Comprehensive genomic profiling of 443 cases of renal cell carcinoma to reveal frequent clinically relevant genomic alterations.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 433-433 ◽  
Author(s):  
Sumanta Kumar Pal ◽  
Siraj M. Ali ◽  
Zachary Chalmers ◽  
Jose A. Karam ◽  
Julia Andrea Elvin ◽  
...  
Keyword(s):  
Targeted Therapies ◽  
Collecting Duct ◽  
Medullary Carcinoma ◽  
Patient Specific ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Medical Need ◽  
Comprehensive Genomic Profiling ◽  
Metastatic Sites

433 Background: Despite the availability of targeted therapy, effective management of advanced RCC is an unmet medical need as treatment is not personalized and is not guided by patient-specific genomic alterations (GAs). To assess the spectrum of clinically relevant GAs (CRGAs) in advanced RCC, comprehensive genomic profiling (CGP) of clinical RCC samples was performed with the goal of informing use of existing and novel targeted therapies. Methods: DNA was extracted from 40 microns of FFPE sections from 443 consecutive patients with relapsed/metastatic RCC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 646X for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The CGP assay included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. CRGA were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: There were 73% male and 27% female patients with a mean age of 56 years, and the majority of cases were advanced stage with 198/443 specimens (44.6%) from metastatic sites. 400/443 patients (89%) had at least 1 GA on CGP with a mean 3.1 GA/case. 396/400 RCC harboring GA had at least 1 CRGA involving 111 individual genes with a mean of 1.32 CRGA/UC. The most common novel CRGA in order of frequency were: CDKN2A (21%), BAP1 (12%), ATM (11%), PTEN(8.5%), TSC1(8.3%), mTOR (7%), MET (6.5%), AR (5.3%), DNMT3A (5%) and TSC2 (5%). Moreover, VHL harbored a diversity of GA’s in in 49% of cases. Collecting duct carcinomas harbored an enrichment of NF2 truncating alterations (>40%), distinct from renal medullary carcinoma which did not harbor such GA. Multiple clinical antitumor responses to targeted therapies will be presented. Conclusions: Using a CGP assay capable of detecting all classes of GA simultaneously, a high frequency of CRGA was identified in a large series of patients with advanced RCC. The diversity of CRGA suggests opportunities for the rational application of existing and investigational targeted therapies, and for possible deeper characterization of histological types of RCC.

scholarly journals OA03.05 Characterization of Genomic Alterations in Chinese LCNEC and SCLC via Comprehensive Genomic Profiling

2019 ◽  
Vol 14 (10) ◽  
pp. S212-S213
Author(s):  
L. Wu ◽  
L. Cao ◽  
L. Chen ◽  
B. Zhu ◽  
X. Hu ◽  
...  
Keyword(s):  
Genomic Profiling ◽  
Genomic Alterations ◽  
Comprehensive Genomic Profiling

Comprehensive genomic profiling of neuroendocrine carcinoma of the prostate.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 187-187
Author(s):  
Sumanta K. Pal ◽  
Matthew I. Milowsky ◽  
Julia Andrea Elvin ◽  
Siraj Mahamed Ali ◽  
Jean H. Hoffman-Censits ◽  
...  
Keyword(s):  
Neuroendocrine Carcinoma ◽  
Stage Iv ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Tumor Type ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Carcinoma Of The Prostate ◽  
Comprehensive Genomic Profiling ◽  
Metastatic Sites

