ductal adenocarcinoma.

Identification of somatic driver mutations in the noncoding genome remains challenging. To comprehensively characterize noncoding driver mutations for pancreatic ductal adenocarcinoma (PDAC), we first created genome-scale maps of accessible chromatin regions (ACRs) and histone modification marks (HMMs) in pancreatic cell lines and purified pancreatic acinar and duct cells. Integration with whole-genome mutation calls from 506 PDACs revealed 314 ACRs/HMMs significantly enriched with 3,614 noncoding somatic mutations (NCSMs). Functional assessment using massively parallel reporter assays (MPRA) identified 178 NCSMs impacting reporter activity (19.45% of those tested). Focused luciferase validation confirmed negative effects on gene regulatory activity for NCSMs near CDKN2A and ZFP36L2 . For the latter, CRISPR interference (CRISPRi) further identified ZFP36L2 as a target gene (16.0 - 24.0% reduced expression, P = 0.023-0.0047) with disrupted KLF9 binding likely mediating the effect. Our integrative approach provides a catalog of potentially functional noncoding driver mutations and nominates ZFP36L2 as a PDAC driver gene.

Genomic profiles and clinical presentation of chordoma

Chordoma is a rare bone cancer with variable clinical outcomes. Here, we recruited 184 sporadic chordoma patients from the US and Canada and collected their clinical and treatment data. The average age at diagnosis was 45.5 years (Range 5–78) and the chordoma site distribution was 49.2% clivus, 26.2% spinal, and 24.0% sacral. Most patients (97.5%) received surgery as the primary treatment, among whom 85.3% also received additional treatment. Except for the most prevalent cancers like prostate, lung, breast, and skin cancer, there was no discernible enrichment for any specific cancer type among patients or their family members. Among a subset of patients (N = 70) with tumor materials, we conducted omics analyses and obtained targeted panel sequencing and SNP array genotyping data for 51 and 49 patients, respectively. The most recurrent somatic driver mutations included PIK3CA (12%), followed by chromatin remodeling genes PBRM1 and SETD2. Amplification of the 6q27 region, containing the chordoma susceptibility gene TBXT, was detected in eight patients (16.3%). Clival patients appeared to be less likely to carry driver gene mutations, chromosome arm level deletion events (e.g., 5p, 5p, and 9p), or 6q27 amplification compared to sacral patients. After adjusting for age, sex, tumor site, and additional treatment, patients with somatic deletions of 14q (OR = 13.73, 95% CI 1.96–96.02, P = 0.008) and 18p (OR = 13.68, 95% CI 1.77–105.89, P = 0.012) were more likely to have persistent chordoma. The study highlights genomic heterogeneity in chordoma, potentially linked to location and clinical progression.

Genetic landscape of colorectal cancer (CRC) across genetic ancestries: Implications for early cancer detection (ECD).

e15527 Background: Blood-based ECD has the potential to reduce mortality rates by improving strategies for adoption of and adherence to screening. As health disparities in the incidence of CRC across minority populations are known to exist, we evaluated the genomic landscape in patients with CRC across genetic ancestries. Methods: De-identified patients (N = 16,337) with stage I-IV CRC had personalized, tumor-informed commercial ctDNA testing (SignateraTM) based on whole exome sequencing. Genetic ancestry determined via supervised local ancestry inference (pmid36042219) included African (AFR, n = 1697), Ashkenazi Jewish (ASJ, n = 1192), East Asian (EAS, n = 2247), European (EUR, n = 9726), Latino (LAT, n = 1291), and South Asian (SAS, n = 184) ancestries. Somatic driver mutations and pathogenic germline variants (PVs) in CRC-associated genes were evaluated. Somatic single nucleotide variants were used for mutational signature inference. Results: Across ancestries, 47-67% of the patients were male and most were aged > 50 years. Among 35 to 50-year-olds, microsatellite instability (MSI) rates were higher in LAT (12.9%, p = 0.04) and SAS (28.3%, p < 0.001) vs EUR (8.2%). Among > 50-year-olds, MSI rates were lower in AFR (10.7%, p < 0.001), EAS (7.9%, p < 0.001), and LAT (10.4%, p < 0.001) vs EUR (16.0%). The POLE signature was more common in AFR (2%, p = 0.001) vs EUR (1.1%). There were significant differences in the frequency of driver mutations and PV rates between non-EUR vs EUR ancestry groups (Table, *p < 0.05, **p < 0.001). Gene-level enrichment was observed in MLH1 for SAS (8.7%, p < 0.001) and LAT (1.8%, p = 0.03), CHEK2 for AFR (0.4%, p = 0.03) and EAS (0.1%, p < 0.001), and PMS2 (1.4%, p = 0.006) for AFR. Among patients aged ≤50 years, similar findings were observed, with differences driven by MSI rates and germline findings in Lynch syndrome (LS) genes. Conclusions: This is the first study to investigate genomic differences between multiple ancestry groups in the largest cohort to date, including EAS, LAT, and SAS populations. The differences observed between ancestries could provide insight into differences in both hereditary risk and subsequent tumor initiation and growth. Findings from this study may provide information for developing risk stratification and prevention strategies for the early detection of cancer and provide the rationale for precision treatment based on ancestry. [Table: see text]

Phase 3 randomized double-blind study evaluating selinexor, an XPO1 inhibitor, plus ruxolitinib in JAKi-naïve myelofibrosis.

