Colorectal cancer: Impact of primary tumor location on genetic alterations.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3578-3578 ◽  
Author(s):  
Mohamed E. Salem ◽  
Heinz-Josef Lenz ◽  
Joanne Xiu ◽  
Jimmy J. Hwang ◽  
Philip Agop Philip ◽  
...  
Keyword(s):  
Tumor Location ◽  
Genetic Alterations ◽  
Hepatic Flexure ◽  
Missense Mutations ◽  
Chi Square ◽  
Molecular Alterations ◽  
Clear Cut ◽  
Comparison Results ◽  
Her 2 ◽  
The Right

3578 Background: Recent data show that patients with left sided colon tumors (LT) have better survival and respond differently to biologics compared to patients with right-sided tumors (RT), likely due to molecular differences. We sought to examine these differences. Methods: Primary colorectal tumors (n = 1730) with origins clearly defined as RT (cecum to hepatic flexure; n = 273), LT (splenic flexure to sigmoid colon; n = 585), or rectal (RC; n = 872) were examined by NextGen sequencing, protein expression and gene amplification. Tumor mutational load (TML) was calculated in 1001 of these tumors using only somatic nonsynonymous missense mutations. Chi-square was used for comparison. Results: When compared to LT, RT carried a significantly higher rate of BRAF (25% vs 7%; p < 0.0001), PTEN (5.4% vs 1.3%; p = 0.008), and ATM (4% vs 1%; p = 0.04) mutations. RT were likely to have more MSI-high tumors (22% vs 5%; p < 0.0001) and PD-1 overexpression (58% vs 44%; p = 0.01). There were no differences in the rate of KRAS (50% vs 42%; p = 0.07) or NRAS mutations (2.2% vs 3.4%; p = 0.4). When compared to RC, RT had a higher rate of BRAF (25% vs 3%; p = 7E-07), PIK3CA (22% vs 11%; p = 0.001), CTNNB1 (3% vs 0.3%; p = 0.02); ATM (3% vs 1%; p = 0.04), PTEN (5% vs 1%; p = 0.004), and BRCA1 mutations (4% vs 0%; p = 0.02), and a lower rate of TP53 (56% vs 71%; p = 0.001) and APC (53% vs 66%; p = 0.003) mutations. When compared to RC, LT showed higher rates of BRAF (6.7% vs 3.2%; p = 0.04) and CTNNB1 (2.1% vs 0.3%; p = 0.04) mutations, and a higher rate of MSI-high tumors (4.6% vs 0.7%; p = 0.04), whereas RC had a higher rate of KRAS mutation (50% vs 42%; p = 0.04). There were no differences between RT, LT, and RC for the frequency of PD-L1 (2%, 2%, and 1%) or Her-2 (1%, 2%, and 3%) overexpression, although Her-2 amplification was significantly different (1%, 3%, and 5%, RT vs RC; p = 0.03). Mean TML was 12, 11, and 8 mutations/megabase for RT, LT, and RC, respectively (RT vs RC; p = 0.01). There was a correlation between TML and PD-L1 (p = 0.04) and PD-1 (p = 0.01). Conclusions: Tumors arising in the right colon carry genetic alterations that are different from LT as well as RC. However, it appears that CRCs carry a continuum of molecular alterations from the right to the left side, rather than displaying sharp, clear-cut differences.

scholarly journals PATH-35. RETROSPECTIVE ANALYSIS OF 145 PATIENTS WITH GLIOBLASTOMA; CORRELATING MOLECULAR ALTERATION INCIDENCE WITH DEMOGRAPHICS, TUMOR LOCATION, AND PROGNOSIS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi150-vi151
Author(s):  
Mina Lobbous ◽  
ZacK Tucker ◽  
Elizabeth Coffee ◽  
Louis Nabors
Keyword(s):  
Progression Free Survival ◽  
Tumor Location ◽  
Genetic Alterations ◽  
Primary Brain Tumor ◽  
Demographic Variables ◽  
The Cancer Genome Atlas ◽  
Missense Mutations ◽  
Molecular Alteration ◽  
Molecular Alterations ◽  
Cdkn2a Deletion

