Alterations In Tumor Suppressor Genes Research Articles

Abstract 230: Characterizing pathogenic germline variants in a large Chinese lung cancer cohort

Abstract Objective: To characterize germline pathogenic/likely pathogenic variants (GPVs) in Chinese lung cancer patients and analyze the prevalence of the GPVs and their association with lung cancer risk as well as various clinical and genomic features. Methods: A total of 17,904 Chinese lung cancer patients were included in the study. Samples of all 17,904 patients were subjected to next-generation targeted sequencing by using a panel covering more than 400 cancer genes, of which 146 are known cancer predisposition genes. Baseline somatic mutations of 5,460 patients were also obtained by targeted sequencing. Germline variants were called from white blood cells, and the GPVs were determined according to the 2015 ACMG Guideline. The prevalence of the GPVs as well as corresponding pathways in the whole cohort and in various subgroups was compared. The odds ratios of the GPVs for lung cancer risk were estimated by case-control analysis based on the local cohort and the gnomAD East Asia database. Interaction between GPVs and somatic mutations was investigated. Results: Among 17,904 patients, 1,738 patients (9.7%) carried 1,840 GPVs from 87 cancer susceptibility genes. SBDS (1.37%), TSHR (1.20%), BLM (0.62%), BRCA2 (0.62%) and ATM (0.45%) were the top 5 genes with the highest prevalence in the whole cohort. GPVs in thirteen genes including FANCF, KIT, LHCGR, MAP2K2, NRAS, etc. have not been reported in lung cancer patients previously. GPVs in certain genes showed histological variation. GPVs in PTEN, BRCA2, WRN, RAD51C, JAK2 and ERBB2 were more enriched in lung squamous cell carcinoma compared with lung adenocarcinoma (LUAD). At pathway level, homologous recombination repair (HRR, 2.09%), TP53 pathway (0.83%), nucleotide excision repair (NER, 0.7%), Fanconi anemia (FA, 0.6%) and DNA damage sensor (0.53%) ranked the first 5 pathways with the highest overall prevalence. Case-control analysis showed SBDS c.184A>T(p.K62*) had the highest odds ratio for lung cancer risk (OR=14.42, P<0.001), followed by JAK2 c.1849G>T(p.V617F)(OR=10.8, P=0.002) and MUTYH c.55C>T(p.R19*)(OR=9.77, P=0.004). The rate of second hit was 4.74% in 464 patients with germline alterations in tumor suppressor genes. Patients with second hit had a higher percentage with family cancer history (68.2% vs. 35.2%, P=0.011), and tumors with second hit showed higher tumor mutation burden (P=3.2e-05) and chromosome instability score (CIS, P=0.12). PGVs in certain genes were associated with early onset of lung cancer, and co-occurrence analysis showed there existed germline-somatic mutation interaction in lung cancer. Conclusion: Chinese lung cancer patients have a relatively high carry rate of PGVs. PGVs are distributed in multiple pathways and dominated by DNA damage repair associated pathways. The association between identified PGVs and lung cancer risk requires further studies to verify. Citation Format: Xiaoying Wu, Xiaojun Fan, Jiaohui Pang, Hua Bao, Jiani Yin, Haimeng Tang, Xue Wu, Yang Shao. Characterizing pathogenic germline variants in a large Chinese lung cancer cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 230.

Gastric Tumor Suppressor Genes Alterations Associated with cag A Positive H pylori among Patients with Gastric Cancer Systemic Review and Meta-Analysis

Introduction: Gastric cancer is the fifth most frequent cancer worldwide After lung, breast, colorectal, and prostate cancers. Helicobacter pylori (H. pylori) is considered the most important causative agent of gastrointestinal diseases such as peptic ulcer, gastritis, gastric adenocarcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma. Objective: to identify the tumor suppressor genes alterations associated with CagA in patients with gastric cancer. Methods: All the available papers published before 2022 were collected by searching in PubMed and Scopus. The keywords included in the research were “H.pylori”, “gastric cancer”, “virulence factors”, “tumor suppressor genes” “ gene mutations” “cagA+” used by Boolean operators to obtain the articles with the keywords in their titles or abstracts. Result: Initial searches yielded 111 articles, four articles were excluded as a duplication using the computer program Zotero (v5), then one hundred and seven articles were screened for the title and abstract evaluation using the Rayyan website, among them seventy-one articles were excluded. Thirty-six articles were scanned for full-text review and eligibility, furthermore, twenty-five articles were excluded because there were either Reviews and case reports, Not relevant studies, Insufficient data, and Unclear methods and results. Eleven articles were included for the literature review. In addition, the studies were in different regions of the world including Asia, Europe, North America, and Latin America. However, most of the studies were related to the USA. Conclusion: Cag A can cause alterations on gastric tumor suppressor genes by either decreased expression by increasing the methylation, inducing point mutation as mentioned, inactivation by increasing the methylation levels, increasing the levels of degradation and methylation the promotor of the tumor suppressor gene as mentioned.