TPS6594 Background: Myelofibrosis (MF) is a myeloproliferative neoplasm with common somatic gene driver mutations in JAK2, CALR, and MPL. Selinexor, an investigational oral XPO1 inhibitor, may inhibit MF-relevant JAK/STAT and non-JAK/STAT pathways. Preclinical studies have shown potential synergy with ruxolitinib treatment. In the phase 1 portion of XPORT-MF-034 evaluating selinexor plus ruxolitinib in JAKi-naïve patients with MF, the most common AEs in the 60 mg cohort were nausea (79%), anemia (64%), thrombocytopenia (64%), and fatigue (57%). Nausea was predominantly Grade 1 and transient in nature. Treatment-related AEs leading to treatment discontinuation were thrombocytopenia (n=1) and neuropathy (n=1). SVR35 and TSS50 was achieved by 79% and 58% of the 60 mg cohort intent-to-treat population at Week 24, respectively. Response rates were consistent across subgroups, including sex and regardless of ruxolitinib starting dose. These data provide strong support to further evaluate selinexor (60 mg) and ruxolitinib in patients with JAKi-naïve MF. Methods: The XPORT-MF-034 (NCT04562389) trial includes a global, Phase 3 randomized, double-blind, placebo-controlled study designed to evaluate selinexor and ruxolitinib. JAKi-naïve patients with MF will be randomized 2:1 to receive oral selinexor 60 mg or placebo once weekly (28-day cycle) and twice daily ruxolitinib. Randomization will be stratified by DIPSS risk category (int-1 vs int-2 or high-risk), spleen volume (<1800 cm3 vs >1800 cm3 by MRI/CT scan), and baseline platelet counts (100-200x109/L vs >200x109/L). Dual anti-emetics for nausea prophylaxis will be required for the first two cycles. Select eligibility criteria include ≥18 years of age, spleen volume ≥450 cm3 by MRI or CT, DIPSS intermediate-1, intermediate-2, or high-risk, active symptoms of MF (MFSAF v4.0), currently not eligible for stem cell transplantation, ECOG≤2, and platelet count ≥100 x 109/L. Select exclusion criteria include >10% blasts in peripheral blood or bone marrow; previous treatment with JAKi for MF, or previous treatment with selinexor or other XPO1 inhibitors. The co-primary study endpoints are SVR35 and TSS50 at Week 24 and will be tested hierarchically. The key secondary endpoint is anemia response at Week 24 per the IWG-MRT and ELN criteria. The XPORT-MF-034 Phase 3 trial is currently open for enrollment; a total of 306 JAKi-naïve MF patients will be enrolled and the study was initiated on June 28, 2023. Clinical trial information: NCT04562389 .

Gene-environment interactions between clonal hematopoiesis of indeterminate potential and air pollution in non-small cell lung cancer among non-smokers.

10514 Background: Small particulate matter air pollution (≤ 2.5µm diameter; PM2.5) is a recognized driver of non-small cell lung cancer (NSCLC) among non-smokers. PM2.5 recruits pro-inflammatory macrophages to the lungs, which facilitate the clonal expansion of mutated epithelial cells and eventual transformation to NSCLC. Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related condition caused by the acquisition of somatic mutations in hematopoietic stem cells. CHIP and its accompanying pro-inflammatory phenotype have been linked with various age-related diseases, including incident NSCLC; however, the mechanisms underlying this relationship are unknown. In this study, we aimed to explore the interaction between CHIP and exposure to PM2.5 in the development of incident NSCLC. Methods: This study was conducted using data from participants in the UK Biobank (n = 451,095). CHIP status was determined from peripheral blood whole exome sequencing data, and defined as the presence of a somatic driver mutation in the blood at variant allele frequency (VAF) ≥2% (PMID: 36652671). Incident NSCLC was determined from UK cancer registry data, and PM2.5 exposure was determined based on ambient regional measures from 2010. Cox proportional hazard models were used to evaluate associations between CHIP, PM2.5, and NSCLC. Proteomics data was measured using OLINK proteomics in a subset of UK Biobank participants (n = 44,625). Results: CHIP was prevalent in 3.4% of UK Biobank participants (n = 15,633; never smokers: 3.0%, n = 6,916/227,133). There were 1983 incident cases of NSCLC (never smokers: n = 307). CHIP status was associated with incident NSCLC when adjusting for smoking status (HR = 1.73, 95% CI: 1.48–2.02) and analyzing exclusively non-smokers (HR = 2.01, 95% CI: 1.34-3.00). PM2.5 levels were not associated with NSCLC in non-smokers (HR = 1.00, 95% CI: 0.89–1.12 per µg/m3 increase in PM2.5); however, there was a significant interaction between PM2.5 and CHIP (HR = 1.46, 95% CI: 1.02–2.11, pint = 0.04), suggesting that it is the interplay between the two that drives incident NSCLC risk. We found no association between PM2.5 levels and increased CHIP prevalence or CHIP VAF. PM2.5 and CHIP were also found to interact to increase systemic inflammatory markers C-reactive peptide (pint = 0.01) and IL-6 (pint = 0.002). Conclusions: PM2.5 and CHIP act as a novel gene x environment interaction pair that play a key role in NSCLC etiology among non-smokers. Rather than acting in isolation to increase risk of NSCLC, PM2.5 intensifies the relationship between CHIP and NSCLC, presumably by exacerbating systemic inflammation and the hyper-inflammatory lung microenvironment. With PM2.5 levels in the UK among the lowest in the world, we posit that the CHIP x PM2.5 interaction contributes substantially to the global burden of NSCLC in non-smokers.