Abstract Glioblastoma is the most common and most aggressive primary brain tumor in adults. Glioblastoma was the first neoplasm to be systemically studied by The Cancer Genome Atlas and is one of the most molecularly well-characterized tumors in humans. Molecular profiling of glioblastoma is increasingly available and had led to the identifications of multiple prognostic factors as well as potential actionable targets for novel therapies. We identified 145 patients diagnosed with glioblastoma whose tumor tissue was analyzed using next generation sequencing (NGS). The NGS was performed using validated, commercially available panels. We studied somatic genetic alterations with a particular focus on TERT (which was altered in 55.9% of patients in the dataset), CDKN2A (44%), TP53 (39%), EGFR (38.6%), PTEN (31%), IDH1 (20%), and CDK4 (9%). These molecular alterations were analyzed in relation to the patients’ tumor locations, demographics, and outcomes. We used multiple binary logistic regressions to assess whether demographics and tumor location were predictive of the above alterations We also assessed the relationship between molecular alterations and outcomes when controlling for treatment and demographic variables. Among demographic variables, age predicted alterations in IDH1, EGFR, TERT, TP53, and PTEN. Frontal lobe tumors were more likely to be IDH1-mutated, irrespective of patient age. Sex and race did not predict the incidence of the molecular alterations of interest. Analysis of outcomes revealed that, when controlling for treatment and demographic variables, TERT promoter mutations, TP53 nonsense mutations, and EGFR A289V were predictive of a decreased progression-free survival, while CDKN2A deletion, PTEN missense mutations, and EGFR A289V were predictive of decreased overall survival. Our experience highlights the importance of incorporating routine NGS in the management of patients with glioblastoma. More studies are required to evaluate the predictive and/or prognostic values of different molecular alterations.

Molecular variances between rectal and left-sided colon cancers.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 522-522 ◽  
Author(s):  
John Marshall ◽  
Heinz-Josef Lenz ◽  
Joanne Xiu ◽  
Wafik S. El-Deiry ◽  
Jeffrey Swensen ◽  
...  
Keyword(s):  
Tumor Infiltrating Lymphocytes ◽  
Genetic Alterations ◽  
Recent Analysis ◽  
Missense Mutations ◽  
Chi Square ◽  
Primary Tumors ◽  
Colon Cancers ◽  
Nextgen Sequencing ◽  
Disease Biology ◽  
Infiltrating Lymphocytes

522 Background: Recent analysis of CALGB 80405 showed that left sided colon tumors (LT) respond differently to biologics compared with right-sided tumors, likely due to molecular differences. Molecular variations between LT and rectal tumors remain undefined. Herein, we report our exploration of these variations. Methods: Tumors with origins clearly defined as splenic flexure to descending colon (SFT), sigmoid colon (SgT), or rectum (RT) were included. Protein expression, gene amplification and NextGen sequencing was tested. Microsatellite instability (MSI) was measured by PCR. Tumor mutational load (TML) was calculated using only somatic nonsynonymous missense mutations. Chi-square tests were used for comparative analyses. Results: In total, 1,457 primary tumors (SFT 125; SgT 460, and RT 872) were examined. When compared with SFT, RT had a higher frequency of TP53 (71% vs. 57%, p = 0.03) and APC (66% vs. 49%, p = 0.01); a lower frequency of PIK3CA (11% vs. 22%, p = 0.02), BRAF (3% vs. 15% p = 0.0001), GNAS (0.9% vs. 4%, p = 0.04), HNF1A (0.7% vs. 5%, p = 0.01), and CTNNB1(0.3% vs. 4%, p = 0.003); and a higher expression of TOPO1 (52% vs. 31%, p = 0.0001), ERCC1 (29% vs. 15%, p = 0.03), and MGMT (64% vs. 53%, p = 0.048). When compared with SgT, RT had higher expression of TLE3 (33% vs. 23%, p = 0.007), TOPO1 (52% vs. 35%, p < 0.001), TUBB3 (41% vs. 28%, p = 0.003), and MGMT (64% vs. 54%, p = 0.003). There were no differences between SFT, SgT, and RT in the frequency of PD-L1 expression (5%, 2%, and 2%) on tumor cells, PD-1 expression on tumor-infiltrating lymphocytes (54%, 42%, and 42%), or Her-2 expression (1%, 2%, and 3%) and amplification (3%, 3%, and 5%). MSI was seen in 7% of SFT, 4% of SgT, and 0.7% of RT (total LT vs. RT, p = 0.01). Mean TML was 23, 6.5, and 7 mutations (mut)/MB (332 tumors), and the portion of tumors carrying a TML of > 17mut/MB was 9%, 1.6%, and 4% for SFT, SgT, and RT, respectively. In all 3 cohorts, a TML > 17 mut/MB was highly concordant with MSI. There was a correlation between PD-1 and TML in RT (p = 0.04) but not in SFT or SgT. There were no correlations between PD-L1 and TML. Conclusions: Tumors arising in the rectum may carry genetic alterations that are distinct from LT. A better understanding of disease biology may help to identify therapeutic targets and advance precision medicine