Comprehensive Genomic Profiling of NF2-Mutated Kidney Tumors Reveals Potential Targets for Therapy.

Genomic alterations (GA) in NF2 tumor-suppressor gene have been associated with aggressive behavior in kidney tumors. We used comprehensive genomic profiling (CGP) to evaluate the frequencies of NF2 GA in histologic subtypes of kidney tumors and co-occurring GA in other genes and biomarkers. Advanced kidney tumors included 1875 clear cell (ccRCC), 405 papillary (pRCC), 108 chromophobe (chRCC), 171 sarcomatoid (sRCC), 61 collecting duct (cdRCC), 49 medullary (mRCC), 134 unclassified (uRCC), 906 urothelial carcinoma of renal pelvis (UC), and 147 Wilms tumors underwent hybrid-capture based CGP to evaluate all classes of GA. 192 (4.9%) of kidney tumors featured NF2 GA which were predominantly structural variant mutations (89%), followed by copy number alterations (9%). Gender and age were similar between NF2-mutant (NF2mut) and NF2-wild type (NF2wt) cohorts with male preponderance. NF2 GA frequency was highest in cdRCC (30%), sRCC (21%), uRCC (15%), and pRCC (12%) while lowest in ccRCC (3%), UC (3%) Wilms tumor (1%), and chRCC (0%). NF2 mutational status was associated with loss of Ch 22 (P < .001). NF2mut RCC harbored co-occurring GA including CDKN2A, CDKN2B, SETD2, and BAP1. VHL, PBRM1, PTEN, and FGFR3 GA were significantly more frequent in NF2wt than in NF2mut tumors. MTOR pathway GAs were uncommon in NF2mut tumors. No NF2 mutated RCC featured MSI-high or high TMB. sRCC was associated with high PD-L1 expression. PD-L1 SP142 tumoral (P = .04) and immune cells (P = .013) were more frequent in NF2mut as compared to NF2wt group. Among histologic subtypes of RCC, cdRCC, sRCC, pRCC, and uRCC are enriched in NF2 GA. Co-occurrent GA in CDKN2A/B, SETD2, and BAP1 may represent potential therapeutic targets. Higher level of PD-L1 expression in NF2mut cohort suggests that these tumors might be sensitive to immune checkpoint inhibitor therapies.

Discovering cryptic splice mutations in cancers via a deep neural network framework.

Somatic mutations can disrupt splicing regulatory elements and have dramatic effects on cancer genes, yet the functional consequences of mutations located in extended splice regions is difficult to predict. Here, we use a deep neural network (SpliceAI) to characterize the landscape of splice-altering mutations in cancer. In our in-house series of 401 liver cancers, SpliceAI uncovers 1244 cryptic splice mutations, located outside essential splice sites, that validate at a high rate (66%) in matched RNA-seq data. We then extend the analysis to a large pan-cancer cohort of 17714 tumors, revealing>100 000 cryptic splice mutations. Taking into account these mutations increases the power of driver gene discovery, revealing 126 new candidate driver genes. It also reveals new driver mutations in known cancer genes, doubling the frequency of splice alterations in tumor suppressor genes. Mutational signature analysis suggests mutational processes that could give rise preferentially to splice mutations in each cancer type, with an enrichment of signatures related to clock-like processes and DNA repair deficiency. Altogether, this work sheds light on the causes and impact of cryptic splice mutations in cancer, and highlights the power of deep learning approaches to better annotate the functional consequences of mutations in oncology.

Tumoral Intraductal Neoplasms of the Bile Ducts Comprise Morphologically and Genetically Distinct Entities.