Proteogenomic profiling of clonal hematopoiesis in the solid tumor microenvironment.

2567 Background: Clonal hematopoiesis (CH) is caused by somatic mutations that provide a fitness advantage in hematopoietic stem cells, contributing to inflammation and disease. CH is common in solid tumor patients, and has shown context-dependent associations with survival; however, its contribution to the tumor microenvironment (TME) remains unclear. Here, we employ proteogenomic methods to define CH-associated alterations in the TME. Methods: We tested 1,550 patients across 10 primary, treatment-naïve cancers in the Clinical Proteomic Tumor Analysis Consortium cohort. CH calls were derived from peripheral blood and tumour whole exome sequencing (WES) data, and CH was defined as the presence of a somatic driver mutation at variant allele frequency (VAF) ≥2% in blood. Overall survival (OS) analysis was conducted using Cox proportional hazard models, controlled for age, sex, tumor type, metastatic status, and smoking. Tumor bulk RNA-sequencing and mass spectrometry proteomics data were processed for differential expression and gene set enrichment analyses. Abundance of immune cell populations was estimated with CibersortX. Results: 349 CH mutations were identified in 283 patients (18.3%). CH was strongly associated with age and mutations were mostly found in the epigenetic regulators DNMT3A(37.8%, n=132) and TET2(20.6%, n=72). CH was most prevalent in ovarian cancer (30%, n=27/90) and colorectal cancer (CRC; 28.3%, n=30/106). 103 blood CH mutations were also detected in tumor WES (CHTum), with presence in the tumor associated with higher tumor immune infiltration and peripheral blood VAF ≥10%. CHTum, but not CH, was associated with worse OS (CHTum HR = 1.74 [1.13-2.69]; CH HR = 1.12 [0.83-1.50]). CHTum was also associated with a reduced likelihood of patients being classified as tumor free at follow up (OR = 0.39 [0.19-0.82]). We did not identify a pan-cancer proteogenomic signature of CH in the TME. At the tumor-specific level, we consistently observed associations between CH and its subtypes with dysregulated inflammation, with high transcriptomic-proteomic concordance. In CRC, TET2-mutant CH was associated with greater infiltration of CD4+ T cells, monocyte/macrophages, NK cells, and B cells, alongside an inflammatory response characterized by IL6/JAK/STAT3 signalling, TNF signalling via NFκB, and IL2/STAT5 signalling. Conclusions: CH is common, even prior to therapy, in solid tumor patients and the infiltration of CH-mutant immune clones into the TME is linked with poor outcomes. Beyond confounding molecular tumor diagnostics, CH in the TME also dysregulates the anti-tumor immune response, highlighting the value of a blood reference in precision oncology. The lack of a pan-cancer CH signature in the TME supports a tumor-specific influence of CH. Further study is needed for mechanistic discovery and biomarker development to realize the potential of CH in immuno-oncology and improve patient outcomes.

Genomic profiling of pleomorphic rhabdomyosarcoma reveals a genomic signature distinct from that of embryonal rhabdomyosarcoma.

Pleomorphic rhabdomyosarcoma (PRMS) is a rare and highly aggressive sarcoma, occurring mostly in the deep soft tissues of middle-aged adults and showing a variable degree of skeletal muscle differentiation. The diagnosis is challenging as pathologic features overlap with embryonal rhabdomyosarcoma (ERMS), malignant Triton tumor, and other pleomorphic sarcomas. As recurrent genetic alterations underlying PRMS have not been described to date, ancillary molecular diagnostic testing is not useful in subclassification. Herein, we perform genomic profiling of a well-characterized cohort of 14 PRMS, compared to a control group of 23 ERMS and other pleomorphic sarcomas (undifferentiated pleomorphic sarcoma and pleomorphic liposarcoma) using clinically validated DNA-targeted Next generation sequencing (NGS) panels (MSK-IMPACT). The PRMS cohort included eight males and six females, with a median age of 53 years (range 31-76 years). Despite similar tumor mutation burdens, the genomic landscape of PRMS, with a high frequency of TP53 (79%) and RB1 (43%) alterations, stood in stark contrast to ERMS, with 4% and 0%, respectively. CDKN2A deletions were more common in PRMS (43%), compared to ERMS (13%). In contrast, ERMS harbored somatic driver mutations in the RAS pathway and loss of function mutations in BCOR, which were absent in PRMS. Copy number variations in PRMS showed multiple chromosomal arm-level changes, most commonly gains of chr17p and chr22q and loss of chr6q. Notably, gain of chr8, commonly seen in ERMS (61%) was conspicuously absent in PRMS. The genomic profiles of other pleomorphic sarcomas were overall analogous to PRMS, showing shared alterations in TP53, RB1, and CDKN2A. Overall survival and progression-free survival of PRMS were significantly worse (p < 0.0005) than that of ERMS. Our findings revealed that the molecular landscape of PRMS aligns with other adult pleomorphic sarcomas and is distinct from that of ERMS. Thus, NGS assays may be applied in select challenging cases toward a refined classification. Finally, our data corroborate the inclusion of PRMS in the therapeutic bracket of pleomorphic sarcomas, given that their clinical outcomes are comparable.

