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Secondary pathogenic/likely pathogenic germline variants (P/LPGVs) identified on solid tumor genomic profiling (TGP) are a commonly encountered clinical issue. A proportion of oncology patients that undergo TGP will have a secondary P/LPGV identified that may not have been otherwise discovered based on clinical and family history criteria for hereditary cancer syndrome screening. The confirmation of P/LPGVs on germline sequencing has potential treatment implications for patients. The study design was a retrospective review for secondary data analysis. The inclusion criteria for this study were adult patients with solid tumor malignancy who underwent TGP and germline sequencing. The objective of this study is to evaluate the concordance rate of secondary P/LPGVs on TGP of adult patients with solid tumor malignancy at Hoag Presbyterian Hospital and Tower Health-Reading Hospital. The second and third aims are to analyze if the confirmed P/LPGVs are concordant with the patient's tumor type and to analyze the variant allele frequencies (VAFs) of the identified secondary P/LPGVs on the tumor genomic profiling. The data included 75 patients who underwent both TGP and germline sequencing, with a median age of 62.5 years. The most represented genes with P/LPGVs in the combined data included and , both with 14, and , with 9. The overall germline concordance rate for the combined population was 64.1%, with 59 out of 92 P/LPGVs identified on both germline and somatic tumor testing. The overall germline concordance rate of 64% for the combined population is in accordance with the reported literature. Possible reasons for the variability in rates could be related to reporting guidelines for secondary germline variants, which can vary by company, and differences between somatic and germline variant curation. The study of P/LPGVs in populations from community cancer centers has the potential to increase the data of underrepresented minority groups regarding this important clinical issue and help expand understanding of hereditary cancer syndrome phenotypes.

BRAF inhibitors have a 50–70% response rate in melanoma but are less effective for thyroid cancer. Differential response may be from activation or expression of downstream mitogen-activated protein kinase (MAPK) pathway genes. Retrospective analysis compared whole exome and transcriptome sequencing in melanoma and thyroid cancers from April 2019 to October 2023. The MAPK Activation Score (MPAS) was calculated using Z-score normalized/log-transformed values indicating expression across 10 MAPK-associated genes. Our tumor registry provided outcome data. BRAF V600E mutations were identified in 33 of 200 (17%) melanomas and 14 (7%) had other BRAF mutations (V600K/R). Of 49 thyroid tumor samples, BRAF V600E mutations were found in 19 (39%). RNA expression of BRAF and the 10 MAPK-associated genes were increased in melanomas with V600E compared to wild-type BRAF (p = 0.02). Conversely, BRAF V600E mutation in thyroid cancer was not associated with increased expression nor MAPK pathway activation. No significant difference in overall survival based on BRAF mutation was observed in the subset of patients where data was available. The MAPK pathway is differentially affected by the different cancers, with increased MAPK activation observed in melanoma and not in thyroid cancer. This may account in part for the observed differential response to BRAF inhibitors.

BACKGROUNDMetastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis.METHODSWe analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites.RESULTSWe included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC.CONCLUSIONWe demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.

Molecular profiling of clear cell RCC (ccRCC) tumors of clinical trial patients has identified distinct transcriptomic signatures with predictive value, yet data in non-clear cell variants (nccRCC) are lacking. We examined the transcriptional profiles of RCC tumors representing key molecular pathways, from a multi-institutional, real-world patient cohort, including ccRCC (n = 508) and centrally-reviewed nccRCC (n = 149) samples. ccRCC had increased angiogenesis signature scores compared to the heterogeneous group of nccRCC tumors (mean z-score 0.37 vs -0.99, P < 0.001), while cell cycle, fatty acid oxidation (FAO)/AMPK signaling, fatty acid synthesis (FAS)/pentose phosphate signature scores were increased in one or more nccRCC subtypes. Among both ccRCC and nccRCC tumors, T-effector scores statistically correlated with increased immune cell infiltration and were more commonly associated with immunotherapy-related markers (PD-L1+/TMB-High/MSI-High). In conclusion, this study provides evidence of differential gene transcriptional profiles among ccRCC vs nccRCC tumors, providing new insights for optimizing personalized and histology-specific therapeutic strategies for patients with advanced RCC.