Tumoral (grossly visible) intraductal neoplasms of the bile ducts are still being characterized. To investigate their morphologic, immunohistochemical, and molecular features. Forty-one cases were classified as gastric-, intestinal-, pancreatobiliary-type intraductal papillary neoplasm (IPN), intraductal oncocytic papillary neoplasm (IOPN), or intraductal tubulopapillary neoplasm (ITPN) on the basis of histology. All neoplasms were subjected to targeted next-generation sequencing. The mean age at diagnosis was 69 years (42-81 years); male to female ratio was 1.3. Most neoplasms (n = 23, 56%) were extrahepatic/large (mean size, 4.6 cm). The majority (n = 32, 78%) contained high-grade dysplasia, and 68% (n = 28) revealed invasion. All gastric-type IPNs (n = 9) and most ITPNs/IOPNs showed consistent colabeling for CK7/MUC6, which was less common among others (P = .004). Intestinal-type IPNs (n = 5) showed higher rates of CK20 expression than others (P < .001). Overall, the most commonly mutated genes included TP53 and APC, while copy number variants affected ELF3 and CDKN2A/B. All gastric-type IPNs contained an alteration affecting the Wnt signaling pathway; 7 of 9 (78%) showed aberrations in the MAPK pathway. Mutations in APC and KRAS were common in gastric-type IPNs as compared with others (P = .01 for both). SMAD4 was more frequently mutated in intestinal-type IPNs (P = .02). Pancreatobiliary-type IPNs (n = 14) exhibited frequent alterations in tumor suppressor genes including TP53, CDKN2A/B, and ARID2 (P = .04, P = .01 and P = .002, respectively). Of 6 IOPNs analyzed, 3 (50%) revealed ATP1B1-PRKACB fusion. ITPNs (n = 6) showed relatively few recurrent genetic aberrations. Follow-up information was available for 38 patients (median, 58.5 months). The ratio of disease-related deaths was higher for the cases with invasion (56% versus 10%). Tumoral intraductal neoplasms of the bile ducts, similar to their counterparts in the pancreas, are morphologically and genetically heterogeneous.

Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma

More than half of patients with malignant mesothelioma show alterations in the BAP1 tumor-suppressor gene. Being a member of the Polycomb repressive deubiquitinating (PR-DUB) complex, BAP1 loss results in an altered epigenome, which may create new vulnerabilities that remain largely unknown. Here, we performed a CRISPR-Cas9 kinome screen in mesothelioma cells that identified two kinases in the mevalonate/cholesterol biosynthesis pathway. Furthermore, our analysis of chromatin, expression, and genetic perturbation data in mesothelioma cells suggests a dependency on PR complex 2 (PRC2)-mediated silencing. Pharmacological inhibition of PRC2 elevates the expression of cholesterol biosynthesis genes only in BAP1-deficient mesothelioma, thereby sensitizing these cells to the combined targeting of PRC2 and the mevalonate pathway. Finally, by subjecting autochthonous Bap1-deficient mesothelioma mice or xenografts to mevalonate pathway inhibition (zoledronic acid) and PRC2 inhibition (tazemetostat), we demonstrate a potent anti-tumor effect, suggesting a targeted combination therapy for Bap1-deficient mesothelioma.

Somatic BAP1 Loss in Ovarian Serous Borderline Tumor and Recurrent Low-grade Serous Carcinoma From a Germline BAP1 Mutation Carrier.

To the Editor: In a recent issue, Dr. Oliva and colleagues proposed the use of the immunohistochemical markers, Claudin-4 and BAP1, to distinguish between low-grade serous neoplasms and peritoneal mesothelioma 1. This article is of particular interest to us, as we have recently published on a cohort of 119 clinically annotated low-grade serous carcinomas, confirmed by central pathology review, with molecular profiling by targeted next-generation sequencing 2. In this cohort, we encountered 1 patient who represents an unusual exception to relying on loss of BAP1 expression to exclude the diagnosis of a low-grade serous neoplasm. This was a 59-yr-old female who underwent comprehensive surgical staging for bilateral ovarian masses. Final pathology revealed a stage IIIC serous borderline tumor involving bilateral ovaries (Fig. 1A), associated with noninvasive peritoneal implants and involvement of pelvic lymph nodes. After 7 yrs, she developed recurrent disease involving the sigmoid colon, in the form of metastatic low-grade serous carcinoma (Fig. 1B). Both primary and recurrent tumors showed a similar immunophenotype, characterized by strong diffuse expression of epithelial/Mullerian markers, including Claudin-4 (Fig. 1C), BerEP4, PAX8, ER, and PR, while negative for markers of mesothelial differentiation, namely, calretinin, and D2-40. Somatic mutational profiling by targeted next-generation sequencing revealed the low-grade serous carcinoma to harbor a BAP1 frameshift mutation (Y241Lfs*2). Germline testing further revealed a heterozygous BAP1 germline mutation (c.1110dupC, p.Met371Hisfs*27). Loss of BAP1 expression by immunohistochemistry in the low-grade serous carcinoma, as well as the prior serous borderline tumor (Fig. 1D), was consistent with bi-allelic inactivation of BAP1 as an early event in the molecular pathogenesis of this case.FIG. 1: Low-grade serous neoplasms associated with germline BAP1 mutation. (A) Ovarian serous borderline tumor showing characteristic hierarchical branching papillae lined by stratified columnar epithelium (inset: ciliated cells observed at high-magnification, consistent with tubal differentiation). (B) Recurrent invasive low-grade serous carcinoma involving muscularis propria of the sigmoid colon, showing infiltrating nests and micropapillae composed of tumor cells with small monotonous nuclei, and scattered psammoma bodies. Immunohistochemical analysis of the serous borderline tumor showing (C) diffuse expression of Claudin-4 and (D) loss of BAP1 expression in tumor cells with retained nuclear staining in non-neoplastic stromal cells.To our knowledge, this represents the first reported case of a BAP1-deficient low-grade serous neoplasm. It illustrates how genetic alterations of oncogenes and tumor suppressor genes are not tissue or disease-specific and emphasizes the importance of applying several cell lineage markers, along with morphologic correlation, for appropriate diagnostic classification of tumor type.