scholarly journals Molecular Alterations in Lung Adenocarcinoma With Ground-Glass Nodules: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Zihan Wei ◽  
Ziyang Wang ◽  
Yuntao Nie ◽  
Kai Zhang ◽  
Haifeng Shen ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Early Stage ◽  
Meta Analysis ◽  
Genetic Alterations ◽  
Ground Glass ◽  
Cochrane Library ◽  
Chi Square ◽  
Test Analysis ◽  
Molecular Alterations ◽  
Chi Square Test

Background and AimsNodular ground-glass lesions have become increasingly common with the increased use of computed tomography (CT), while the genomic features of ground-glass opacities (GGOs) remain unclear. This study aims to comprehensively investigate the molecular alterations of GGOs and their correlation with radiological progression.MethodsStudies from PubMed, Embase, Cochrane Library, and Web of Science, using PCR, targeted panel sequencing, whole exosome sequencing, and immunohistochemistry, and reporting genomic alterations or PD-L1 expressions in lung nodules presenting as GGOs until January 21, 2021 were included in this study. Chi-square test, random-effects model, and Z-test analysis were adopted to analyze the data.ResultsA total of 22 studies describing mutations in lung adenocarcinoma (LUAD) with GGOs were analyzed. EGFR was the most frequently mutative gene (51%, 95%CI 47%–56%), followed by TP53 (18%, 95%CI 6%–31%), HER2 (10%, 95%CI 0%–21%), ROS1 (6%, 95%CI 0%–18%), and KRAS (6%, 95%CI 3%–9%). The correlation between the frequency of EGFR mutation and radiological was observed and the differences were found to be not statistically significant in the subgroups, which are listed as below: radiological: gGGO 47.40%, 95%CI [38.48%; 56.40%]; sGGO 51.94%, 95%CI [45.15%; 58.69%]. The differences of the frequency of KRAS mutation in the different subgroups were also consistent with this conclusion, which are listed as: radiological gGGO 3.42, 95%CI [1.35%; 6.13%]; sGGO 12.27%, 95%CI [3.89%; 23.96%]. The pooled estimated rate of PD-L1 was 8.82%, 95%CI [5.20%–13.23%]. A total of 11.54% (3/26) of the SMGGNs were confirmed to be intrapulmonary spread by WES.ConclusionsSomatic genetic alterations are considered in early-stage GGO patients without distinct changes of the frequency following the progress of the tumor. This review sheds insight on molecular alterations in LUAD with GGOs.

scholarly journals Clinical impact of combined epigenetic and molecular analysis of pediatric low-grade gliomas

2020 ◽  
Vol 22 (10) ◽  
pp. 1474-1483 ◽  
Author(s):  
Kohei Fukuoka ◽  
Yasin Mamatjan ◽  
Ruth Tatevossian ◽  
Michal Zapotocky ◽  
Scott Ryall ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Progression Free Survival ◽  
Lymphocytic Infiltration ◽  
Tumor Location ◽  
Genetic Alterations ◽  
Pleomorphic Xanthoastrocytoma ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Additional Information ◽  
Molecular Alterations

