scholarly journals Cytogenetic Prognostication Within Medulloblastoma Subgroups

2014 ◽  
Vol 32 (9) ◽  
pp. 886-896 ◽  
Author(s):  
David J.H. Shih ◽  
Paul A. Northcott ◽  
Marc Remke ◽  
Andrey Korshunov ◽  
Vijay Ramaswamy ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Prognostic Significance ◽  
Molecular Biomarkers ◽  
Low Risk ◽  
Chromosome 11 ◽  
Group 4 ◽  
Clinical Biomarkers ◽  
Group 3 ◽  
Very High

Purpose Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.

Identification of Molecular Biomarkers and Pathways for Risk Stratification in Human Papilloma Virus-Associated Cancers

2021 ◽  
Author(s):  
Eun Jung Kwon ◽  
Hye Ran Lee ◽  
Ju Ho Lee ◽  
Mihyang Ha ◽  
Yun Hak Kim ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Expression Patterns ◽  
Risk Groups ◽  
Molecular Biomarkers ◽  
Low Risk ◽  
Receptor Interaction ◽  
Prognostic Impact ◽  
Tumor Microenvironments ◽  
Cell Immunity

Abstract Background: Human papillomavirus (HPV) is the major cause of cervical cancer (CC) etiology; its contribution to head and neck cancer (HNC) incidence is steadily increasing. As individual patients’ response to the treatment of HPV-associated cancer is variable, there is a pressing need for the identification of biomarkers for risk stratification that can help determine the intensity of treatment. Methods: We have previously reported a novel prognostic and predictive indicator (HPPI) scoring system in HPV-associated cancers regardless of the anatomical locations by analyzing the TCGA and GEO databases. In this study, we comprehensively investigated the association of group-specific expression patterns of common differentially expressed genes (DEGs) between high-risk and low-risk groups in HPV-associated CC and HNC, identifying a molecular biomarkers and pathways for the risk stratification. Results: Among the identified 174 DEGs, expression of the genes associated with extracellular matrix (ECM)-receptor interaction pathway (ITGA5, ITGB1, LAMB1, LAMC1) were increased in high-risk groups in both HPV-associated CC and HNC while expression of the genes associated with the T-cell immunity (CD3D, CD3E, CD8B, LCK, and ZAP70) were decreased vise versa. The individual genes showed statistically significant prognostic impact on HPV-associated cancers but not on HPV-negative cancers. The expression levels of identified genes were similar between HPV-negative and HPV-associated high-risk groups with distinct expression patterns only in HPV-associated low-risk groups. Each group of genes showed negative correlations, and distinct patterns of immune cell infiltration in tumor microenvironments. Conclusion: These results identify molecular biomarkers and pathways for risk stratification in HPV-associated cancers regardless of anatomical locations. The identified targets are selectively working in only HPV-associated cancers, but not in HPV-negative cancers indicating possibility of the selective targets governing HPV-infective tumor microenvironments.

scholarly journals Comparação da Aplicação da EER Hema-Obs a 250 Gestações da Consulta de Hematologia-Obstetrícia do Centro Hospitalar São João, Portugal Versus EER Galit Sarig a 90 Gestações no Rambam Health Care Campus, Israel

2015 ◽  
Vol 28 (2) ◽  
pp. 189
Author(s):  
Ana Salselas ◽  
Inês Pestana ◽  
Francisco Bischoff ◽  
Mariana Guimarães ◽  
Joaquim Aguiar Andrade
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Pregnant Women ◽  
Receiver Operating Characteristic ◽  
Operating Characteristic ◽  
Characteristic Curve ◽  
Risk Groups ◽  
Low Risk ◽  
Very High ◽  
Receiver Operating

<strong>Introduction:</strong> Pregnant women with thromboembolic diseases, previous thrombotic episodes or thrombophilia family history were supervised in a multidisciplinary Obstetrics/ Hematology consultation in Centro Hospitalar São João EPE, Porto, Portugal. For the evaluation and medication of these women, a risk stratification scale was used.<br /><strong>Purposes:</strong> The aim of this study was to validate a Risk Stratification Scale and thromboprophylaxis protocol by means of comparing it with a similar scale, developed and published by Sarig.<br /><strong>Material and Methods:</strong> We have compared: The distribution, by risk groups, obtained through the application of the two scales on pregnant women followed at Centro Hospitalar São João, Porto, Portugal, consultation; the sensibility and specificity for each one of the scales (DeLong scale, applied to Receiver Operating Characteristic) curves; the outcomes in pregnancies followed in Hospital São João, Porto, Portugal<br /><strong>Results:</strong> According to our Hema-Obs risk stratification scale, 29% were allocated to low-risk, 47% to high-risk and 24% to very-high-risk groups. According to Galit Sarig risk stratification scale, 24% were considered low-risk, 53% moderate, 16% high-risk and 7% as very high-risk group. In our study we observed 9% of spontaneous abortions, in comparison with 18% in the Galit Sarig cohort. From the application of Receiver Operating Characteristic curve to both risk stratification scales, the results of the calculated areas were 58,8% to our Hema-Obs risk stratification scale and 38,7% to Galit Sarig risk stratification scale, with a Delong test significancie of p = 0.0006.<br /><strong>Conclusions:</strong> We concluded that Hema-Obs risk stratification scale is an effective support for clinical monitoring of therapeutic strategies.