Background/Objectives: Immune checkpoint inhibitors (ICIs) are frontline treatment for advanced Merkel Cell Carcinoma (MCC), regardless of viral status. Frontline ICIs provide durable benefit to only half of patients, highlighting a need for alternative therapies. In this study, the objective is to leverage whole exome sequencing (WES) and transcriptome sequencing (WTS) to distinguish genomic alterations associated with ICI response. Investigate differential genomic alterations between virus-positive (VP) and virus-negative (VN)-MCC to identify novel therapeutic targets. Methods: A total of 95 MCC cases underwent WES and WTS. Utilizing computational pipelines applied to WES, we identified viral status and tumor mutational burden (TMB). RNA-seq data was used to characterize the immune microenvironment. Results: Of 95 MCC cases, 57 (60%) were VP-MCC and 38 (40%) were VN-MCC. Median TMB was higher in VN-MCC (27.5 vs. 1 Muts/Mb). Mutations in TP53, RB1, NOTCH1, KMTD2, KMT2C, and PIK3CA were primarily found in VN-MCC. MAPK Pathway Activity Score, NK cell infiltration, and the immune checkpoint gene CD276 in VN-MCC tumors were upregulated. No overall survival (OS) difference was identified between VP and VN-MCC, even after ICIs. Conclusions: MCC oncogenesis and treatment response transcend viral status. While mutational analysis confirms previous findings, assessment of the transcriptome and tumor microenvironment suggests alternate therapeutic targets.

Background: Small bowel carcinoids are insidious tumors that are often metastatic when diagnosed. Limited mutation landscape studies of carcinoids indicate that these tumors have a relatively low mutational burden. The development of targeted therapies will depend upon the identification of mutations that drive the pathogenesis and metastasis of carcinoid tumors. Methods: Whole exome and RNA sequencing of 5 matched sets of normal tissue, primary small intestine carcinoid tumors, and liver metastases were investigated. Germline and somatic variants included: single nucleotide variants (SNVs), insertions/deletions (indels), structural variants, and copy number alterations (CNAs). The functional impact of mutations was predicted using Ensembl Variant Effect Predictor. Results: Large-scale CNAs were observed including the loss of chromosome 18 in all 5 metastases and 3/5 primary tumors. Certain somatic SNVs were metastasis-specific; including mutations in ATRX, CDKN1B, MXRA5 (leading to the activation of a cryptic splice site and loss of mRNA), SMARCA2, and the loss of UBE4B. Additional mutations in ATRX, and splice site loss of PYGL, leading to intron retention observed in primary and metastatic tumors. Conclusions: We observed novel mutations in primary/metastatic carcinoid tumor pairs, and some have been observed in other types of neuroendocrine tumors. We confirmed a previously observed loss of chromosome 18 and CDKN1B. Transcriptome sequencing added relevant information that would not have been appreciated with DNA sequencing alone. The detection of several splicing mutations on the DNA level and their consequences at the RNA level suggests that RNA splicing aberrations may be an important mechanism underlying carcinoid tumors.