187 Background: Neuroendocrine carcinoma of the prostate (NCAP) is an aggressive high grade malignancy that often presents as metastatic disease. Current treatments of this tumor have only modest benefit leading investigators to query whether comprehensive genomic profiling (CGP) would have potential to discover novel targets of therapy. Methods: DNA was extracted from 40 microns of FFPE sections from 37 consecutive cases of relapsed/metastatic NCAP. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 583X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Genomic alterations (GA) included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: The median age of the men in this study was 65.1 years (range 43 to 83 years). All (100%) cases were positive for neuroendocrine markers on immunohistochemical staining and were Stage IV at the time of CGP. Samples used for sequencing were obtained from the primary tumor in 9 (24%) of NCAP and from metastatic sites in 28 (76%) of NCAP (12 liver, 6 LN, 2 each from bladder, pelvis and soft tissue, and 1 each from rectum, bone, urethra and ureter. There were 213 total GA (5.8 GA/sample) and 47 CRGA (1.3 CRGA/sample). The most frequent GA were non-CRGA mutations in TP53 (68%) and RB1 (51%). TMPRSS:ERG fusions were identified in 32% of cases whereas AR was altered in 8% (1 mutation and 2 amplifications). The most frequent CRGA involved PTEN (32%), BRCA2 (14%), FGFR1 (5%), PIK3CA (5%) and AKT2 (3%). No alterations in BRAF were identified. Clinical responses to MTOR inhibitors in patients with MTOR pathway alterations will be presented. Conclusions: NCAP has distinctive genomic alterations from classic acinar CAP including reduced frequencies of alterations in TMPRSS:ERG and AR and frequent RB1 mutations. Multiple alterations in the MTOR pathway identified in this infrequent tumor type suggest that these patients may be candidates for MTOR inhibitors and other targeted therapies.

Genomic profiling of nephrectomy and metastatic sites in patients with advanced clear cell renal cell carcinoma (RCC).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 513-513 ◽  
Author(s):  
Guillermo de Velasco ◽  
Russell Madison ◽  
Siraj Mahamed Ali ◽  
Sabina Signoretti ◽  
Stephanie Anne Mullane ◽  
...  
Keyword(s):  
Clear Cell ◽  
Clinical Care ◽  
Point Mutations ◽  
Distant Metastases ◽  
Patient Specific ◽  
Genomic Profiling ◽  
Cell Renal Cell Carcinoma ◽  
Mutation Burden ◽  
Comprehensive Genomic Profiling ◽  
Metastatic Sites

513 Background: Novel biomarkers are required to accurately assess response in renal cancer. Genomic alterations (GAs) in samples from primary (nephrectomy) (N) as compared distant metastases (M) in clear cell RCC (ccRCC) may have clinical implications as well as mutations in circulating tumour DNA (ctDNA). Methods: 237 primary ccRCC nephrectomy specimens and 156 samples from distant metastases were assayed by hybrid capture based comprehensive genomic profiling (CGP) in the course of clinical care to identify GAs suggesting benefit from targeted therapy. Tumor mutation burden (TMB) was assessed as the number of somatic coding point mutations per megabase of targeted territory. Aditionally, 17 patient-specific assays were developed to quantify ctDNA allele fraction (AF) in plasma of mRCC patients. Results: 1263 GAs and 34 clinically relevant GA (CRGAs) were identified. Most common GA identified were VHL (74%/72%), PBRM1 (40%/51%), SETD2 (28%/26%) in N and m respectively (Table). Additionally, most common CRGA identified were TP53 (8%/15%), PTEN (10%/10%), TSC1 (6%/6%), and TERT(5%/9%) in N and m respectively. No difference in TMB was seen between primary and metastatic samples. By site of metastases, soft tissue, and adrenal gland had the highest TMB and lymph node the lowest. In the 17 patients with available ctDNA, 15/17 (88.2%) have a maximum somatic AF < 1% (median 0.33% [0% - 22%]) suggesting generally low tumor content. Interestingly, ctDNA in 3 patients were successfully sequenced including a patient with an EML4-ALKfusion treated with alectinib. Conclusions: This data supports that both primary and metastatic RCC share the majority of common GA. Quantitation of ctDNA is a promising biomarker for response. [Table: see text]

Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets

2015 ◽  
Vol 69 (5) ◽  
pp. 403-408 ◽  
Author(s):  
Hwajeong Lee ◽  
Kai Wang ◽  
Adrienne Johnson ◽  
David M Jones ◽  
Siraj M Ali ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Intrahepatic Cholangiocarcinoma ◽  
Targeted Therapies ◽  
Genomic Profiling ◽  
Gene Fusions ◽  
Single Patient ◽  
Genomic Alterations ◽  
Extrahepatic Cholangiocarcinoma ◽  
Long Tail ◽  
Comprehensive Genomic Profiling

