Mutations In Tumor Suppressor Gene Research Articles

EPCO-27. REVEALING TUMOR HETEROGENEITY AND IMMUNE MICROENVIRONMENT IN NF-1 GLIOMA BY SINGLE-CELL GENE EXPRESSION PROFILING

Abstract Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF-1), the most common human genetic cancer predisposition syndrome. NF1 patients are prone to develop peripheral and central nervous system tumors, with glioma occurring in 15-20% of patients. The molecular profiles of glioma from patients with NF-1 have been previously explored by large scale DNA and RNA bulk analyses, providing the first comprehensive genetic landscape of NF-1 glioma. However, the intra-tumoral architecture and the microenvironment organization remained largely concealed within the global bulk profile. Here, to characterize the complexity of molecular states of both malignant and non-malignant cells, we profiled NF-1 glioma gene expression at individual cell resolution. We performed single-nuclei RNA sequencing (Nucseq) on frozen NF-1 glioma specimens, including high-grade and low-grade tumors. The functional classification of the transcriptional programs activated in the individual tumor cells identified three main molecular states that partially overlapped with the cellular subtypes of sporadic glioblastoma. Tumor cells of low-grade NF-1 glioma exhibited marked enrichment of neuronal functions, suggesting that the gliomagenesis process in the context of NF1 inactivation might be supported by specialized neuronal activities. Conversely, the proliferative state characterized high-grade NF-1 glioma, indicating that cell cycle-associated pathways are drivers of tumor progression. The single-cell deconvolution of immune microenvironment in NF-1 low grade glioma revealed infiltration of CD8+ T lymphocytes and the active crosstalk of these cells with pro-inflammatory macrophages and mature dendritic cells, supporting a possible anti-tumor cell-mediated response. The identification of divergent tumor cell states as well as the characterization of the immune infiltrates provide new insights for accurate stratification of NF-1 glioma patients and to inform personalized therapeutics.

Smooth Muscle Proliferation in Hamartomatous Polyps Mimicking Prolapse in Pediatric Patients with PTEN Hamartoma Tumor Syndrome

Abstract Introduction/Objective In the field of pediatric pathology, it is vital to find recognize cases that could be associated with cancer predisposition syndromes. PTEN hamartoma tumor syndrome (PHTS) is an inherited set of disorders caused by germline inactivating mutations of the PTEN tumor suppressor gene. In the GI tract, PHTS is associated with hamartomatous polyps that can display smooth muscle overgrowth. We therefore present a series of three cases of colonic polyps with smooth muscle overgrowth, mimicking prolapse, in pediatric patients with PTEN mutations. Methods/Case Report The first case is a 19-year-old male with PHTS who underwent colonoscopy due to hematochezia. Two pedunculated polyps were removed from the transverse and descending colon. Both polyps showed prominent smooth muscle and ganglion cells in the lamina propria. In the second case, a 9-year-old male with PHTS also underwent colonoscopy due to hematochezia. At least 20 sessile 2-4mm polyps were present in the colon. Histology showed smooth muscle proliferation and ganglion cells in the lamina propria. The third case is a 13-year-old male with undiagnosed PHTS, but a history of Chron’s disease, trichilemmoma, and plantar wart like lesions. He underwent upper and lower endoscopy for Chron’s disease assessment. Three polyps were removed from the descending colon. One was a juvenile polyp while the other two showed prominent smooth muscle proliferation and ganglion cells in the lamina propria. Results (if a Case Study enter NA) NA Conclusion Histologically, all hamartomatous polyps had smooth muscle overgrowth, confirmed by SMA immunostain, which could easily be confused with prolapse type changes such as in solitary rectal ulcer syndrome. The key in distinguishing between the two is by recognizing ganglion cells within the lamina propria, confirmed by S100 immunostain. Additional clues include identifying mucosal ganglion cells, disarray of crypt architecture, and fibromuscular proliferation as well as considering the location and number of polyps. It is vital for pathologists to recognize the differential diagnosis of polyps with smooth muscle proliferation, especially in pediatric populations where a diagnosis of cancer predisposition syndromes may not be established. Furthermore, is important to discuss pursuing PTEN genetic testing with clinical colleagues as it has immense medical implications and requires a thorough future medical following.