Heterozygous CDKN2A Loss is Associated with Recurrence and Survival in High, But Not Low Grade Meningiomas

INTRODUCTION: Homozygous loss of CDKN2A/B is associated with more aggressive meningiomas and is now considered in the updated WHO grading criteria. The relevance of heterozygous loss (hetloss) of CDKN2A/B is less clear and the potential association of hetloss CDKN2A with aggressive meningioma phenotype remains underexplored. METHODS: Clinical and whole exome sequencing data for patients who underwent resection of sporadic meningiomas were analyzed. RESULTS: Of the 564 meningiomas included, 16 tumors harbored hetloss of CDKN2A; 7 of these were low grade (WHO grade I) and 9 high grade (grade II or III). Compared to high-grade hetloss meningiomas, low-grade ones were less likely to have an NF2 somatic driver mutation (p = 0.041) and were more common along the skull base (p = 0.005). Low-grade meningiomas with hetloss CDKN2A had more aggressive clinical characteristics compared to wild type (WT), with higher proliferative indices (p = 0.044), increased cellularity (p = 0.032) and higher copy number variations (p = 0.004) and patients were more likely to be symptomatic (p = 0.007); there was no difference in progression-free survival (PFS) (p = 0.4). High-grade hetloss CDKN2A meningiomas, however, had higher mitotic count (p = 0.014), increased chromosomal instability (p = 0.004), and higher recurrence rates (p &lt; 0.001), as well as decreased PFS (p &lt; 0.001) and overall survival (OS) (p = 0.002), compared to high-grade WT. Interestingly, these findings remained significant amongst high-grade hetloss CDKN2A meningiomas even when controlling for underlying NF2 mutation. CONCLUSIONS: Hetloss of CDKN2A is associated with more aggressive histological and genomic characteristics in both low- and high-grade meningiomas. Only high-grade meningiomas with hetloss CDKN2A, however, differ from those without the mutation in recurrence and PFS. This effect does not seem related to underlying somatic NF2 mutation. These findings may have clinical implications for high-grade meningiomas harboring heterozygous CDKN2A mutations.

Abstract 6231: Multi-omic characterisation of clear cell renal carcinoma reveals endogenous and exogenous processes related to its aetiology

Abstract Endogenous and exogenous exposures are associated with distinctive molecular marks in somatic tissues, including human tumours. Integrative multi-omic approaches could help improving the resolution to detect the molecular marks associated with disease aetiology. Here, we leveraged the overlapping molecular information of clear cell renal cell carcinomas (ccRCC) tumours from Mutographs cohort by integrating DNA methylation, transcriptome, and whole-genome sequencing-based somatic mutation data to explore and gain new insights into exposures linked to ccRCC aetiology. Our novel framework identified important sources of biological variance across ccRCC tumours that were summarized as molecular components. We inferred these molecular ccRCC components into independent datasets to further explore their relationship with molecular and epidemiological features of ccRCC, normal adjacent kidney tissues, and other cancer types. Our results revealed a major ccRCC molecular component correlating with cellular mitotic age-related features, particularly the mitotic epigenetic clock (age-adjusted epiTOC2), clock-like DNA mutational signatures (SBS1/ID1), and telomere attrition. This molecular component was overrepresented in ccRCC tumours in comparison with normal paired kidney tissues, associating with PBRM1 and SETD2 somatic cancer driver mutations, genome stability, tumor stage, grade and ccRCC patient survival, independently to chronological age. Pan-cancer analysis supported the mitotic-age effect, represented by this molecular component, in other cancer types. Another ccRCC component was associated with tobacco usage, the presence of tobacco related DNA mutational and methylation signatures, increased total mutation burden, and sex. This component was also related to the epigenetic regulation of xenobiotic metabolism-related genes (e.g., GSTP1), further suggesting a relationship with genotoxic compounds. We further identified molecular components related to the ccRCC tumour microenvironment and cell proliferation, including one component related to BAP1 cancer driver mutations, pro-inflammatory immune cells, and ccRCC patient survival. In conclusion, our study reports a novel framework to molecular characterize ccRCC tumours using an integrative multi-omic approach, providing additional insights into the molecular footprints of endogenous and exogenous exposures in ccRCC tumours, including molecular components with prognostic value for patients. Citation Format: Ricardo Cortez Cardoso Penha, Alexandra Sexton Oates, Sergey Senkin, Han La Park, Nicolas Alcala, Matthieu Foll, Karl Smith-Byrne, Paul Brennan, James Mckay. Multi-omic characterisation of clear cell renal carcinoma reveals endogenous and exogenous processes related to its aetiology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6231.