Abstract Background Both genetic and methylation analysis have been shown to provide insight into the diagnosis and prognosis of many brain tumors. However, the implication of methylation profiling and its interaction with genetic alterations in pediatric low-grade gliomas (PLGGs) are unclear. Methods We performed a comprehensive analysis of PLGG with long-term clinical follow-up. In total 152 PLGGs were analyzed from a range of pathological subtypes, including 40 gangliogliomas. Complete molecular analysis was compared with genome-wide methylation data and outcome in all patients. For further analysis of specific PLGG groups, including BRAF p.V600E mutant gliomas, we compiled an additional cohort of clinically and genetically defined tumors from 3 large centers. Results Unsupervised hierarchical clustering revealed 5 novel subgroups of PLGG. These were dominated by nonneoplastic factors such as tumor location and lymphocytic infiltration. Midline PLGG clustered together while deep hemispheric lesions differed from lesions in the periphery. Mutations were distributed throughout these location-driven clusters of PLGG. A novel methylation cluster suggesting high lymphocyte infiltration was confirmed pathologically and exhibited worse progression-free survival compared with PLGG harboring similar molecular alterations (P = 0.008; multivariate analysis: P = 0.035). Although the current methylation classifier revealed low confidence in 44% of cases and failed to add information in most PLGG, it was helpful in reclassifying rare cases. The addition of histopathological and molecular information to specific methylation subgroups such as pleomorphic xanthoastrocytoma–like tumors could stratify these tumors into low and high risk (P = 0.0014). Conclusion The PLGG methylome is affected by multiple nonneoplastic factors. Combined molecular and pathological analysis is key to provide additional information when methylation classification is used for PLGG in the clinical setting.

Impact of patient age on molecular alterations in left-sided colorectal tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3592-3592 ◽  
Author(s):  
Benjamin Adam Weinberg ◽  
Kelsey Poorman ◽  
David Arguello ◽  
John Marshall ◽  
Mohamed E. Salem
Keyword(s):  
Checkpoint Inhibitors ◽  
Tumor Biology ◽  
Distal Colon ◽  
Predictive Biomarker ◽  
Missense Mutations ◽  
Chi Square ◽  
Molecular Alterations ◽  
Nextgen Sequencing ◽  
Colon And Rectum ◽  
The Impact

3592 Background: The incidence of colorectal cancer (CRC) in younger patients (pts) is rising. This increase is most pronounced in tumors arising from the distal colon and rectum. Since tumor sidedness has emerged as an important prognostic and predictive biomarker in CRC, we aim to explore the impact of age on the tumor biology of left-sided colon cancer (LCC). Herein, we compare profiles of LCC from younger (≤ 45 years) and older pts (≥ 65 years). Methods: LCCs (splenic flexure to rectum; n = 1,602) were examined by NextGen sequencing, protein expression, gene amplification, and microsatellite instability fragment analyses. Tumor mutational load (TML) was calculated using only somatic nonsynonymous missense mutations. Chi-square tests were used for comparisons. Results: LCCs from younger (median age 40, range 22-45 years, n = 229) and older (median age 71, range 65-89, n = 503) pts were studied. The most frequently mutated genes included APC, TP53, KRAS, PIK3CA, ARID1A, FBXW7, SMAD4, ATM, BRAF, and NRAS. Comparing younger v. older pts, there were no significant differences in the rates of APC (75.3% v. 82.9%, P = 0.139), TP53 (79.5% v. 73.1%, P = 0.261), KRAS (37.6% v. 43.0%, P = 0.403), PIK3CA (9.4% v. 14.6%, P = 0.234), ARID1A (14.3% v. 13.2%, P = 0.884), FBXW7 (11.4% v. 10.5%, P = 0.830), SMAD4 (13.1% v. 7.4%, P = 0.129), BRAF (4.8% v. 5.7%, P = 0.762), or NRAS (3.5% v. 2.6%, P = 0.680) mutations. Additionally there were no significant differences in protein overexpression. However, there was a trend towards increased HER2 amplification in younger pts (5.7% v. 2.1%, P = 0.05). MSH6 (4.8% v. 0.5%, P = 0.015), MSH2 (2.4% v. 0%, P = 0.032), POLE (2.4% v. 0%, P = 0.032), and NF1 (7.9% v. 0%, P < 0.001) mutations were observed at higher rates in younger pts. High TML (≥ 17 mutations per megabase) was seen more frequently in younger pts (8.2% v. 2.6%, P = 0.02). Conclusions: The molecular differences between LCC in younger and older pts are mostly due to mutations in mismatch repair genes. Higher TML may predict a higher response rate to checkpoint inhibitors in younger pts with LCC. The differences in tumor biology observed here warrant further study and may eventually be used to tailor therapy.