LBODP065 Rare Cause Of Bone Pain In MEN Syndrome

Abstract Introduction: MEN 1 syndrome is a rare disease in children and young adults, with prevalence reported as 2 per 100,000. MEN 1 caused by mutations in the MEN1 tumor suppressor gene, characterized by 2 or more MEN1 tumors: parathyroid, anterior pituitary, pancreatic islet tumors. To the best of our knowledge, osteomyelitis of the pelvis has not been reported as a complication in the literature in patients who were diagnosed with MEN1Case21 yo male from Honduras with PMHx of remote asthma presented with a common complaint of abdomen pain but found to have a rare diagnosis. He had 2 days of lower abdomen pain associated with non-bilious non bloody vomiting. Initial were significant for calcium 12.9, phosphorus 1.5 magnesium 1.8 and PTH 360. 4 mm renal stone 4 mm was detected on CT abdomen/pelvis. The initial EKG demonstrated J point elevation due to the hypercalcemia. He was admitted to the PICU for continuous telemetry monitoring due to the abnormal EKG related to electrolyte abnormalities. Hypercalcemia treatment was initiated with aggressive hydration, calcitonin administration as well as zoledronic acid administration. The patient's calcium levels improved as well as EKG. The parathyroid scan was positive for a right-sided parathyroid adenoma. He underwent right Inferior Parathyroidectomy, Intraoperative Nerve Monitoring, Cryopreservation of Parathyroid Tissue. As part of his diagnostic work-up for hyperparathyroidism, he was screened for MEN. His pituitary function was abnormal: ACTH and cortisol levels were high, his testosterone and gonadotropins were inappropriately low as well as TSH and T4. A microadenoma was present on brain MRI. No Pancreatic Neuroendocrine Neoplasia was found. The diagnosis of MEN 1 was made. Despite the improvements in his endocrinopathies, he continued to have lower abdomen pain associated with intermittent fevers. He was seen by urology and orthopedics. Initially MRI demonstrated bone erosion thought to be secondary to hypercalcemia but repeat MRI imaging of the pelvis was suspicious for phlegmon vs. developing abscess secondary to osteitis pubis. His blood cultures were positive for MSSA. He was started on antibiotics with continued clinical improvementThis patient presented with one of the most common complaints in the ED, abdomen pain and was found to have two rare and potentially fatal diagnosis which was identified and treated with a good clinical outcome Discussion: This case highlights a rare disease in the setting of osteomyelitis which could easily be missed as a manifestation of bone pain from hypercalcemia. The patient did experience fevers and malaise that was initially attributed to zoledronic acid administration. When his pain did not resolve MRI found osteomyelitis, allowing early antibiotic administration and prevention of sepsis. Presentation: No date and time listed

RF27 | LBSUN362 Germline CDKN1B Variants Type And Site Are Associated With Specific Phenotype In Multiple Endocrine Neoplasia 4