Abstract 2145: Genetic ancestry associations with pancreatic cancer mutational profiles from a diverse 9,274-patient real-world cohort

Abstract Pancreatic cancer is an aggressive malignancy associated with racial/ethnic disparities. Notably, Black patients have a higher incidence and mortality compared to their White counterparts. However, low representation of Black and Hispanic patients in cancer genomics studies hampers our understanding of genomic factors contributing to differential outcomes. Furthermore, comparisons between racial groups fail to capture differences in genomic ancestry. We studied the associations between genetic ancestry and race/ethnicity categories with mutational profiles, using a large, diverse real-world pancreatic cancer cohort. We analyzed 9,274 de-identified pancreatic cancer patients (8,483 with ductal adenocarcinoma, PDAC) who underwent tumor profiling with the Tempus xT 648-gene assay. We used 654 ancestry-informative markers to estimate continental ancestry for five regions: Africa (AFR), Americas (AMR), East Asia (EAS), Europe (EUR), and South Asia (SAS). We imputed Asian (ASN, n=431), Hispanic/Latino/Native American (HLN, n=593), Non-Hispanic Black (NHB, n=875) and Non-Hispanic White (NHW, n=7,309) categories from genetic ancestry using a previously published machine learning method. Associations between either race/ethnicity categories or ancestry proportions and somatic variants (copy number alterations or CNAs, small nonsynonymous, OncoKB L1/2 &amp; R1, and predicted driver somatic mutations using boostDM) were assessed for 172 pancreatic cancer-related genes or gene sets using logistic regression models. Models with and without race/ethnicity or ancestry terms were compared with likelihood ratio (LR) tests, and p-values were adjusted to control the FDR at 5%. We tested for associations of race/ethnicity groups with TMB using a Kruskal-Wallis rank sum test. Tests of TMB and small variants used only patients with available matched normal tissue to avoid artifacts from misclassification of germline variants. Among pancreatic cancer patients, having either a CNA or small nonsynonymous mutation in a receptor tyrosine kinase (RTK) gene (ERBB2, EGFR, MET, FGFR1) was associated with genetic ancestry (LR adjusted p=0.027). Specifically, AMR ancestry was positively associated (OR=1.08 per doubling of ancestry proportion, p=0.004) and EUR negatively associated (OR=0.93, p=0.002). Associations in PDAC were similar but not significant. Race/ethnicity was associated with RTK changes in both groups, with ASN and HLN having more mutations than NHW, but the associations were not significant after correcting for multiple hypotheses. There was no association of race/ethnicity and TMB .Somatic changes in RTK genes were associated with AMR genetic ancestry; however, despite the relatively large cohort size, these results are modest, suggesting there is not a large somatic mutation component contributing to differences in pancreatic cancer outcomes by ancestry. Citation Format: Brooke Rhead, Vignesh Vudatha, Yannick Pouliot, Edward Williamns, Andrea N. Riner, Francisco M. De La Vega, Jose Trevino. Genetic ancestry associations with pancreatic cancer mutational profiles from a diverse 9,274-patient real-world cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2145.

Abstract 2147: Genetic ancestry associations with prostate adenocarcinoma mutational profiles: New Insights from a diverse 5,959-patient real-world cohort

Abstract In prostate cancer, Black men face higher incidence rates, more advanced diagnoses and worse outcomes than White men. These disparities partially stem from environmental, socioeconomic, and healthcare access factors. Recent data highlight racial differences in prostate cancer molecular profiles, with tumors from Black men showing increased SPOP and decreased PIK3CA mutations and amplified androgen receptor signaling and inflammatory pathway activations. Thus, somatic mutation patterns may also contribute to these disparities. We sought to identify associations of mutational profiles in prostate adenocarcinoma (PRAD) with genetic ancestry instead of race and ethnicity categories, analyzing a de-identified cohort of 5,959 patients who underwent the Tempus xT 648-gene NGS tumor profiling test. We used 654 ancestry-informative markers to estimate genetic ancestry by calculating similarity to reference populations for five regions: Africa (AFR), Americas (AMR), East Asia (EAS), Europe (EUR), and South Asia (SAS). Associations between genetic ancestry proportions and somatic variants were assessed for 67 PRAD-related genes using logistic regression models. Analyses included copy number alterations (CNAs), oncogenic gene fusions, small splice and non-synonymous mutations (NS), OncoKB L1/2 &amp; R1, and small missense driver somatic mutations predicted with boostDM. Likelihood ratio tests were employed to compare models with and without ancestry terms. The Benjamini-Hochberg method was utilized to adjust p-values and control the FDR at 5%. We confirmed reported associations in PRAD between AFR ancestry and SPOP NS mutations (OR=1.03 per doubling of AFR ancestry proportion, p=0.03) and decreased AFR with PIK3CA OncoKB and driver mutations (OR=0.94, p=0.02), PTEN CNAs (OR=0.95, p=0.0001), and TMPRSS2-ERG fusions (OR=0.95, p&amp;lt;0.0001). However, we also observed negative associations between AFR and AR CNAs (OR=0.95, p=0.004), EAS and PTEN CNAs (OR=0.96, p=0.01), and EAS and TMPRSS2-ERG fusions (OR=0.97, p=0.02). Additionally, a negative association was found between EAS and TP53 driver NS mutations (OR=0.96, p=0.04), while positive associations with driver mutations in FOXA1 (OR=1.06, p=0.03) and NS mutations in the PI3K/AKT/mTOR pathway genes (OR=1.04, p=0.01) were noted. Lastly, we identified novel positive associations between AMR and driver mutations in PIK3C3A (OR=1.12, p=0.0003) as well as small NS mutations or CNAs in the PI3K/AKT/mTOR pathway genes (OR=1.03, p=0.04). By analyzing a large, diverse real-world cohort and leveraging NGS-inferred genetic ancestry, our study confirms known associations between somatic alterations in PRAD cancer genes and race and ethnicity, while unveiling novel associations in understudied populations of potential significance for understanding disparities in disease outcomes. Citation Format: Brooke Rhead, Yannick Pouliot, Francisco M. De La Vega, David W. Craig, John Carpten. Genetic ancestry associations with prostate adenocarcinoma mutational profiles: New Insights from a diverse 5,959-patient real-world cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2147.