Molecular correlates of PD-L1 expression in patients (pts) with gastroesophageal (GE) cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4558-4558
Author(s):  
Jingyuan Wang ◽  
Joanne Xiu ◽  
Anthony Frank Shields ◽  
Axel Grothey ◽  
Benjamin Adam Weinberg ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Epigenetic Modification ◽  
Gene Mutations ◽  
Mutation Rates ◽  
Missense Mutations ◽  
Chi Square ◽  
Expression Levels ◽  
Molecular Alterations ◽  
Molecular Features ◽  
The Impact

4558 Background: The increased PD-L1 expression evaluated by combined positive score (CPS) is associated with improved efficacy of immunotherapy in GE cancers. The impact of tumor molecular alterations on PD-L1 expression is still not well-studied. We aimed to characterize specific molecular features of tumors with different CPS levels in GE cancers. Methods: 2,707 GE tumors [1,662 gastric/GE junction adenocarcinoma (GA), 856 esophageal adenocarcinoma (EA), 75 esophageal squamous (ES) and 114 GE unspecified] collected between 2000.8 and 2019.7 were analyzed using NextGen DNA sequencing (NGS), immunohistochemistry (IHC) and fragment analysis (FA) (Caris Life Sciences, Phoenix, AZ). Tumor mutation burden (TMB) was calculated based on somatic nonsynonymous missense mutations. dMMR/MSI status was evaluated by a combination of IHC, FA and NGS. PD-L1 expression measured by IHC (22c3) was evaluated by CPS scores. Molecular alterations were compared in three groups (CPS ≥ 10, H; CPS = 1~9, M; CPS = 0, L) using Fisher-Exact or Chi-square and adjusted for multiple comparison by Benjamini-Hochberg. Significance was determined by adjusted (adj) p < .05. Results: Overall, CPS-H, M, and L were seen in 18% (n = 494), 28% (n = 765) and 53% (n = 1,448) of GE tumors respectively. CPS-H was the most prevalent in ES (43%) followed by GA (19%) and lowest in EA (14%). Overall, TMB was similar between CPS-L and M, but was significantly increased in H (average TMB = 8.4 vs. 8.6 vs. 11 mt/MB, adj p < .0001); the effect was seen in EA and GA, but not in ES. An overall significant association between MSI/dMMR status and PD-L1 expression levels was seen (2%, 3.2% and 12% in CPS-L, M and H, adj p < .05) in GE tumors; the significance was seen in GA, but not in EA or ES. Amplifications of PD-L1 (H: 1.5%, M: 0.1% and L: 0) and PD-L2 (H: 1.1%, M: 0.1%, L: 0) were the highest in CPS-H, while ASPSCR1 (H: 0, M: 0, L: 1%) and TNFRSF14 (H: 0, M: 0.4, L: 2%) were the lowest (adj p < .01). Genes involved in epigenetic modification (top 5: ARID1A, ASXL1, BCL9, BCOR, CREBBP), MAPK ( KRAS, MAP2K1) and mismatch repair ( MLH1, MSH6) had the highest mutation rates in CPS-H, compared to M and L ( p < .0001). In contrast, CDH1 had higher mutation rates in CPS-L (12%), compared to M and H (5% and 5%) ( p < .0001). Conclusions: This is the largest study to investigate the distinct molecular landscape of pts with different PD-L1 expression levels in GE cancers. Our data may provide novel insights for pt selection (e.g. pts with gene mutations involved in epigenetic modification) and the development of rational combination immunotherapy (e.g. drugs targeting MAPK pathway).

scholarly journals Clinical and Molecular Features of Disseminated Pediatric Low Grade Glioma - A Systematic Review of Literature

2021 ◽  
Author(s):  
Joseline Haizel-Cobbina ◽  
Rut Thakkar ◽  
Kelsey Richard ◽  
Adrian Levine ◽  
Julie Bennett ◽  
...  
Keyword(s):  
Systematic Review ◽  
Disease Surveillance ◽  
Tumor Location ◽  
Genetic Alterations ◽  
Risk Of Bias ◽  
Low Grade ◽  
Molecular Alterations ◽  
Molecular Features ◽  
1P Deletion ◽  
Csf Diversion