Treatment stratification in B-cell PTLD after solid organ transplantation (SOT) by international prognostic index (IPI) and response to rituximab: Interim results from the PTLD-2 trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8045-8045
Author(s):  
Ralf Ulrich Trappe ◽  
Christian Koenecke ◽  
Martin H. Dreyling ◽  
Christiane Pott ◽  
Ulrich Duehrsen ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Risk Stratification ◽  
B Cell ◽  
Primary Endpoint ◽  
Risk Group ◽  
High Risk Group ◽  
Low Risk ◽  
Solid Organ ◽  
Very High

8045 Background: The PTLD-1 trials have established risk-stratified sequential treatment of B-cell PTLD. After rituximab induction, patients (pts) in complete remission (25 %) received rituximab consolidation, while all others received R-CHOP. The PTLD-2 trial tests modified risk-stratification including clinical risk factors. These are the results of the 2nd scheduled interim analysis (40/60 planned pts). Methods: The prospective, multicenter phase II PTLD-2 trial (NCT02042391) enrols treatment-naïve adult SOT recipients with CD20-positive PTLD. Key exclusion criteria are CNS involvement, ECOG > 2, pregnancy, and severe organ dysfunction or severe, active infection. Treatment consists of rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22. After restaging, pts in CR as well as those in PR with ≤ 2 IPI risk factors at diagnosis (low-risk group) continue with four three-weekly courses of rituximab. Most other pts (high-risk group) receive 4 cycles of R-CHOP-21, while thoracic SOT recipients who progress under rituximab (very-high-risk group) receive six cycles of alternating R-CHOP-21 and R-DHAOx. The primary endpoint (event-free survival in the low-risk group) is not analyzed here. Secondary endpoints presented here are response and overall response (ORR) by computed tomography, overall survival (OS), time to progression (TTP) and treatment-related mortality (TRM) overall and by risk group. Results: 40 pts were recruited at 12 centers (2015 – 2019). 21/40 were kidney, 11 lung, 4 liver, 3 heart, and 1 liver/kidney transplant recipients. Median age was 54 years. 38/40 PTLD were monomorphic and 15/40 EBV-associated. 38 pts were evaluated for response at interim staging: 13 were allocated to the low-risk, 17 to the high-risk and 8 to the very-high-risk group. ORR was 28/30 (93 %, CR: 16/30 [53 %]). With a median follow-up of 1.9 years, the 1-year/3-year Kaplan-Meier (KM) estimates of TTP and OS in the intention-to-treat population (40 pts) were 85 %/80 % and 70 %/70 %, respectively. In the low-risk group, the 2-year KM estimate of OS was 100 %. The frequency of infections (all grades) was 50 %, and TRM occurred in 3/40 pts (8 %). Conclusions: One third of enrolled pts were treated in the low-risk group and the recruitment goal for evaluation of the primary endpoint will likely be reached. Interim efficacy and toxicity data with rituximab SC and modified risk-stratification are encouraging despite the inclusion of 35 % thoracic SOT recipients. Clinical trial information: NCT02042391 .

scholarly journals MBCL-16. EFFICACY OF CARBOPLATIN GIVEN CONCOMITANTLY WITH RADIATION AND ISOTRETINOIN AS A PRO-APOPTOTIC AGENT IN MAINTENANCE THERAPY IN HIGH-RISK MEDULLOBLASTOMA: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii391-iii391
Author(s):  
Sarah Leary ◽  
Roger Packer ◽  
Alok Jaju ◽  
Linda Heier ◽  
Peter Burger ◽  
...  
Keyword(s):  
High Risk ◽  
Residual Disease ◽  
High Risk Group ◽  
Chromosome 17 ◽  
Rank Test ◽  
Chromosome 11 ◽  
Molecular Subgroup ◽  
Group 4 ◽  
Survival Difference ◽  
Group 3