AimWe queried whether extrahepatic cholangiocarcinoma featured clinically relevant genomic alterations that could lead to targeted therapy.MethodsComprehensive genomic profiling by hybridisation capture of up to 315 genes was performed on 99 clinically advanced extrahepatic cholangiocarcinoma.ResultsThere were 60 male and 39 female patients with a median age of 60.5 years. A total of 400 alterations were identified (mean 4.0; range 0–13) in 84 genes. Eighty-two (83%) of extrahepatic cholangiocarcinoma patients featured at least one clinically relevant genomic alterations including KRAS (43%); ERBB2 (9%), PTEN (7%); ATM and NF1 (6%) and CCND1, FBXW7, GNAS, MDM2 and NRAS (all at 5%). BRAF, BRCA2, CDK4, CDK6, FGFR1, FGFR3, PTCH1, RAF1 and STK11 were each altered in a single patient. No IDH1/2 mutations or FGFR2 gene fusions were identified.ConclusionsComprehensive genomic profiling of extrahepatic cholangiocarcinoma differs significantly from intrahepatic cholangiocarcinoma and pancreatic adenocarcinoma, and reveals diverse opportunities for the use of targeted therapies.

Comprehensive genomic profiling of biliary tract cancers to reveal tumor-specific differences and genomic alterations.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 231-231 ◽  
Author(s):  
Jeffrey S. Ross ◽  
Kai Wang ◽  
Daniel Virgil Thomas Catenacci ◽  
Juliann Chmielecki ◽  
Siraj M. Ali ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Targeted Therapies ◽  
Kras Mutation ◽  
Mutation Frequency ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Extrahepatic Cholangiocarcinoma ◽  
Biliary Tract Cancers ◽  
Comprehensive Genomic Profiling ◽  
Tumor Types

231 Background: Intrahepatic cholangiocarcinoma (IHCCA), extrahepatic cholangiocarcinoma (EHCCA) and gallbladder carcinomas (GBCA) typically present at an advanced stage and systemic chemotherapy provides only modest benefit in most cases. We queried whether comprehensive genomic profiling (GCP) of IHCCA, EHCCA and GBCA would reveal clinically relevant genomic alterations (CRGA) that could lead to targeted therapies. Methods: DNA was extracted from 40µ of FFPE sections from 412 IHCCA, 57 EHCCA and 85 GBCA. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of >600X for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The CGP assay included base substitutions, INDELs, copy number alterations and fusions/rearrangements. CRGA were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: Patient characteristics were similar for all three tumor types. IHCCA and GBCa were more common in females and EHCCA were more common males. CGP revealed the results in the Table. Multiple antitumor responses to targeted therapies in each of the 3 tumor types will be presented. Conclusions: IHCCA, EHCCA and GBCA share GA in cell cycle regulation (CDKN2B) and chromatin remodeling (ARID1A). IHCCA features FGFR fusions, IDH1/2 substitutions, BRAF substitutions and MET amplification with a low KRAS mutation frequency. EHCCA and GBCA feature ERBB2 amplifications (GBCA > EHCCA) and PIK3CA/MTOR pathway alterations. EHCCA has a high KRAS mutation frequency whereas the KRAS GA in GBCA is low. The diverse landscape of CRGA in biliary tract cancers can serve as targets for therapies for patients with CCA, BDCA and GBCA and have the potential to improve outcomes for these aggressive forms of malignancy. [Table: see text]

Comprehensive genomic profiling of cancer of the appendix to reveal new routes to targeted therapies.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 608-608 ◽  
Author(s):  
Daniel A. Goldstein ◽  
Julia Andrea Elvin ◽  
Kai Wang ◽  
Walid Labib Shaib ◽  
Michael R. Rossi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Targeted Therapies ◽  
Low Frequency ◽  
Standard Of Care ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Tp53 Mutations ◽  
Base Substitutions ◽  
Comprehensive Genomic Profiling ◽  
Egfr Antibody