Abstract Background The latest of the multiple endocrine neoplasia (MEN) syndromes described is MEN4, caused by germline CDKN1B tumor suppressor gene mutation. The main clinical manifestations of MEN4 are primary hyperparathyroidism (PHPT), neuroendocrine tumors (NET) and pituitary adenomas (PitAd). CDKN1B codes for the nuclear protein p27, a key regulator of cell cycle. This protein is an intrinsically unstructured protein, that folds upon interacting a putative interactor. It is comprised of two major domains: a kinase inhibitory domain (CDKi) that binds to cyclins and cyclin dependent kinase (CDK), and a scatter domain. p27 acts by inhibiting complexes of cyclins and CDKs, thus preventing the transition between phases of the cell cycle. Less than sixty cases of MEN4 syndrome were described thus far, with clinical manifestations resembling in part to a late onset of MEN1. Hypothesis Specific alterations in p27 protein will result in distinct clinical phenotypes. Methodology Case report We collected published and unpublished data on all currently known patients with MEN4 worldwide, including newly identified kindreds from our clinic, and performed a thorough genotype-phenotype analysis of the various MEN4 manifestations. Whole exome sequencing was performed, revealing a germline CDKN1B frameshift variant (p.Q107fs*12), that was further verified by Sanger sequencing. A detailed literature review, including requests of unpublished clinical data from past studies was undertaken. Based on the data we performed a time-dependent risk analysis for the three main manifestations of MEN4 by various genotype-related parameters: variant type (single-nucleotide variant vs. indels) and site (variant- and domain-specific analyses). Major results Of 73 cases, 53.4% developed PHPT, 28.8% had PitAD and 19.2% - NET. PitAd developed earlier (age, 34.4±21.4 years) compared with PHPT (50.6±13.9 years) and NET (52.9±13.9 years). The risk to develop PHPT, PitA and NET in patients with MEN4 were 53.4%, 23.2% and 16.2% by age 60 years, respectively.CDKN1B variants clustered in genetic locations, or "hotspots" (i.e., codon 41 frameshift: n=13, codon 107 frameshift: n=11, c.-29-(-26)AGAG deletion: n=4). Although founder effect is relevant, this finding is in contrast to MEN1 genotype. We then performed time-dependent risk analysis for developing clinical manifestation by each gene domain alteration (either point mutation or upstream indel). We found a higher risk to develop PHPT or PitAd with variants affecting codons 94-96 (Log-rank, p values 0.014 and 0.047, respectively), and trend towards higher risk for PHPT for Scatter domain variants (p=0.09). Moreover, indels were associated Conclusions: MEN4 genotype is distinct than MEN1, by the presence of hotspots, and genotype-phenotype association. Further, the risk for PHPT is lower than MEN1, with a lower penetrance, and older age at diagnosis. Presentation: Monday, June 13, 2022 1:12 p.m. - 1:17 p.m.

The Clinical and Molecular Features in the VHL Renal Cancers; Close or Distant Relatives with Sporadic Clear Cell Renal Cell Carcinoma?

Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited cancer syndrome caused by germline mutations in the VHL tumor suppressor gene, characterized by the susceptibility to a wide array of benign and malign neoplasms, including clear-cell renal cell carcinoma. Moreover, VHL somatic inactivation is a crucial molecular event also in sporadic ccRCCs tumorigenesis. While systemic biomarkers in the VHL syndrome do not currently play a role in clinical practice, a new promising class of predictive biomarkers, microRNAs, has been increasingly studied. Lots of pan-genomic studies have deeply investigated the possible biological role of microRNAs in the development and progression of sporadic ccRCC; however, few studies have investigated the miRNA profile in VHL patients. Our review summarize all the new insights related to clinical and molecular features in VHL renal cancers, with a particular focus on the overlap with sporadic ccRCC.

WIN Symposium 2022 - Abstract Poster Presentations.

WIN Symposium 2022 - Abstract Poster Presentations.

KDM6A Loss Recruits Tumor-Associated Neutrophils and Promotes Neutrophil Extracellular Trap Formation in Pancreatic Cancer.

KDM6A loss in pancreatic cancer cells alters the immune microenvironment by increasing CXCL1 secretion and neutrophil recruitment, providing a rationale for targeting the CXCL1-CXCR2 signaling axis in tumors with low KDM6A.

Identifying tumor immunity-associated molecular features in liver hepatocellular carcinoma by multi-omics analysis.

Background: Although current immunotherapies have achieved some successes for hepatocellular carcinoma (HCC) patients, their benefits are limited for most HCC patients. Therefore, the identification of biomarkers for promoting immunotherapeutic responses in HCC is urgently needed. Methods: Using the TCGA HCC cohort, we investigated correlations of various molecular features with antitumor immune signatures (CD8+ T cell infiltration and cytolytic activity) and an immunosuppressive signature (PD-L1 expression) in HCC. These molecular features included mRNAs, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), proteins, and pathways. Results: We found that the mutations of several oncogenes and tumor suppressor genes significantly correlated with reduced antitumor immune signatures, including TTN, CTNNB1, RB1, ZFHX4, and TP53. It indicates that these genes' mutations may inhibit antitumor immune responses in HCC. Four proteins (Syk, Lck, STAT5, and Caspase-7) had significant positive expression correlations with CD8+ T cell enrichment, cytolytic activity, and PD-L1 expression in HCC. It suggests that these proteins' expression could be useful biomarkers for the response to immune checkpoint inhibitors Similiarly, we identified other types of biomarkers potentially useful for predicting the response to ICIs, including miRNAs (hsa-miR-511-5p, 150-3p, 342-3p, 181a-3p, 625-5p, 4772-3p, 155-3p, 142-5p, 142-3p, 155-5p, 625-3p, 1976, 7702), many lncRNAs, and pathways (apoptosis, cytokine-cytokine receptor interaction, Jak-STAT signaling, MAPK signaling, PI3K-AKT signaling, HIF-1 signaling, ECM receptor interaction, focal adhesion, and estrogen signaling). Further, tumor mutation burden showed no significant correlation with antitumor immunity, while tumor aneuploidy levels showed a significant negative correlation with antitumor immunity. Conclusion: The molecular features significantly associated with HCC immunity could be predictive biomarkers for immunotherapeutic responses in HCC patients. They could also be potential intervention targets for boosting antitumor immunity and immunotherapeutic responses in HCC.