Variations in the genomic profiles and clinical behavior of meningioma by racial and ethnic group.

The influence of socioeconomic factors on racial disparities among patients with sporadic meningiomas is well established, yet other potential causative factors warrant further exploration. The authors of this study aimed to determine whether there is significant variation in the genomic profile of meningiomas among patients of different races and ethnicities and its correlation with clinical outcomes. The demographic, genomic, and clinical data of patients aged 18 years and older who had undergone surgery for sporadic meningioma between September 2008 and November 2021 were analyzed. Statistical analyses were performed to detect differences across all racial/ethnic groups, as were direct comparisons between Black and non-Black groups plus Hispanic and non-Hispanic groups. This study included 460 patients with intracranial meningioma. Hispanic patients were significantly younger at surgery (53.9 vs 60.2 years, p = 0.0006) and more likely to show symptoms. Black patients had a higher incidence of anterior skull base tumors (OR 3.2, 95% CI 1.7-6.3, p = 0.0008) and somatic hedgehog mutations (OR 5.3, 95% CI 1.6-16.6, p = 0.003). Hispanics were less likely to exhibit the aggressive genomic characteristic of chromosome 1p deletion (OR 0.28, 95% CI 0.07-1.2, p = 0.06) and displayed higher rates of TRAF7 somatic driver mutations (OR 2.96 95% CI 1.1-7.8, p = 0.036). Black patients had higher rates of recurrence (OR 2.6, 95% CI 1.3-5.2, p = 0.009) and shorter progression-free survival (PFS; HR 2.9, 95% CI 1.6-5.4, p = 0.002) despite extents of resection (EORs) similar to those of non-Black patients (p = 0.745). No significant differences in overall survival were observed among groups. Despite similar EORs, Black patients had worse clinical outcomes following meningioma resection, characterized by a higher prevalence of somatic hedgehog mutations, increased recurrence rates, and shorter PFS. Meanwhile, Hispanic patients had less aggressive meningiomas, a predisposition for TRAF7 mutations, and no difference in PFS. These findings could inform the care and treatment strategies for meningiomas, and they establish the foundation for future studies focusing on the genomic origins of these observed differences.

Thrombotic Prediction Model Based on Epigenetic Regulator Mutations in Essential Thrombocythemia Patients Using Survival Analysis in Recurrent Events.

Essential thrombocythemia (ET) involves the proliferation of megakaryocytes and platelets and is associated with an increased risk of thrombosis. We aimed to evaluate thrombotic risks in patients with epigenetic regulator mutations and generate a model to predict thrombosis in ET. This cohort study enrolled patients aged > 15 years diagnosed with ET at the Songklanakarind Hospital between January 2002 and December 2019. Twenty-five targeted gene mutations, including somatic driver mutations (JAK2, CALR, MPL), epigenetic regulator mutations (TET2, DNMT3A, IDH1, IDH2, TET2, ASXL1, EZH2, SF3B1, SRSF2) and other genes relevant to myeloid neoplasms, were identified using next-generation sequencing. Thrombotic events were confirmed based on clinical condition and imaging findings, and thrombotic risks were analyzed using five survival models with the recurrent event method. Ninety-six patients were enrolled with a median follow-up of 6.91 years. Of these, 15 patients experienced 17 arterial thrombotic events in total. Patients with JAK2 mutation and IDH1 mutation had the highest frequency of thrombotic events with somatic driver mutations (17.3%) and epigenetic regulator mutations (100%). The 10-year thrombosis-free survival rate was 81.3% (95% confidence interval: 72.0-91.8%). IDH1 mutation was a significant factor for thrombotic risk in the multivariate analysis for all models. The Prentice, William, and Peterson (PWP) gap-time model was the most appropriate prediction model. The PWP gap-time model was a good predictive model for thrombotic risk in patients with ET. IDH1 mutation was significant risk factors for thrombosis; however, further studies with a larger sample size should confirm this and provide more insight.

Pediatric Tumors as Disorders of Development: The Case for In Vitro Modeling Based on Human Stem Cells.