Abstract BACKGROUND Metastasis, residual disease, and diffuse anaplasia are high-risk features in medulloblastoma. METHODS This was a randomized phase 3 study. Patients age 3–21 years with high-risk medulloblastoma received (+/-) daily carboplatin with 36Gy craniospinal radiation and weekly Vincristine followed by six cycles of maintenance chemotherapy with Cisplatin, Cyclophosphamide and Vincristine (+/) 12 cycles of isotretinoin during and following maintenance. The primary endpoint was event-free survival, with exact log-rank test to compare arms. Retrospective molecular analysis included DNA methylation and exome sequencing. RESULTS Of 294 medulloblastoma patients enrolled, 261 were eligible by central review of radiology and pathology, median age 8.6 years (range 3.3–21.2), 70% male, 189 (72%) with metastatic disease, 58 (22%) with diffuse anaplasia, 14 (5%) with &gt;1.5cm2 residual disease. The 5-year EFS and OS for all subjects was 63%+4 and 73%+3, respectively. Isotretinoin randomization was closed due to futility. 5-year EFS was 66 + 5 with carboplatin versus 59 + 5 without (p=0.11), with effect exclusively observed in Group 3 subtype: 73%+8 with carboplatin versus 54%+9 without (p&lt;0.05). Overall survival differed by molecular subgroup (p=0.006): WNT 100%, SHH 54%+11, Group 3 74%+6, Group 4 77%+5 at 5 years. MYC amplification or isochromosome 17 were unfavorable in Group 3 (p=0.029). Chromosome 11 loss or chromosome 17 gain were favorable in group 4 (p&lt;0.001). No survival difference was observed with TP53 mutation in SHH subtype in this high-risk cohort. CONCLUSIONS Therapy intensification with carboplatin improved survival for high-risk group 3 medulloblastoma. These findings further support an integrated clinical and molecular risk stratification for medulloblastoma.

scholarly journals EMBR-25. GENOME-WIDE GENETIC AND EPIGENETIC ASSESSMENT OF GROUP 4 MEDULLOBLASTOMA FOR IMPROVED, BIOMARKER DRIVEN, PROGNOSTICATION AND RISK-STRATIFICATION

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i11-i11
Author(s):  
Jack Goddard ◽  
Jemma Castle ◽  
Emily Southworth ◽  
Stephen Crosier ◽  
Idoia Martin-Guerrero ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Stratification ◽  
Molecular Biomarkers ◽  
Chromosome 8 ◽  
Next Generation ◽  
Chromosome 11 ◽  
Methylation Array ◽  
Molecular Subgroup ◽  
Group 4 ◽  
Dna Methylation Array

Abstract Introduction Medulloblastoma (MB) is the most common malignant brain tumour in children. The most frequent molecular subgroup, Group 4 (MBGrp4) accounts for ~35/40% of cases, however it has the least understood underlying biology. Clinical outcomes are heterogeneous in MBGrp4 and are not accounted for by established clinico-pathological risk factors. There is now a requirement for a comprehensive study of MBGrp4, considering established clinico-pathological features and novel molecular biomarkers to enhance risk-stratification and identify novel therapeutic targets. Methods A clinically-annotated, retrospective MBGrp4 discovery cohort (n = 420) was generated from UK CCLG institutions, collaborating European centres and SIOP-UKCCSG-PNET3 and HIT-SIOP-PNET4 clinical trials. Contemporary, multi-omics profiling was performed. Focal and arm level copy number aberrations (CNAs) were determined from molecular inversion probe (MIP) or DNA methylation array which additionally provided next generation non-WNT/non-SHH (Grp3/Grp4) subtype classifications. Targeted next-generation DNA sequencing was performed to overlay the mutational landscape. Survival modelling was carried out with patients &gt;3 years old who received craniospinal irradiation. Results MBGrp4 subtypes were assigned to 88% of tumours with available data. Subtype VIII was strongly associated with i17q (p&lt;0.0001). The favourable-risk cytogenetic signature (2 or 3 of; chromosome 7 gain, chromosome 8 loss and/or chromosome 11 loss) associated with both subtypes VI and VII (p&lt;0.0001). MYCN amplifications were strongly associated with subtype V (p&lt;0.0001) in addition to 16q loss (p&lt;0.0001). The high-risk CNA group was enriched for mutations in genes involved in chromatin remodelling (p&lt;0.0001). Risk factors were identified from multivariate survival modelling. Subtype and CNA groups contributed to improved risk-stratification models that outperformed current clinical schemes. Conclusion Comprehensive genetic and epigenetic profiling in this large retrospective cohort has improved our understanding of the molecular and clinical heterogeneity within MBGrp4. Incorporation of molecular biomarkers improved risk-stratification for MBGrp4.