Why responses to immune checkpoint inhibitors are heterogeneous in head and neck cancers: Contributions from tumor-intrinsic and host-intrinsic factors.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment including in head and neck squamous cell carcinomas (HNSCCs); however, only a fraction of HNSCC patients respond to ICI, whereas the majority fail to do so. The mechanisms underlying such variable responses remain incompletely understood. A better understanding of such mechanisms may broaden the spectrum of responding patients and enhance the rate of ICI response. HNSCCs exhibit a high level of genetic heterogeneity, manifested as mutations or amplifications of oncogenes (e.g., PIK3CA) and mutations of tumor suppressor genes (e.g., TP53). The immune tumor microenvironment (TME) of HNSCCs also varies significantly in composition and in relative abundance of distinct immune subsets such as CD8 tumor-infiltrating lymphocytes (TILs) or tumor-associated macrophages (TAMs), which represents a high degree of immunological heterogeneity. Here, we briefly discuss how heterogeneous ICI responses may be attributed to tumor-intrinsic factors, including genetic, transcriptional, and functional variations in tumor cells, and host-intrinsic factors, including cellular composition of the TME (e.g., CD8 TILs and TAMs), and host-intrinsic differences in the T cell receptor (TCR) repertoire of CD8 TILs. We also discuss the potential impact of these factors on designing strategies for personalized immunotherapy of HNSCCs.

PIK3CA mutations associated with a poor postoperative prognosis in patients with pulmonary pleomorphic carcinoma: a retrospective cohort study

BackgroundPulmonary pleomorphic carcinoma (PPC) is a rare type of non-small cell lung cancer characterized by high malignancy and a poor prognosis. PPC is associated with a high frequency of postoperative relapse, and shows resistance to chemotherapy. The high malignancy of cancers is associated with genomic instability, which is related to mutations of tumor suppressor genes, such as tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM). In addition, signaling pathways involving the oncogenes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and epidermal growth factor receptor (EGFR) are associated with resistance to chemotherapy. However, the association of PPC with these gene mutations remains unknown. We investigated the impact of TP53, ATM, PIK3CA, and EGFR mutations on the postoperative prognosis of PPC.MethodsFifty-five patients with PPC who underwent complete resection were studied. A gene mutation analysis was performed using next-generation sequencing. Postoperative overall survival of patients with gene mutations was evaluated using a multivariable Cox proportional hazards model in which the explanatory variables were the presence of each gene mutation, and the confounding factors were pathological stage and age. The robustness of the results was evaluated by a sensitivity analysis.ResultsThe frequencies of pathogenic mutations in TP53, ATM, PIK3CA, and EGFR were 47, 0, 7, and 9%, respectively. A multivariable analysis adjusted for pathological stage and age showed a significant difference for only PIK3CA mutations. The hazard ratio (HR) for overall survival in cases with pathogenic mutations of PIK3CA for wild type or non-pathogenic mutations was 4.5 (95% confidence interval [CI] 1.1–18.8). Likewise, sensitivity analyses adjusted for pathological stage and sex (HR, 7.5; 95% CI 1.7–32.4) and for age and sex (HR, 5.4; 95% CI 1.4–21.7) resulted in similar findings. Although three patients with pathogenic mutations of PIK3CA that recurred postoperatively were treated by chemotherapy or immunotherapy, they survived for less than 2 years.ConclusionsThe postoperative prognosis of PPC with PIK3CA pathogenic mutations is particularly poor. Pathogenic mutations of PIK3CA may be a postoperative prognostic marker. Inhibition of signaling pathways associated with PIK3CA mutations may also be a target for chemotherapy after relapse of PPC.