Genetic Studies of Actinic Keratosis Development: Where Are We Now?

Actinic keratosis (AK) is a common precancerous skin lesion that can develop into cutaneous squamous cell carcinoma (CSCC). AK is characterized by atypical keratinocytes in the skin's outer layer and is commonly found in sun-exposed areas. Like many precancerous lesions, the development of AK is closely associated with genetic mutations. The molecular biology and transcriptional mechanisms underlying AK development are not well understood. Ultraviolet (UV) light exposure, especially UVA and UVB radiation, is a significant risk factor for AK, causing DNA damage and mutagenic effects. Besides UV exposure, comorbidities like diabetes, rheumatoid arthritis, and psoriasis may also influence AK development. AK patients have shown associations with various internal malignancies, indicating potential vulnerability in cancer-associated genes. Treatment for AK includes cryosurgery, electrodesiccation and curettage, chemotherapeutic creams, photodynamic therapy, or topical immune-modulators. Genomic studies have identified genetic aberrations in AK, with common mutations found in genes like TP53, NOTCH1, and NOTCH2. The progression from AK to CSCC involves chromosomal aberrations and alterations in oncogenes and tumor-suppressor genes. The functional relationships among these genes are not fully understood, but network analysis provides insights into their potential mechanisms. Further research is needed to enhance our understanding of AK's pathogenesis and develop novel therapeutic approaches.

Concurrent inactivating mutations and expression losses of RGS2, HNF1A, and CAPN12 candidate tumor suppressor genes in colon cancers.

Microsatellite instability-high (MSI-H) colorectal cancer (CRC) is different from microsatellite stable (MSS) CRC concerning biological, and clinical features. In MSI-H CRCs, defects of mismatch repair genes produce increased mutation accumulation in repetitive DNA sequences. To see whether candidate tumor suppressor genes (TSGs) are altered in MSI-H CRC, we studied frameshift mutation and protein expression of candidate TSGs of RGS2, HNF1A, HNF1B, CAPN12, RCBTB2, ATE1, PKNOX1, and USP19. We found frameshift mutations of RGS2 in 5 (5%), HNF1A in 6 (6%), HNF1B in 2 (2%), CAPN12 in 3 (3%), RCBTB2 in 4 (4%), ATE1 in 2 (2%), PKNOX1 in 2 (2%), and USP19 in 2 (2%) MSI-H CRCs. However, we found no such mutations in MSS CRCs. RCBTB2, CAPN12, HNF1A, and HNF1B frameshift mutations revealed the regional difference in the same tumors. In addition, we identified loss of RGS2, HNF1A, and CAPN12 protein expression irrespective of MSI phenotype in 13-29% of CRCs. The results indicate that many TSGs harbor concurrent inactivating mutations and protein loss in MSI-H CRCs with intratumoral mutational heterogeneity, and that MSS CRCs are altered by protein losses. These alterations could contribute to CRC development and underlying mechanisms and consequences of the TSG alterations remain to be clarified.

A contemporary guide to chromosomal copy number profiling in the diagnosis of renal cell carcinoma.