Despite improvements in patient outcomes, pediatric cancer remains a leading cause of non-accidental death in children. Recent genetic analysis of patients with pediatric cancers indicates an important role for both germline genetic predisposition and cancer-specific somatic driver mutations. Increasingly, evidence demonstrates that the developmental timepoint at which the cancer cell-of-origin transforms is critical to tumor identity and therapeutic response. Therefore, future therapeutic development would be bolstered by the use of disease models that faithfully recapitulate the genetic context, cell-of-origin, and developmental window of vulnerability in pediatric cancers. Human stem cells have the potential to incorporate all of these characteristics into a pediatric cancer model, while serving as a platform for rapid genetic and pharmacological testing. In this review, we describe how human stem cells have been used to model pediatric cancers and how these models compare to other pediatric cancer model modalities.

Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are chronic cancers characterized by overproduction of mature blood cells. Their causative somatic mutations, for example, JAK2V617F, are common in the population, yet only a minority of carriers develop MPN. Here we show that the inherited polygenic loci that underlie common hematological traits influence JAK2V617F clonal expansion. We identify polygenic risk scores (PGSs) for monocyte count and plateletcrit as new risk factors for JAK2V617F positivity. PGSs for several hematological traits influenced the risk of different MPN subtypes, with low PGSs for two platelet traits also showing protective effects in JAK2V617F carriers, making them two to three times less likely to have essential thrombocythemia than carriers with high PGSs. We observed that extreme hematological PGSs may contribute to an MPN diagnosis in the absence of somatic driver mutations. Our study showcases how polygenic backgrounds underlying common hematological traits influence both clonal selection on somatic mutations and the subsequent phenotype of cancer.

Hepatoid adenocarcinoma in ureter with next-generation sequencing: A case report and literature review

BackgroundHepatoid adenocarcinoma (HAC) is rare in the urinary system, with only 7 reported cases in upper urinary tract. This report aimed to explore the genetic characteristics of ureteral HAC for first time, and to describe the treatment prognosis of ureteral HAC.Case presentationWe present a rare case of ureteral HAC in a 53-year-old female, showing elevated serum levels of AFP and CEA, prolonged chronic irritation may be an important cause of her ureteral HAC. Radical nephroureterectomy was performed, the serum levels of AFP and CEA decreased significantly, and metastasis in lymph nodes was found at 9 months after surgery, she had no related symptoms after 18 months postoperatively without adjuvant chemotherapy. Three driver somatic mutations in cancer were identified by NGS testing, including: TP53D281H, KMT2DL1211Ifs*2, KMT2DT1843Nfs*5, demonstrating that ureteral HAC has the similar mutational features to upper tract urothelial carcinoma. Homologous-recombination deficiency (HRD) was positive in this tumor with no mutations in HRD-related genes, which was possibly induced by the copy number deletion of SETD2 gene.ConclusionsWe report a rare case of ureteral HAC with elevated serum levels of AFP and CEA. NGS testing demonstrated that ureteral HAC has the similar mutational features to upper tract urothelial carcinoma, which is an important guide for the diagnosis and treatment of ureteral HAC.

A Novel Germline Mutation of BRCA1 and Integrated Analysis With Somatic Mutation in a Chinese Multi-Cancer Family.

The presence of mutations in the BRCA1 gene (MIM: 113705) is widely recognized as a significant genetic predisposition for ovarian cancer. This study investigated the genomic mutations in a Chinese family with a history of ovarian, breast, and rectal adenocarcinoma. A novel germline mutation (Phe1695Val) in BRCA1 was identified through whole-exome sequencing. Subsequently, we performed whole-genome sequencing to identify somatic mutations and analyze mutational signatures in individuals carrying the novel germline mutation. Our findings revealed a correlation between somatic mutational signatures and the BRCA1 germline mutation in the proband with ovarian cancer, while no such association was observed in the tumor tissue from the patient with breast cancer. Furthermore, distinct somatic driver mutations were identified, a truncated mutation in the TP53 gene in the ovarian tumor tissue, and a hotspot mutation in the PIK3CA gene in the breast cancer. According to our findings, the BRCA1 F1695V mutation is linked to ovarian cancer susceptibility in the family and causes specific somatic mutational profiles.

Clinicogenomic associations in patients with Langerhans cell histiocytosis: a cohort study

This article presents an analysis of genotype and phenotype correlations in a pediatric cohort with Langerhans cell histiocytosis (LCH). Approximately 60% of LCH patients carry BRAF V600E somatic point mutation. Numerous studies have demonstrated that the presence of this mutation is associated with a more severe course of the disease and a higher risk of relapse. Apart from BRAF V600E mutation, other mutations in genes involved in the RAS/RAF/MEK/ERK signaling pathway have been identified in LCH. Next generation sequencing of DNA with high coverage of target regions is considered an optimal approach to detect somatic mutations other than BRAF V600E. The identification of somatic driver mutations holds great potential for enhancing our understanding of the phenotypic heterogeneity of LCH and developing targeted therapeutic strategies. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology.