130 (PB120) - Characterization of KRAS-driven NSCLC cell lines with diverse mutational landscape and assessment of their response to MYC inhibition

Introduction: Lung cancer is the second most common cancer type both in males and females and the leading cause of cancer death worldwide. Inside lung cancer, Non-Small-Cell Lung Cancer (NSCLC) represents around 85% of the cases, where KRAS is the leading mutated oncogene (∼25%) and confers poor prognosis and a high risk of tumor recurrence. Subsets of mutant KRAS NSCLC have been described based on the presence of concurrent mutations in tumor suppressor genes (TSGs), being the most common TP53, KEAP1 and LKB1 (also called STK11).

58 (PB048) - HIF-2α inhibitor AB521 modulates erythropoietin levels in healthy volunteers following a single oral dose

Background: Hypoxia-inducible factor (HIF)-2α is a transcription factor that is an oncogenic driver in clear cell renal cell carcinoma (ccRCC). The posttranslational regulation of the HIF-2α protein is oxygen-dependent and, in hypoxic or pseudohypoxic conditions, results in the stabilization of HIF-2α and downstream transcription of tumor-inducing genes. HIF-2α inhibition has been shown to mitigate tumor growth in ccRCC cases with mutation or dysregulation of the von Hippel-Lindau tumor suppressor gene.

The convergence of tumor suppressors on the type I interferon pathway in clear cell renal cell carcinoma and its therapeutic implications.

In clear cell renal cell carcinoma (ccRCC), the von Hippel-Lindau tumor suppressor gene/hypoxia inducible factor (VHL/HIF) axis lays the groundwork for tumorigenesis and is the target of many therapeutic agents. HIF activation alone, however, is largely insufficient for kidney tumor development, and secondary mutations in PBRM1, BAP1, SETD2, KDM5C, or other tumor suppressor genes are strong enablers of tumorigenesis. Interestingly, it has been discovered that VHL loss and subsequent HIF activation results in upregulation of a negative feedback loop mediated by ISGF3, a transcription factor activated by type I interferon (IFN). Secondary mutations in the aforementioned tumor suppressor genes all partially disable this negative feedback loop to facilitate tumor growth. The convergence of several cancer genes on this pathway suggests that it plays an important role in ccRCC development and maintenance. Tumors with secondary mutations that dampen the negative feedback loop may be exquisitely sensitive to its reactivation, and pharmacological activation of ISGF3 either alone or in combination with other therapies could be an effective method to treat patients with ccRCC. In this review, we examine the relevance of the type I IFN pathway to ccRCC, synthesize our current knowledge of the ccRCC tumor suppressors in its regulation, and explore how this may impact the future treatment of patients with ccRCC.

New lead compounds identification against KRas mediated cancers through pharmacophore-based virtual screening and in vitro assays

Cancer remains the leading cause of mortality and morbidity in the world, with 19.3 million new diagnoses and 10.1 million deaths in 2020. Cancer is caused due to mutations in proto-oncogenes and tumor-suppressor genes. Genetic analyses found that Ras (Rat sarcoma) is one of the most deregulated oncogenes in human cancers. The Ras oncogene family members including NRas (Neuroblastoma ras viral oncogene homolog), HRas (Harvey rat sarcoma) and KRas are involved in different types of human cancers. The mutant KRas is considered as the most frequent oncogene implicated in the development of lung, pancreatic and colon cancers. However, there is no efficient clinical drug even though it has been identified as an oncogene for 30 years. Therefore there is an emerging need to develop potent, new anticancer drugs. In this study, computer-aided drug designing approaches as well as experimental methods were employed to find new and potential anti-cancer drugs. The pharmacophore model was developed from an already known FDA approved anti-cancer drug Bortezomib using the software MOE. The validated pharmacophore model was then used to screen the in-house and commercially available databases. The pharmacophore-based virtual screening resulted in 26 and 86 hits from in-house and commercial databases respectively. Finally, 6/13 (in-house database) and 24/64 hits (commercial databases) were selected with different scaffolds having good interactions with the significant active residues of KRasG12D protein that were predicted as potent lead compounds. Finally, the results of pharmacophore-based virtual screening were further validated by molecular dynamics simulation analysis. The 6 hits of the in-house database were further evaluated experimentally. The experimental results showed that these compounds have good anti-cancer activity which validate the protocol of our in silico studies. KRasG12D protein is a very important anti-cancer target and potent inhibitors for this target are still not available, so small lead compound inhibitors were identified to inhibit the activity of this protein by blocking the GTP-binding pocket. Communicated by Ramaswamy H. Sarma

Von Hippel-Lindau disease: insights into oxygen sensing, protein degradation, and cancer.