608 Background: Cancers of the appendix are rare forms of malignancy that include two major mucin producing tumors, mucinous adenocarcinoma (MA) and goblet cell carcinoid (GCC). There is no clear standard of care for management of these malignancies. We queried whether comprehensive genomic profiling (CGP) of MA and GCC would reveal differences in the pattern of genomic alterations (GA) of these two subtypes of appendiceal cancer and serve as a guide for targeted therapies for this disease. Methods: DNA was extracted from 40 microns of FFPE sections from 20 clinically advanced appendiceal carcinomas (9 GCC and 11 MA). Comprehensive genomic profiling was performed on hybridization-captured, adaptor ligation based libraries to a high mean coverage depth of >600X for 3,230 exons of 182 cancer-related genes, plus 37 introns from 14 genes frequently rearranged in cancer. The results were evaluated for all classes of GA including base substitutions, short insertions and deletions, copy number alterations and fusions/rearrangements. Clinically relevant GAs were defined as GAs linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: Base substitutions in KRAS were seen in 73% of MA and 11% of GCCs. TP53 mutations were seen in 64% of MA and 22% of GCCs. MYC (36%), SMAD4 (27%), and APC (27%) mutations were found in MA but were absent in GCC. Other GA of low frequency, but clinically relevant in both subsets included ERBB2, GNAS, ARID1A, PIK3CA, NRAS, CTNNB1, BRCA1, BRAF, KDR, PTEN, MCL1, IDH1, FBXW7, and RICTOR. Conclusions: KRAS and TP53 mutations are common in appendiceal MA, but rare in appendiceal GCCs. This confirms the differences in biology and has implications regarding the use of targeted therapies such as anti-EGFR antibody treatments. The high frequency of clinically relevant genomic alterations uncovered in this study that can potentially serve as targets for therapies, either approved or in clinical trials, raises hope that CGP can lead to improvement in outcomes for patients with this aggressive form of malignancy.

Carcinomas of the renal medulla: A comprehensive genomic profiling (CGP) study.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 640-640
Author(s):  
Gennady Bratslavsky ◽  
Joseph M Jacob ◽  
Oleg Shapiro ◽  
Julia Andrea Elvin ◽  
Jo-Anne Vergilio ◽  
...  
Keyword(s):  
Targeted Therapies ◽  
Sickle Cell Trait ◽  
Collecting Duct ◽  
Renal Medulla ◽  
Medullary Carcinoma ◽  
High Status ◽  
Duct Carcinoma ◽  
Ffpe Specimen ◽  
Comprehensive Genomic Profiling ◽  
Tumor Types

640 Background: Collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) represent rare tumors that arise in the renal medulla are therapy resistant tumors that progress rapidly. Methods: DNA was extracted from 40 microns of FFPE specimen from refractory CDC (46 cases) and RMC (24 cases). CGPwas performed using a hybrid-capture, adaptor ligation based next generation sequencing assayto a mean coverage depth of > 800X. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA as previously described and reported as mutations/Mb. Microsatellite instability status (MSI) was determined on 114 loci. Results: All CDC patients were older and more frequently male (Table). Sickle cell trait was identified in both CDC and RMC, but far more frequently associated with RMC. All (100%) of CDC and RMC were clinically advanced Stage III and IV tumors with the primary tumor used for CGP in 70% of cases and a metastasis biopsy was sequenced in 30%. All (100%) CDC and RMC were intermediate (Grade 3) or high grade (Grade 4). In both tumor types, the GA/tumor was relatively low and there were no (0%) VHL GA. SMARCB1 GA were significantly more frequent in RMC than CDC but common in both tumors. Targeted therapies for kinase ( EGFR, RET) and MTOR ( NF2, TSC2) pathways were more frequent in CDC than RMC. At 1.8 mut/Mb, the median TMB was low for both tumor types with no (0%) of cases showing≥20 mut/Mb. No (0%) of the CDC or RMC cases featured MSI-high status. Conclusions: In addition to their histologic differences, the frequencies and types of GA seen in CDC differ significantly from that seen in RMC. The opportunities for biomarker driven targeted therapies for bothCDCand RMC appear limited with rare opportunities to target GA in TKGFR and MTOR pathways for CDC. Similarly, the relatively low TMB and absence of MSI-High status in CDC and RMCalso predicts that these tumors may be resistant to immunotherapies.[Table: see text]

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