Abstract C119: Somatic and germline heterogeneity across colorectal cancer patient characteristics: Implications for early cancer detection

Abstract A deeper understanding of germline and somatic genomic landscapes across a broad population is critical to optimal performance of early cancer detection assays for all patients. Here, we investigated germline and somatic landscapes in patients with colorectal cancer (CRC). A total of 2,303 de-identified patients with stage I-IV CRC who had commercial, personalized, tumor-informed ctDNA testing (SignateraTM) ordered were included. Ancestry was inferred based on DNA extracted from blood samples using Principal Component Analysis and assigned to African (AFR), East Asian (EAS), European (EUR) and Southeast Asian (not included in ancestry-specific analyses because of sample size). Proportions of patients with somatic driver mutations and pathogenic germline variants (PGVs) in CRC-associated genes were calculated overall and across patient characteristics including age of disease onset (&amp;lt;45 years: 15.8%, 45-65 years: 49.5%, &amp;lt;65 years: 34.7%), sex (female, 47.3%), disease stage (I: 5.8%, II: 29.8%, III: 41.1%, IV: 18.0%), microsatellite stability vs instability (MSS: 83.8%, MSI: 16.2%). Among all patients, the most common somatic driver mutations were in APC (75.5%), TP53 (65.3%), TTN (48.6%), and KRAS (41.9%). PGVs were observed in 7.6% of patients (high-penetrance 4.3%, moderate-penetrance 0%, low-penetrance 2.7%, uncertain-penetrance 0.6%). Lynch syndrome (LS) genes were responsible for most high-penetrance findings (78.8%). PGV rates decreased with older age (&amp;lt;45 years: 13.2%, 45-65 years: 8.1%, &amp;gt;65 years: 5.1%) and was higher in patients with MSI (21.5%) compared to MSS (5.2%). PGV rates were similar regardless of patient sex (male, 8.2%; female, 7.5%) and CRC stage (I: 6.0%, II: 9.3%, III: 7.4%, IV: 8.0%). The genomic landscape of CRC was influenced by genetic ancestry. MSI rates were highest in EAS patients (20.6%, EUR: 16.4%, AFR: 9.9%). The most common somatic driver mutations were similar to the overall cohort: APC (AFR: 83.4%, EAS: 76.7%, EUR: 74.3%), TP53 (AFR: 68.4%, EAS: 70.4%, EUR: 64.2%), TTN (AFR: 47.8%, EAS: 48.4%, EUR: 48.9%) and KRAS (AFR: 51.4%, EAS: 35.0%, EUR: 41.2%). PGV rates were similar across ancestries (AFR: 8.3%, EAS: 7.6%, EUR: 7.6%), but high-penetrance genes were most common in EAS (6.7%) compared to AFR (5.5%) and EUR (3.7%) patients. LS genes were enriched in EAS patients compared to EUR patients (EAS 6.7%, EUR 2.8%, p&amp;lt;0.005). 80% of patients with PGVs in LS genes underwent loss of heterozygosity in the tumor. Mutational signature 1 (aging) was the most common among all cancers, regardless of germling findings. Mutational signatures 6 (mismatch repair deficiency) and 18 (8-oxoguanine-associated mutagenesis) were enriched in patients with high-penetrance PGVs (i.e., LS genes) and low-penetrance PGVs (i.e., monoallelic MUTYH), respectively. These results demonstrate that integrated analysis of germline and somatic findings across various patient characteristics is critical for an optimal approach for developing risk stratification strategies pertaining to early cancer detection. Citation Format: Preethi Srinivasan, Boris Gutman, Sara L. Bristow, Hsin-Ta Wu, Raheleh Salari, Ryan Swenerton, Trupti Kawli, Alexey Aleshin, Matthew Rabinowitz, Bernhard Zimmermann, Breeana L. Mitchell, Johannes G. Reiter. Somatic and germline heterogeneity across colorectal cancer patient characteristics: Implications for early cancer detection [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C119.

Clinical and genomic differences in supratentorial versus infratentorial NF2 mutant meningiomas.

Mutations in NF2 are the most common somatic driver mutation in sporadic meningiomas. NF2 mutant meningiomas preferentially arise along the cerebral convexities-however, they can also be found in the posterior fossa. The authors investigated whether NF2 mutant meningiomas differ in clinical and genomic features based on their location relative to the tentorium. Clinical and whole exome sequencing (WES) data for patients who underwent resection of sporadic NF2 mutant meningiomas were reviewed and analyzed. A total of 191 NF2 mutant meningiomas were included (165 supratentorial, 26 infratentorial). Supratentorial NF2 mutant meningiomas were significantly associated with edema (64.0% vs 28.0%, p < 0.001); higher grade-i.e., WHO grade II or III (41.8% vs 3.9%, p < 0.001); elevated Ki-67 (55.0% vs 13.6%, p < 0.001); and larger volume (mean 45.5 cm3 vs 14.9 cm3, p < 0.001). Furthermore, supratentorial tumors were more likely to harbor the higher-risk feature of chromosome 1p deletion (p = 0.038) and had a larger fraction of the genome altered with loss of heterozygosity (p < 0.001). Infratentorial meningiomas were more likely to undergo subtotal resection than supratentorial tumors (37.5% vs 15.8%, p = 0.021); however, there was no significant difference in overall (p = 0.2) or progression-free (p = 0.4) survival. Supratentorial NF2 mutant meningiomas are associated with more aggressive clinical and genomic features as compared with their infratentorial counterparts. Although infratentorial tumors have higher rates of subtotal resection, there is no associated difference in survival or recurrence. These findings help to better inform surgical decision-making in the management of NF2 mutant meningiomas based on location, and may guide postoperative management of these tumors.