Germline loss-of-function mutations of the VHL tumor suppressor gene cause von Hippel–Lindau disease, which is associated with an increased risk of hemangioblastomas, clear cell renal cell carcinomas (ccRCCs), and paragangliomas. This Review describes mechanisms involving the VHL gene product in oxygen sensing, protein degradation, and tumor development and current therapeutic strategies targeting these mechanisms. The VHL gene product is the substrate recognition subunit of a ubiquitin ligase that targets the α subunit of the heterodimeric hypoxia-inducible factor (HIF) transcription factor for proteasomal degradation when oxygen is present. This oxygen dependence stems from the requirement that HIFα be prolyl-hydroxylated on one (or both) of two conserved prolyl residues by members of the EglN (also called PHD) prolyl hydroxylase family. Deregulation of HIF, and particularly HIF2, drives the growth of VHL-defective ccRCCs. Drugs that inhibit the HIF-responsive gene product VEGF are now mainstays of ccRCC treatment. An allosteric HIF2 inhibitor was recently approved for the treatment of ccRCCs arising in the setting of VHL disease and has advanced to phase III testing for sporadic ccRCCs based on promising phase I/II data. Orally available EglN inhibitors are being tested for the treatment of anemia and ischemia. Five of these agents have been approved for the treatment of anemia in the setting of chronic kidney disease in various countries around the world.

BRCA2 BRC missense variants disrupt RAD51-dependent DNA repair.

Pathogenic mutations in the BRCA2 tumor suppressor gene predispose to breast, ovarian, pancreatic, prostate, and other cancers. BRCA2 maintains genome stability through homology-directed repair (HDR) of DNA double-strand breaks (DSBs) and replication fork protection. Nonsense or frameshift mutations leading to truncation of the BRCA2 protein are typically considered pathogenic; however, missense mutations resulting in single amino acid substitutions can be challenging to functionally interpret. The majority of missense mutations in BRCA2 have been classified as Variants of Uncertain Significance (VUS) with unknown functional consequences. In this study, we identified three BRCA2 VUS located within the BRC repeat region to determine their impact on canonical HDR and fork protection functions. We provide evidence that S1221P and T1980I, which map to conserved residues in the BRC2 and BRC7 repeats, compromise the cellular response to chemotherapeutics and ionizing radiation, and display deficits in fork protection. We further demonstrate biochemically that S1221P and T1980I disrupt RAD51 binding and diminish the ability of BRCA2 to stabilize RAD51-ssDNA complexes. The third variant, T1346I, located within the spacer region between BRC2 and BRC3 repeats, is fully functional. We conclude that T1346I is a benign allele, whereas S1221P and T1980I are hypomorphic disrupting the ability of BRCA2 to fully engage and stabilize RAD51 nucleoprotein filaments. Our results underscore the importance of correctly classifying BRCA2 VUS as pathogenic variants can impact both future cancer risk and guide therapy selection during cancer treatment.

P11.58.A Case of a complex neurocutaneous syndrome characterized by extensive peripheral nerve sheath tumors and somatic ERBB2 mutation