The routine clinical implementation of molecular methods other than fluorescence in situ hybridization in the evaluation of renal neoplasia is currently limited, as the current standard of care primarily involves a combination of morphologic and immunophenotypic analysis of such tumors. Amongst various molecular techniques, global copy number profiling using single nucleotide polymorphism-based microarrays, colloquially referred to as SNP-arrays, is being increasingly utilized to profile renal tumors, as several subtypes have characteristic recurrent patterns of copy number alterations. Recurrent copy number alterations in common tumor types include loss of chromosome 3p in clear cell renal cell carcinoma (RCC), gain of chromosomes 7 and 17 in papillary RCC and multiple losses in chromosomes 1, 2, 6, 10, 13, 17, and 21 in chromophobe RCC. Such assays are being increasingly utilized in the clinical setting. Herein, we discuss some common clinical applications of such testing that includes high yield diagnostic and prognostic applications. Diagnostic utility includes evaluation of tumor types that are primarily defined by underlying copy number alterations, establishing the underlying subtype in high grade dedifferentiated (unclassified) renal tumors, as well as assessment of loss of heterozygosity, which is an important component in the workup for germline alterations in tumor suppressor genes. Universal adoption of these techniques across clinical laboratories will likely be significantly affected by variables such as cost, reimbursement, and turnaround time.

Isolated BAP1 Genomic Alteration in Malignant Pleural Mesothelioma Predicts Distinct Immunogenicity with Implications for Immunotherapeutic Response.

Malignant pleural mesothelioma (MPM), an aggressive cancer of the mesothelial cells lining the pleural cavity, lacks effective treatments. Multiple somatic mutations and copy number losses in tumor suppressor genes (TSGs) BAP1, CDKN2A/B, and NF2 are frequently associated with MPM. The impact of single versus multiple genomic alterations of TSG on MPM biology, the immune tumor microenvironment, clinical outcomes, and treatment responses are unknown. Tumors with genomic alterations in BAP1 alone were associated with a longer overall patient survival rate compared to tumors with CDKN2A/B and/or NF2 alterations with or without BAP1 and formed a distinct immunogenic subtype with altered transcription factor and pathway activity patterns. CDKN2A/B genomic alterations consistently contributed to an adverse clinical outcome. Since the genomic alterations of only BAP1 was associated with the PD-1 therapy response signature and higher LAG3 and VISTA gene expression, it might be a candidate marker for immune checkpoint blockade therapy. Our results on the impact of TSG genotypes on MPM and the correlations between TSG alterations and molecular pathways provide a foundation for developing individualized MPM therapies.

Abstract A081: Molecular phenotyping and risk stratification of intraductal papillary mucinous neoplasms

Abstract Objective: Morphological subtyping of intraductal papillary mucinous neoplasms of the pancreas (IPMNs) into pancreatobiliary-type, intestinal-type, or gastric-type is a prognostic factor, however, molecular foundations explaining the difference of clinical behaviors are unknown. Our research aimed to elucidate the molecular phenotypes associated with subtypes of IPMNs and establish a risk stratification model. Design: In 171 IPMNs with high-grade dysplasia (HGD) and invasive carcinoma, we analyzed protein expressions of p16, p53, SMAD4, STK11, and β-catenin by immunohistochemistry, and mutations and copy number variations of KRAS and GNAS by droplet digital PCR, and analyzed the association with clinicopathological factors. Results: In HGD components of IPMNs of pancreatobiliary- (n=66), intestinal- (n=70), and gastric-type (n=35), alterations were detected respectively as follows: KRAS mutation; 98%, 62%, and 83% (P&amp;lt;0.05), GNAS mutation; 11%, 82%, and 51% (P&amp;lt;0.05), p53; 59%, 33%, and 20% (P&amp;lt;0.05), SMAD4; 67%, 1%, 37% (P&amp;lt;0.05), STK11; 43%, 3%, and 6% (P&amp;lt;0.05), β-catenin; 48%, 68%, and 23% (P&amp;lt;0.05), and p16; 65%, 52%, and 40% (P=0.105). Aberrations of 4 driver genes, p16, p53, SMAD4, and STK11, were succeeded from components of low-grade dysplasia to invasive carcinoma and associated with the risk of invasion of intraductal neoplasms and the patients’ outcomes. The combinatorial system by the number of accumulated gene alterations well stratified the risk of invasion (0–1 vs 2; odds ratio (OR) 4.62, 0–1 vs 3–4; OR 12.90) and patients’ outcome (0–1 vs 2; hazard ratio (HR) 4.01, 2 vs 3–4; HR 3.98, 0–1 vs 3–4; HR 15.99 in disease-free survival, 0–1 vs 2; HR 6.62, 2 vs 3–4; HR 4.43, 0–1 vs 3–4; HR 29.32 in overall survival). Moreover, GNAS amplification was an independent risk factor of invasion (OR 7.79) and showed poor prognosis (overall survival, log-rank P&amp;lt;0.05) in intestinal-type IPMNs, while sole GNAS activating mutation was an independent low risk factor for invasion (OR 0.33). KRAS amplification might be a poor prognostic factor in pancreatobiliary-type IPMNs (HR 2.7, P=0.07). Conclusion: The molecular patterns involving the malignant progression are different among epithelial subtypes of IPMNs. The molecular phenotypes of combinatorial genomic alterations of tumor suppressor genes with signature of KRAS and GNAS of intraductal components may stratify the risk of invasion and survival in IPMN patients. Molecular phenotyping using liquid biopsy of pancreatic juice during the surveillance might be additional value of decision making for operative timing in IPMNs showing equivocal radiological findings. Citation Format: Yuko Omori, Yusuke Ono, Takashi Kokumai, Fumiko Date, Ryota Higuchi, Goro Honda, Yusuke Mizukami, Takanori Morikawa, Michiaki Unno, Toru Furukawa. Molecular phenotyping and risk stratification of intraductal papillary mucinous neoplasms [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A081.