Background: Reversion mutations in BRCA1/2, resulting in restoration of the open reading frame, have been identified as a mechanism of resistance to platinum-based chemotherapy or PARP inhibition. We sought to explore the incidence of BRCA1/2 reversion mutations in different tumor types. Methods: We retrospectively analyzed molecular profiling results from primary and/or metastatic tumor samples submitted by multiple institutions. The samples underwent DNA and RNA sequencing at a CLIA/CAP-certified clinical lab. Reversion mutations were called only in patients whose available clinical records showed the use of PARP inhibitors or platinum agents prior to tumor profiling. Results: Reversion mutations were identified in 75 of 247,926 samples profiled across all tumor types. Among patients carrying pathogenic or likely pathogenic BRCA1/2 mutations, reversion mutations in BRCA1/2 genes were seen in ovarian cancer (OC) (30/3424), breast cancer (BC) (27/1460), endometrial cancer (4/564), pancreatic cancer (2/340), cholangiocarcinoma (2/178), prostate cancer (5/461), cervical cancer (1/117), cancer of unknown primary (1/244), bladder cancer (1/300), malignant pleural mesothelioma (1/10), and a neuroendocrine tumor of the prostate. We identified 22 reversion mutations in BRCA1 and 8 in BRCA2 in OC. In BC, we detected 6 reversion mutations in BRCA1 and 21 in BRCA2. We compared molecular profile results of 14 high-grade serous ovarian cancers (HGSOC) with reversion mutations against 87 control HGSOC with pathogenic BRCA1/2 mutations without reversion mutations. Tumors with reversion mutations trended to have had lower ER expression (25% vs. 64%, p = 0.024, q = 0.82) and higher KDM6A mutation rate (15% vs. 0, p = 0.016, q = 0.82). Conclusions: We present one of the largest datasets reporting reversion mutations in BRCA1/2 genes across various tumor types. These reversion mutations were rare; this may be because some patients may not have had repeat profiling post-treatment. Repeat tumor profiling at times of treatment resistance can help inform therapy selection in the refractory disease setting.

Urachal cancer, a rare malignancy, generally presents in the clinical setting with advanced stages of disease. Systemic treatment with chemotherapy is generally utilized in this setting. However, there remains a paucity of data on the effectiveness of immune checkpoint inhibitors or targeted therapies for urachal cancer. We analyzed the genomic profile of urachal cancer in order to identify potentially targetable mutations and evaluate the tumor microenvironment. 42 urachal samples were retrospectively analyzed. Our results showed that TP53, GNAS and KRAS mutations were common in urachal cancer with increased prevalence of TP53 mutation in urachal cohorts without MAPK-alterations. The tumor microenvironment demonstrated increased NK cells in MAPK-altered urachal cancer. Finally, we show that urachal cancer shares genomic and transcriptomic similarity with colorectal cancer compared to bladder cancer. This study provides new insights into the molecular profiles of urachal tumor samples and possibility of association with colorectal cancer that might guide future clinical trial design.

BackgroundMerkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine cancer with rapid progression and mortality rates of 33–46%.1 The majority of MCC is caused by Merkel Cell Polyomavirus (MCPyV) with the remainder induced by UV-mediated damage.1 2 Regardless of virus positivity or tumor mutational burden (TMB), immune checkpoint inhibitors (ICIs) are first line treatment for MCC1 with half of patients not responding or developing resistance. Few options exist for those refractory to immunotherapy.3 There is a need to identify the MCC-specific factors driving resistance and to identify alternate molecular targets.Methods205 MCC tumors were analyzed using next-generation sequencing (592, NextSeq; WES, NovaSeq) and WTS (NovaSeq) (Caris Life Sciences, Phoenix, AZ). TMB was measured by totaling somatic mutations per tumor (TMB-H: >10 mutations/MB). MCPy viral (MCPyV) status was determined for 68 WES profiled cases using a cut-off of 1000 reads after concordance testing with IHC. Immune cell infiltrates were estimated by Quantiseq. Significance was determined using Chi-square and Mann-Whitney U tests and adjusted for multiple comparisons (q-value <0.05).ResultsThe majority (89.3%) of MCPyV-negative MCC tumors were TMB-high (>10 mutations/Mb), with 96.4% having mutations in TP53 and 80.8% in RB1. Other gene mutations included NOTCH1 (37%), KMT2C (28.6%), TERT (17.9%), FAT1 (14.3%), and PIK3CA (14.3%). In contrast, MCPyV-positive tumors were frequently TMB-low (100%) and rarely harbored mutations in TP53 and RB1 (10.3% and 2.6%, respectively). Immune checkpoint gene (CD80, CD86, CD274, PD1, PD1L, and CTLA4) expression was similar between MCPyV-positive and -negative tumors. Estimated NK cell infiltration was significantly higher in MCPyV-negative tumors. MCPyV-negative MCC also had significantly higher expression of a MAPK pathway activation signature (MPAS).ConclusionsMCPyV-positive and -negative MCC represent two classes of molecularly distinct tumors and can be differentiated based on their TMB and mutational profile. The significantly increased NK cell infiltration seen in MCPyV-negative MCC represents a potential therapeutic pathway with the efficacy of NK cell-stimulating agents currently under investigation in the Quilt-3.063 trial.4 MPAS up-regulation in MCPyV-negative MCC suggests that MAPK inhibitors could be used as an alternative to ICIs, which is supported by preclinical data.3 5 MCPyV-negative and -positive MCC are distinct tumor subtypes whose molecular and immune cell profiles warrant further investigation to optimize use of current ICIs and identify therapeutic targets.ReferencesPark SY, Doolittle-Amieva C, Moshiri Y, Akaike T, Parvathaneni U, Bhatia S, Zaba LC, Nghiem P. How we treat Merkel cell carcinoma: within and beyond current guidelines. Future Oncol. 2021 Apr;17(11):1363−1377.Knepper TC, Montesion M, Russell JS, Sokol ES, Frampton GM, Miller VA, Albacker LA, McLeod HL, Eroglu Z, Khushalani NI, Sondak VK, Messina JL, Schell MJ, DeCaprio JA, Tsai KY, Brohl AS. The Genomic Landscape of Merkel Cell Carcinoma and Clinicogenomic Biomarkers of Response to Immune Checkpoint Inhibitor Therapy. Clin Cancer Res. 2019 Oct 1;25(19):5961−5971.Fang B, Kannan A, Zhao S, Nguyen QH, Ejadi S, Yamamoto M, Barreto JC, Zhao H, Gao L. Inhibition of PI3K by copanlisib exerts potent antitumor effects on Merkel cell carcinoma cell lines and mouse xenografts. Sci Rep. 2020 Jun 1;10(1):8867.ImmunityBio,Inc. QUILT-3.063: A Study of N-803, haNK and Avelumab in Patients With Merkel Cell Carcinoma That Has Progressed After Checkpoint Therapy. ClinicalTrials.gov identifier: NCT03853317. Updated June 18, 2023. Accessed June 27, 2023.Temblador A, Topalis D, Andrei G, Snoeck R. Synergistic targeting of the PI3K/mTOR and MAPK/ERK pathways in Merkel cell carcinoma. Tumour Virus Res. 2022 Dec;14:200244.Ethics ApprovalThis study was conducted in accordance with guidelines of the Declaration of Helsinki, Belmont report, and U.S. Common rule utilizing retrospective, deidentified clinical data in keeping with 45 CFR 46.101(b)(4). Therefore, this study is considered Institutional Review Board (IRB) exempt and no consent was necessary from the subjects.

Melanoma brain metastases (MBM) are clinically challenging to treat and exhibit variable responses to immune checkpoint therapies. Prior research suggests that MBM exhibit poor tumor immune responses and are enriched in oxidative phosphorylation. Here, we report results from a multi-omic analysis of a large, real-world melanoma cohort. MBM exhibited lower interferon-gamma (IFNγ) scores and T cell-inflamed scores compared to primary cutaneous melanoma (PCM) or extracranial metastases (ECM), which was independent of tumor mutational burden. Among MBM, there were fewer computationally inferred immune cell infiltrates, which correlated with lower TNF and IL12B mRNA levels. Ingenuity pathway analysis (IPA) revealed suppression of inflammatory responses and dendritic cell maturation pathways. MBM also demonstrated a higher frequency of pathogenic PTEN mutations and angiogenic signaling. Oxidative phosphorylation (OXPHOS) was enriched in MBM and negatively correlated with NK cell and B cell-associated transcriptomic signatures. Modulating metabolic or angiogenic pathways in MBM may improve responses to immunotherapy in this difficult-to-treat patient subset.