Abstract INTRODUCTIONGliomas account for approximately 46% of all pediatric CNS tumors. There is growing awareness of pediatric low-grade gliomas (PLGG) that disseminate to distant parenchymal or leptomeningeal locations either at the time of initial diagnosis or upon disease surveillance. Disseminated PLGGs (dPLGGs) are associated with a poorer prognosis than non-disseminated PLGGs. To date there is no comprehensive report characterizing the genome profile of dPLGGs and their associated management. This systematic review aims to identify the pattern of genetic alterations and treatment outcomes described for dPLGG.METHODSA systematic review of the literature was performed to identify relevant articles. A quality and risk of bias assessment of articles was done using the GRADE framework and ROBINS-I tool, respectively.RESULTSFifty-two studies published from 1994 to 2020 were included in this review with 368 cases reported. There was sporadic reporting of genetic alterations. The most common genetic alteration observed among study subjects was 1p deletion (76%) and BRAF-KIAA1549 fusion (55%). BRAF p.V600E mutation was found in 7% of subjects. A higher proportion of cases demonstrated primary dissemination compared to secondary dissemination (65% vs 25%). First-line chemotherapy consisted primarily of an alkylation-based regimen and vinca alkaloids. Surgical intervention ranged from biopsy alone to surgical resection and CSF diversion, and depended largely upon tumor location and timing of dissemination. Overall, 73% of cases were alive at last follow-up (median, 40.2 months). All studies reviewed either ranked low or moderate for both quality and risk of bias assessments. CONCLUSIONWhile 1p deletion and BRAF-KIAA1549 fusion are the most commonly described molecular alterations in dPLGG, these tumors appear to express heterogeneous molecular and biological characteristics distinct from non-disseminated PLGGs. Additional studies on the molecular and biological features of these tumors are needed to better understand the pathogenesis of dPLGG and to inform the development of additional targeted regimens.

Receptor tyrosine kinase gene amplification is predictive of intraoperative seizures during glioma resection with functional mapping

2020 ◽  
Vol 132 (4) ◽  
pp. 1017-1023 ◽  
Author(s):  
Bryan D. Choi ◽  
Daniel K. Lee ◽  
Jimmy C. Yang ◽  
Caroline M. Ayinon ◽  
Christine K. Lee ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Univariate Analysis ◽  
Tumor Resection ◽  
Tumor Grade ◽  
Molecular Data ◽  
Genetic Alterations ◽  
Functional Mapping ◽  
Chi Square ◽  
Kinase Gene ◽  
Glioma Resection

OBJECTIVEIntraoperative seizures during craniotomy with functional mapping is a common complication that impedes optimal tumor resection and results in significant morbidity. The relationship between genetic mutations in gliomas and the incidence of intraoperative seizures has not been well characterized. Here, the authors performed a retrospective study of patients treated at their institution over the last 12 years to determine whether molecular data can be used to predict the incidence of this complication.METHODSThe authors queried their institutional database for patients with brain tumors who underwent resection with intraoperative functional mapping between 2005 and 2017. Basic clinicopathological characteristics, including the status of the following genes, were recorded: IDH1/2, PIK3CA, BRAF, KRAS, AKT1, EGFR, PDGFRA, MET, MGMT, and 1p/19q. Relationships between gene alterations and intraoperative seizures were evaluated using chi-square and two-sample t-test univariate analysis. When considering multiple predictive factors, a logistic multivariate approach was taken.RESULTSOverall, 416 patients met criteria for inclusion; of these patients, 98 (24%) experienced an intraoperative seizure. Patients with a history of preoperative seizure and those treated with antiepileptic drugs prior to surgery were less likely to have intraoperative seizures (history: OR 0.61 [95% CI 0.38–0.96], chi-square = 4.65, p = 0.03; AED load: OR 0.46 [95% CI 0.26–0.80], chi-square = 7.64, p = 0.01). In a univariate analysis of genetic markers, amplification of genes encoding receptor tyrosine kinases (RTKs) was specifically identified as a positive predictor of seizures (OR 5.47 [95% CI 1.22–24.47], chi-square = 5.98, p = 0.01). In multivariate analyses considering RTK status, AED use, and either 2007 WHO tumor grade or modern 2016 WHO tumor groups, the authors found that amplification of the RTK proto-oncogene, MET, was most predictive of intraoperative seizure (p < 0.05).CONCLUSIONSThis study describes a previously unreported association between genetic alterations in RTKs and the occurrence of intraoperative seizures during glioma resection with functional mapping. Future models estimating intraoperative seizure risk may be enhanced by inclusion of genetic criteria.