BIOM-65. SAFE MAXIMAL RESECTION OF IDH-WILDTYPE GLIOBLASTOMA WITH TUMOR-FREE MOLECULAR MARGIN RESULTS IN PROLONGED PROGRESSION-FREE SURVIVAL

Abstract Purpose Although maximal resection of wild-type GBM tumors is associated with longer survival, the association of genomic alterations with the ability to resect disease has not been elucidated. This study aimed to determine whether certain molecular alterations are less amenable to surgical resection and whether achieving a surgical margin devoid of tumor cell burden provides a clinical benefit. Methods Molecular profiling of 148 consecutive tumor samples from newly diagnosed patients with IDH-WT GBM SNaPshot genotyping, and methylation-specific PCR for MGMT promoter methylation. The association of alterations with residual volume and progression-free survival was evaluated in regression analyses. We prospectively investigated the impact of TERTp status at the surgical margin on progression-free survival (PFS) in 47 patients. PFS and overall survival (OS) were evaluated with the log-rank test and Cox regression models.Results Overall, 148 patients (91 men [61.5%], median age, 62.5 years [range 56–70 years] had maximally safe surgery. The median follow-up duration was 18 months (IQR, 4-32 months). The rate of PFS was significantly lower in MGMT promoter unmethylated IDH-WT GBM amenable to resection with residual volume &amp;gt;4.9cc (hazard ratio [HR], 2.35; 95% CI, 1.44-3.84; P=.005). Gene amplification (PDGFRA, KIT, KDR) on 4q12 and TP53 and RB1 mutations were associated with greater RV. Prospective trial revealed median PFS for tumors with TERTp mutations in the surgical margin was 10.1 months while tumors with undetectable TERTp mutations in the margin did not progress (median follow-up 8.1 months, IQR 1.6-14.6). Surgical tumor margins devoid of TERTp mutations were associated with significantly different probability of PFS (0.23; 95%CI 0.15-0.43; P&amp;lt; 0.01)Conclusion In conclusion, 4q12 amplification (KDR/PDGFRA/KIT) and tumor suppressor gene alterations (RB1, TP53) were associated with greater residual volume. Tumor-free margins defined spatially by intraoperative navigation as assessed by quantifying TERTp mutation allelic fraction was correlated with prolonged PFS.

A critical review of datasets and computational suites for improving cancer theranostics and biomarker discovery

Cancer has been constantly evolving and so is the research pertaining to cancer diagnosis and therapeutic regimens. Early detection and specific therapeutics are the key features of modern cancer therapy. These requirements can only be fulfilled with the integration of diverse high-throughput technologies. Integration of advanced omics methodology involving genomics, epigenomics, proteomics, and transcriptomics provide a clear understanding of multi-faceted cancer. In the past few years, tremendous high-throughput data have been generated from cancer genomics and epigenomic analyses, which on further methodological analyses can yield better biological insights. The major epigenetic alterations reported in cancer are DNA methylation levels, histone post-translational modifications, and epi-miRNA regulating the oncogenes and tumor suppressor genes. While the genomic analyses like gene expression profiling, cancer gene prediction, and genome annotation divulge the genetic alterations in oncogenes or tumor suppressor genes. Also, systems biology approach using biological networks is being extensively used to identify novel cancer biomarkers. Therefore, integration of these multi-dimensional approaches will help to identify potential diagnostic and therapeutic biomarkers. Here, we reviewed the critical databases and tools dedicated to various epigenomic and genomic alterations in cancer. The review further focuses on the multi-omics resources available for further validating the identified cancer biomarkers. We also highlighted the tools for cancer biomarker discovery using a systems biology approach utilizing genomic and epigenomic data. Biomarkers predicted using such integrative approaches are shown to be more clinically relevant.