scholarly journals Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03)

2021 ◽  
pp. JCO.20.01372
Author(s):  
Amar Gajjar ◽  
Giles W. Robinson ◽  
Kyle S. Smith ◽  
Tong Lin ◽  
Thomas E. Merchant ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Groups ◽  
Genetic Alterations ◽  
Low Risk ◽  
Phase Iii ◽  
Average Risk ◽  
Molecular Features ◽  
Group 4 ◽  
Risk Patients ◽  
Group 3

PURPOSE SJMB03 (ClinicalTrials.gov identifier: NCT00085202 ) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. PATIENTS AND METHODS Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. RESULTS Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( P = .74) or when patients were stratified by clinical risk ( P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%). CONCLUSION These results establish a new risk stratification for future medulloblastoma trials.

scholarly journals Proposal for the use of echocardiography in bloodstream infections due to different streptococcal species

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Sandra Chamat-Hedemand ◽  
Niels Eske Bruun ◽  
Lauge Østergaard ◽  
Magnus Arpi ◽  
Emil Fosbøl ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
High Risk ◽  
Blood Culture ◽  
Positive Blood Culture ◽  
Bloodstream Infections ◽  
Low Risk ◽  
Moderate Risk ◽  
Streptococcal Species ◽  
Very High

Abstract Background Infective endocarditis (IE) is diagnosed in 7–8% of streptococcal bloodstream infections (BSIs), yet it is unclear when to perform transthoracic (TTE) and transoesophageal echocardiography (TOE) according to different streptococcal species. The aim of this sub-study was to propose a flowchart for the use of echocardiography in streptococcal BSIs. Methods In a population-based setup, we investigated all patients admitted with streptococcal BSIs and crosslinked data with nationwide registries to identify comorbidities and concomitant hospitalization with IE. Streptococcal species were divided in four groups based on the crude risk of being diagnosed with IE (low-risk < 3%, moderate-risk 3–10%, high-risk 10–30% and very high-risk > 30%). Based on number of positive blood culture (BC) bottles and IE risk factors (prosthetic valve, previous IE, native valve disease, and cardiac device), we further stratified cases according to probability of concomitant IE diagnosis to create a flowchart suggesting TTE plus TOE (IE > 10%), TTE (IE 3–10%), or “wait & see” (IE < 3%). Results We included 6393 cases with streptococcal BSIs (mean age 68.1 years [SD 16.2], 52.8% men). BSIs with low-risk streptococci (S. pneumoniae, S. pyogenes, S. intermedius) are not initially recommended echocardiography, unless they have ≥3 positive BC bottles and an IE risk factor. Moderate-risk streptococci (S. agalactiae, S. anginosus, S. constellatus, S. dysgalactiae, S. salivarius, S. thermophilus) are guided to “wait & see” strategy if they neither have a risk factor nor ≥3 positive BC bottles, while a TTE is recommended if they have either ≥3 positive BC bottles or a risk factor. Further, a TTE and TOE are recommended if they present with both. High-risk streptococci (S. mitis/oralis, S. parasanguinis, G. adiacens) are directed to a TTE if they neither have a risk factor nor ≥3 positive BC bottles, but to TTE and TOE if they have either ≥3 positive BC bottles or a risk factor. Very high-risk streptococci (S. gordonii, S. gallolyticus, S. mutans, S. sanguinis) are guided directly to TTE and TOE due to a high baseline IE prevalence. Conclusion In addition to the clinical picture, this flowchart based on streptococcal species, number of positive blood culture bottles, and risk factors, can help guide the use of echocardiography in streptococcal bloodstream infections. Since echocardiography results are not available the findings should be confirmed prospectively with the use of systematic echocardiography.

scholarly journals MPC-08 Molecular risk stratification using genome-wide DNA methylation data of standard-risk medulloblastomas treated with 18-Gy craniospinal irradiation

2020 ◽  
Vol 2 (Supplement_3) ◽  
pp. ii12-ii12
Author(s):  
Tomoya Irikura ◽  
Kohei Fukuoka ◽  
Makiko Mori ◽  
Koichi Oshima ◽  
Yuki Arakawa ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Disease Onset ◽  
Low Risk ◽  
Craniospinal Irradiation ◽  
Diagnostic Tools ◽  
Late Relapse ◽  
Mycn Amplification ◽  
Group 4 ◽  
Radiation Induced ◽  
Standard Risk