scholarly journals Mutated p53 in HGSC—From a Common Mutation to a Target for Therapy

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3465
Author(s):  
Aya Saleh ◽  
Ruth Perets
Keyword(s):  
Cancer Progression ◽  
Target Genes ◽  
P53 Protein ◽  
Genetic Alterations ◽  
Common Mutation ◽  
Missense Mutations ◽  
P53 Expression ◽  
Histologic Subtype ◽  
Tp53 Mutations

Mutations in tumor suppressor gene TP53, encoding for the p53 protein, are the most ubiquitous genetic variation in human ovarian HGSC, the most prevalent and lethal histologic subtype of epithelial ovarian cancer (EOC). The majority of TP53 mutations are missense mutations, leading to loss of tumor suppressive function of p53 and gain of new oncogenic functions. This review presents the clinical relevance of TP53 mutations in HGSC, elaborating on several recently identified upstream regulators of mutant p53 that control its expression and downstream target genes that mediate its roles in the disease. TP53 mutations are the earliest genetic alterations during HGSC pathogenesis, and we summarize current information related to p53 function in the pathogenesis of HGSC. The role of p53 is cell autonomous, and in the interaction between cancer cells and its microenvironment. We discuss the reduction in p53 expression levels in tumor associated fibroblasts that promotes cancer progression, and the role of mutated p53 in the interaction between the tumor and its microenvironment. Lastly, we discuss the potential of TP53 mutations to serve as diagnostic biomarkers and detail some more advanced efforts to use mutated p53 as a therapeutic target in HGSC.

Predictive and prognostic biomarkers with therapeutic targets in colorectal cancer: A 2021 update on current development, evidence, and recommendation

2021 ◽  
pp. 107815522110055
Author(s):  
Clement Chung
Keyword(s):  
Checkpoint Inhibitors ◽  
Therapeutic Targets ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Tumor Location ◽  
Prognostic Biomarkers ◽  
Her2 Gene ◽  
Braf Mutations ◽  
Therapeutic Implications ◽  
Molecular Alterations

Although therapeutically actionable molecular alterations are widely distributed across many cancer types, only a handful of them show evidence of clinical utility and are recommended for routine clinical practice in the management of cancers of colon and rectum (CRC). This 2021 update aims to provide a succinct summary on the use of prognostic and/or predictive biomarkers (expanded RAS, BRAF, microsatellite-high [MSI-H] or deficient mismatch repair [dMMR], neurotrophic tyrosine receptor kinase [ NTRK] fusion genes, and human epidermal growth factor receptor type II [ HER2] gene amplification) associated with CRC. Therapeutic implications of each relevant predictive or prognostic biomarker for patients with CRC are described, along with discussion on new developments on (1) biomarker-driven therapies such as testing of BRAF, MLH1 promoter methylation and MMR germline genes in differentiating sporadic CRC or hereditary conditions such as Lynch syndrome; (2) first-line use of immune checkpoint inhibitors in metastatic CRC; (3) risk stratification and therapy selection based on primary tumor location (left-sided vs. right-sided colon cancer); (3) atypical BRAF mutations; (4) use of EGFR directed therapy in the perioperative oligometastatic disease setting; (5) re-challenge of EGFR directed therapy and (6) personalizing therapy of fluoropyrimidine and irinotecan based on new evidence in pharmacogenomic testing. Data are collected and analyzed from available systematic reviews and meta-analyses of treatments with known therapeutic targets in CRC, which may be associated with predictive and/or prognostic biomarkers. Discussions are presented in an application-based format, with goal to empower pharmacists or other clinicians to gain awareness and understanding in biomarker-driven cancer therapy issues.

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