Differential expression profiling of onco and tumor-suppressor genes from major-signaling pathways in Wilms' tumor.

Wilms' tumor is the most-frequent malignant-kidney tumor in children under 3-4years of age and is caused by genetic alterations of oncogenes (OG) and tumor-suppressor genes (TG). Wilms' tumor has been linked to many OG-&-TG. However, only WT1 has a proven role in the development of this embryonic-tumor. The study investigates the level of mRNA expression of 16 OGs and 20 TGs involved in key-signaling pathways, including chromatin modification; RAS; APC; Cell Cycle/Apoptosis; Transcriptional Regulation; PI3K; NOTCH-&-HH; PI3K & RAS of 24-fresh Wilms'-tumor cases by capture-and-reporter probe Code-Sets chemistry, as CNVs in these pathway genes have been reported. Upon extensively investigating, MEN1, MLL2, MLL3, PBRM1, PRDM1, SMARCB1, SETD2, WT1, PTPN11, KRAS, HRAS, NF1, APC, RB1, FUBP1, BCOR, U2AF1, PIK3CA, PTEN, EBXW7, SMO, ALK, CBL, EP300-and-GATA1 were found to be significantly up-regulated in 58.34, 62.5, 79.17, 91.67, 58, 66.66,54, 58.34, 66.67, 75, 62.5, 62.5, 58, 79.17, 79.17, 75, 70.84, 50, 50, 75, 66.66, 62.50, 61.66, 58.34-and-62.50% of cases respectively, whereas BRAF, NF2, CDH1, BCL2, FGFR3, ERBB2, MET, RET, EGFR-and-GATA2 were significantly down regulated in 58, 87.50, 79.16, 54.16, 79.17, 91.66, 66.66, 58.33, 91.66-and-62.50% of cases, respectively. Interestingly, the WT1 gene was five-fold down regulated in 41.66% of cases only. Hence, extensive profiling of OGs and TGs association of major-signaling pathways in Wilms' tumor cases may aid in disease diagnosis. PBRM1 (up-regulated in 91.67% of cases), ERBB2 and EGFR (down-regulated in 91.66 and 91.66% of cases, respectively) could be marker genes. However, validation of all relevant results in a larger number of samples is required.

Characterization of prostate cancer adrenal metastases: dependence upon androgen receptor signaling and steroid hormones

Prostate cancer (PCa) typically spreads to the bone, and this distribution is attributed to the central role of the microenvironment in progression. However, metastasis to the adrenal glands, while not as common, does occur. The biology that accounts for adrenal metastases may be attributed to the unique local steroid metabolome and co-clinical characterization may elucidate the role steroid biosynthesis plays in PCa progression. Three patients with metastatic PCa who had archived tumor tissue from an adrenalectomy were retrospectively identified, and one adrenal metastasis was developed into a xenograft (MDA-PCa-250). The adrenal metastases were characterized by performing somatic DNA whole exome sequencing (WES), RNA-Seq, immunohistochemistry (IHC), and steroid metabolite quantitation. The influence of steroid metabolites on adrenal metastasis cells and tumor growth was tested in vitro and in vivo. Clinically, adrenalectomy was performed during castration-resistant oligometastatic disease, and two men experienced resensitization to leuprolide. Somatic DNA WES revealed heterogeneous alterations in tumor suppressor and DNA damage repair pathway genes. Adrenal metastases had active androgen receptor (AR) signaling by IHC, and RNA-Seq supported a potential role for adrenal androgen precursor metabolism in activating the AR. Steroid quantitation suggested the adrenal androgen precursors were converted into testosterone in these metastases, and stable isotope tracing of an organoid from MDA-PCa-250 confirmed the capability of adrenal metastases to biosynthesize testosterone from adrenal precursors. In vitro testing of a cell line derived from MDA-PCa-250 showed that testosterone and cortisol stimulated tumor cell growth. In vivo experiments demonstrated that MDA-PCa-250 grew in intact mice with circulating testosterone, but not in castrated mice. PCa adrenal metastases depend upon AR signaling driven by androgen precursors, androstenedione and dehydroepiandrosterone, available in the microenvironment, despite the presence of heterogeneous somatic DNA alterations. Moreover, MDA-PCa-250 provides a preclinical model that can recapitulate the unique androgen-dependence of adrenal metastases. This study does not report the clinical results of a clinical trial, but it does use samples from a completed clinical trial that is registered with clinicaltrials.gov (NCT01254864).