Abstract Schwannomatosis is a rare genetic tumor predisposition syndrome characterized by the presence of multiple non-intradermal schwannomas and the definitive absence of vestibular nerve involvement. Though considered benign, the burden of tumors can cause significant morbidity in the form of motor dysfunction and refractory neuropathic pain. Treatment is focused on mitigating these symptoms, which includes resection of offending tumors when feasible and anti-angiogenesis therapy with bevacizumab. Options for targeted medical therapies are lacking. Schwannomatosis is molecularly distinct from the other neurofibromatoses and by definition lacks constitutional mutations in NF1 and NF2. Instead, constitutional mutations in SMARCB1 or LZTR1 are often the “first hit” in tumorigenesis. Activating mutations in ERBB2 (also designated HER2) have been identified as oncogenic drivers in peripheral nerve sheath tumors in patients who lack these typical constitutional tumor suppressor gene mutations. Here we report a case of extensive peripheral nerve sheath tumors in the setting of apparent somatic mosaicism of an ERBB2 mutation. A 48-year-old man with history of chronic back pain presented with diffuse enlarging soft tissues masses primarily involving the left neck and occiput. Examination revealed areas of cutaneous heterogeneous hyperpigmentation, decreased muscle bulk and dorsiflexor weakness in the bilateral lower extremities, and steppage gait. Neuroimaging showed extensive T2 hyperintense, mildly enhancing masses within the bilateral thoracic and lumbar spine neuroforamina, intercostal nerves, paraspinal musculature, and lumbosacral plexus. Tissue from two separate tumor sites was morphologically consistent with schwannoma with some features of neurofibroma. Immunohistochemistry revealed partial loss of staining for SMARCB1. Whole exome sequencing (WES) on blood and tumor tissue did not show pathogenic germline or somatic variants for NF1, NF2, SMARCB1, LZTR1, or an array of tumor predisposition syndromes. WES on tumor tissue from both sites however did reveal a somatic ERBB2 variant (p.D769Y), suggesting mosaicism. ERBB2 D769Y has previously been classified as an activating mutation that confers sensitivity to some small molecule receptor tyrosine kinase inhibitors. Patients with ERRB2-mutated peripheral nerve sheath tumors may have broader therapeutic options in the variety of available tyrosine kinase inhibitors studied in other cancers.

697P Lipid profile as a new diagnostic marker in head and neck cancer

Oral squamous cell carcinoma (OSCC) is one of the most common types of cancer and its main etiological factors are smoking, alcohol consumption and HPV infection. OSCC metabolic profile is heterogeneous and related to mutations in several tumor suppressor genes and oncogenes. Patterns have become apparent, such as increased choline metabolism, which indicates active proliferation. Phosphatidylcholine (PC) is a key component of membranes and source of signaling molecules. The project aimed to analyze the glycerophospholipid profile in OSCC patients compared with control samples using mass spectrometry and gene expression techniques to analyze blood, tissue and clinical-pathological characteristics.

EP08.02-095 Successful Treatment of EGFR Exon 19 Deletion with TP53 and ERBB2 20ins Mutation in Stage IVB NSCLC Patient with Aumolertinib

Based on BENEFIT study, EGFR sensitive mutation NSCLC patients could benefit from first-line EGFR-TKI treatment regardless of combination with tumor suppressor or driver gene mutation. However, for patients combined with both tumor suppressor and driver gene mutations, it is still an unresolved challenge for clinical practice. Herein, we reported a case happened to be this intractable situation.

Properties of cancer stem cells

Adult stem cells (ASCs) are pluripotent and make up a small percentage of healthy tissue. ASCs are essential for tissue repair, regeneration and growth. ASCs divide into identical stem cells or transiently proliferating cells. The latter cells mature after a number of divisions and become adult differentiating cells. There are different types of cells in cancerous tissue, as in normal, healthy tissue. Most cancer tissues contain three types of cells: (I) cancer stem cells (CSC); (II) cancer initiating cells; and (III) “differentiated”, non-proliferating cancer cells. In the review, the authors present experimental evidences for the presence of CSC, describe cell surface and intracellular markers of CSC. These markers allow for the appropriate identification and isolation of CSC. In addition, the possible location of these cells and theories of their formation are considered. It should be noted, that the theories of CSC originating are in fact theories of neoplasm formation. Many factors and processes may be involved in the formation of CSC. These include: (I) mutations of oncogenes or tumor suppressor genes in spoczynadult differentiated cells; (II) expression of different regulatory RNA types (microRNAs or long non-coding RNAs); processes of epithelial-mesenchymal transition and mesenchymalepithelial transition; (IV) CSC formation from differentiated cancer cells in a consequence of cancer therapy; (V) formation of CSC in conditions of hypoxy and during cell aging. The presented work synthetically characterizes the features, localization and formation of cancer stem cells. Furthermore, the research on these cells is still ongoing and many properties of CSC have not been fully understood.