Abstract A novel risk stratification of medulloblastoma has been proposed based on retrospective data from patients undergoing standard treatment. However, it remains unclear whether the classification is applicable to patients receiving reduced-dose craniospinal irradiation (CSI). We performed molecular diagnosis and copy number analysis using methylation array on patients with standard-risk medulloblastoma treated with 18 Gy CSI at our institution. Nine tumor samples were available for analysis from seven patients who had a median age of 7.4 years at disease onset and a median observation period of 73 months. Three patients had recurrence, and another patient developed radiation-induced glioblastoma. From the three recurrent cases, one was molecularly diagnosed as SHH subtype with MYCN amplification; another case was a Group 4 tumor without favorable prognostic chromosomal aberrations, and the remaining patient experienced a very late relapse despite low-risk stratification. Of the recurrence-free cases, one was classified as WNT subtype, and another was a Group 4 tumor with chromosome 7 gain, and loss of chromosomes 8 and 11, both of which were associated with good prognosis. Methylation analysis also unveiled the fact that the recurrent tumor diagnosed as relapsing medulloblastoma by conventional diagnostic tools was in fact a radiation-induced glioblastoma. Our data suggested that the new risk stratification may be useful for cases treated with CSI reduced to 18 Gy. However, due to the presence of the late-relapsed case stratified to low risk, further investigations with a larger cohort should be required to confirm the data.

Investigation of a 22-gene genomic classifier (GC) for risk stratification and molecular subtyping in an Asian prostate cancer (PCa) cohort.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 249-249
Author(s):  
Wei Loong Sherman Yee ◽  
Wai Yee Woo ◽  
Adelene Sim ◽  
Kar Perng Low ◽  
Alice Meng ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Racial Differences ◽  
White Men ◽  
Risk Groups ◽  
Molecular Subtyping ◽  
Basal Subtype ◽  
Grid Database ◽  
Risk Patients ◽  
Very High

249 Background: A 22-gene GC has been proposed to refine risk stratification of localized PCa by conventional NCCN criteria, and this may potentially influence treatment recommendations. Nonetheless, majority of studies looking at the utility of GC were conducted in White and non-White men from Western cohorts. We therefore investigated the association of GC with NCCN risk groups (RG) in an Asian PCa cohort. Additionally, we examined for inter-racial differences in molecular subtyping between Asian and White/non-White PCa. Methods: GC (Decipher Biosciences Inc., CA) was performed on diagnostic biopsies of men who were treated with radiotherapy +/- hormonal therapy at a single institution (N = 75). ISUP Gleason’s grade (GG) and tumor cellularity were reviewed by an expert GU pathologist. RNA was extracted from 2 x 2.0-mm tumor cores using Qiagen AllPrep DNA/RNA FFPE Kit (Qiagen, Germany) and gene expression was performed on Affymetrix Human Exon 1.0 ST Array (ThermoFischer, CA). PAM50 molecular subtyping was derived using the DecipherGRID database. Results: We profiled 80 tumors from 75 patients, comprising of 18 (24.0%), 9 (12.0%), 21 (28.0%), and 19 (25.3%) NCCN low-/favorable intermediate-, unfavorable intermediate-, high- and very high-RG, respectively; of note, 8 (10.7%) patients had regional/metastatic disease at diagnosis. Using the GC, 27 (33.8%), 14 (17.5%) and 39 (48.8%) were classified as low- (<0.45), intermediate- (0.45-0.6) and high-RG, respectively (>0.6). When stratified using a three-tier clinico-genomic (CG) classification system (Spratt et al. 2017), 6 of 21 (28.6%) NCCN-defined high-risk and 4 of 19 (21.1%) very high-risk patients were downgraded to CG-defined intermediate-/low-risk, while 2 of 27 (7.4%) NCCN low-/intermediate-risk patients were in fact upgraded to CG high-risk. Next, we interrogated the PAM50 basal-luminal signature in our cohort. Interestingly, when matched to White (N = 5762) and non-White (N = 155) for NCCN RG, ISUP GG and age, we observed a high proportion of basal subtype (62.7%) in Asians, which contrasted the prevalence observed in White (16.7%) and non-White (15.9%) North American patients (Chi-sq P <0.001). Conclusions: Here, we demonstrated the utility of the 22-gene GC for refining the NCCN risk stratification in a largest Asian PCa dataset to-date. An unexpectedly high proportion of PAM50 basal-subtype was observed, suggesting race-specific differences of the tumor transcriptome.

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