EP08.02-125 Tumor Suppressor Gene Alterations Identified at Disease Progression Impact Outcomes in Patients with EGFR-mutant Lung Cancer

Despite improvements in outcomes for patients with EGFR-mutant NSCLC, tumors inevitably relapse during tyrosine kinase inhibitor (TKI) treatment. Alterations in tumor suppressor genes (TSGs) have been described as determinants of molecular and clinical heterogeneity in EGFR-mutant NSCLC, however, detailed outcome analyses based on specific TSGs are limited.

EP07.01-014 Mesothelioma-Associated Fibroblasts Enhance Mesothelioma Aggressiveness and Modulate Drug Response

Malignant pleural mesothelioma (MPM) is an aggressive malignancy, which arises from the pleural linings of the chest wall. Although it is less common than breast, lung or prostate cancer, MPM is almost always fatal, owing to rapid local spreading, limited therapeutic options and frequent recurrence after treatment. Unlike the majority of cancers, MPM rarely exhibits gain-of-function mutations in oncogenes and is rather characterized by inactivating alterations of tumor suppressor genes. Its highly malignant nature in absence of oncogenic driver mutations indicates an extrinsic supply of tumor-stimulating signals by cancer-associated cells of the tumor microenvironment.

Molecular Characterization of Mesothelioma: Impact of Histologic Type and Site of Origin on Molecular Landscape.

Mesothelioma is an aggressive malignancy with heterogeneous outcomes that are partly driven by the differential efficacy of existing therapies across histologic types and sites of origin. Large-scale molecular analysis of mesothelioma and its subtypes has the potential to inform future therapeutic strategies. We analyzed 1,294 mesotheliomas {980 pleural (malignant pleural mesothelioma [MPM]) and 314 peritoneal (malignant peritoneal mesothelioma [MPeM])} using next-generation sequencing, determined programmed death ligand-1 (PD-L1) expression and histology in a subset of cases, and assessed MTAP/CDKN2A copy-number status by fluorescence in situ hybridization and T-cell infiltration in an independent cohort. The molecular landscape of MPM was characterized by inactivating alterations in CDKN2A (49%), BAP1 (44%), CDKN2B (42%), MTAP (34%), and NF2 (33%). Compared with epithelioid MPM, nonepithelioid (ie, biphasic and sarcomatoid) MPM had identical tumor mutational burden (median 1.25 mut/Mb, P = .63), more commonly expressed PD-L1 (74% v 51%, P = .02), and was more likely to harbor MTAP, CDKN2A, and CDKN2B copy loss (P < .05). Fluorescence in situ hybridization confirmed that homozygous MTAP loss was enriched in nonepithelioid MPM. Relative to MPM, MPeM had comparable tumor mutational burden and PD-L1 expression. The molecular profile of MPeM was similar to MPM, with the distinction that PBRM1 alterations occurred at higher frequency (16% v 7%, P < .01). ALK rearrangements were only observed in MPeM. Regardless of histology and location, the molecular landscape of mesothelioma primarily consists of inactivating alterations in tumor suppressor genes, with enrichment of certain alterations in distinct subsets (eg, MTAP loss in nonepithelioid tumors). Given the limited efficacy of current therapies for this disease, novel approaches targeting recurring alterations should be explored.

Application of Novel Molecular Biology in Cancer Therapy

Cancer is a genetic illness that develops for various reasons, including the activation of oncogenes, the failure of tumor suppressor genes, or mutagenesis induced by environmental stimuli. This article was produced using PubMed, Nature, Science Direct, Springer, and Elsevier data. Oncogenes are altered forms of normal proto-oncogenic genes that are important for cell proliferation, development, and regulation. The transformation of a gene to an oncogene is caused by chromosomal translocation or gene mutation due to addition, deletion, duplication, or viral infection. These oncogenes are targeted by medications or the RNAi system to limit malignant cell development. Various molecular biology methods for cancer detection and treatment have been developed, including targeting cancer stem cell pathways for cancer therapy, retroviral therapy, oncogene silencing, and alterations in tumor suppressor genes. Among all the techniques used, RNAi, zinc finger nucleases, and CRISPR have a greater chance of reaching a cancer-free planet.