In search of novel synthetic lethality anti-cancer drug targets in intrahepatic cholangiocarcinoma: MTAP genomic loss.

337 Background: The association of BRCA tumor suppressor gene (TSG) inactivation and PARP inhibitor efficacy through a mechanism of synthetic lethality (SL) is now well-established. Recently, the PRMT5 arginine methyltransferase dependence in cells with MTAP (S-methyl-5'-thioadenosine phosphorylase) genomic alterations (GA) has been proposed as a new SL based anti-tumor strategy and under consideration for development for intrahepatic cholangiocarcinoma (IC). Methods: 2,170 cases of clinically advanced IC were submitted for comprehensive genomic profiling (CGP) to detect genomic alterations (GA), tumor mutational burden (TMB) and microsatellite instability (MSI) using a hybrid capture based assay (F1CDx). PD-L1 expression in tumor cells (Dako 22C3) was measured by IHC and scored using the tumor proportion score (TPS) method. Results: 328 (15%) ICs featured MTAP inactivation (MTAP-IC). 48% of MTAP-IC cases were female and 52% were male with a median age of 66 years (range 26-93 years). MTAP-IC featured 6.3 GA per sample. The median TMB was 2.5 mut/Mb with only 2% of cases with TMB ≥10 mut/Mb. No (0%) MTAP-IC cases were MSI-high. Of 112 MTAP-IC IHC stained for PD-L1, 4% were PD-L1 high (> 50%), 14% were PD-L1 low (1-49%) and 82% were PD-L1 negative. 99% of MTAP inactivation was by copy number (CN) loss and 1% was due to non-CN mutation. In MTAP-IC, 99% featured CDKN2A loss and 95% featured CDKN2B loss (9p21 co-deletion). TP53 was mutated in 31% and KRAS in 24% (3% G12C). Other currently non-targetable GA included ARID1A (19%), BAP1 (16%) and SMAD4 (13%). Among potentially targetable GA, the MTAP-IC featured 12% FGFR2 GA (8% rearrangements), 10% BRAF (8% V600E), 7% IDH1, 7% PIK3CA, 4% BRCA2, 4% ERBB2 (2% amplification) and 3% MET. Conclusions: Comprehensive genomic profiling elucidated that MTAP GA are frequent in IC and features relatively high GA/tumor, including 9p21 co-deletion, but relatively low TMB and PD-L1 expression. Isolated MTAP deletion without CDKN2A/B co-deletion was extremely rare. In addition to the potential targeting of PRMT5 in MTAP-IC tumors, co-altered genes known to be targets in IC such as FGFR2, IDH1 and BRAF are still prevalent in MTAP-IC, indicating potential for combining targeted therapies in some MTAP-IC patients.

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Anal melanoma: A comparative comprehensive genomic profiling study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.9566 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 9566-9566

Author(s):

Jeffrey S. Ross ◽

Russell Madison ◽

Julia Andrea Elvin ◽

Jo-Anne Vergilio ◽

Jonathan Keith Killian ◽

...

Keyword(s):

Uv Light ◽

Light Exposure ◽

Mtor Pathway ◽

Braf V600e ◽

Genomic Profiling ◽

Genomic Alterations ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden ◽

Ffpe Tissues ◽

Tumor Types

9566 Background: We performed a comprehensive genomic profiling (CGP) study of AM and CM to learn of potential genomic alterations (GA) linked to targeted and immune checkpoint inhibitor (ICPI) therapies. Methods: 90 AM and 1804 CM FFPE tissues from late stage underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC. Results: AM and CM had a similar age, but AM females and CM males were significantly more common (P < 0.0001). GA/tumor was significantly higher in CM (UV light exposure) as were the median TMB and frequency of TMB ≥ 10 and 20 mutations/Mb (P < 0.0001 for all comparisons). PD-L1 expression was higher in AM than CM (P = 0.0023). AM and CM were all MS-stable. The contrast in S FB1 mutations in AM and TERT GA in CM were significant (P < 0.0001). Of potentially targetable GA, AM featured significantly more KIT GA than CM (P < 0.0001), whereas CM featured significantly more BRAF GA (P < 0.0001). Only 11% of AM BRAF GA were V600E whereas 74% of CM BRAF GA were V600E (P < 0.0001). MTOR pathway GA were common in both tumor types. Additional potentially targetable alterations in PDGFRA and ERBB2 kinases were seen in AM but not in CM. Conclusions: CM is distinct from AM featuring higher GA/tumor, higher TMB and frequent BRAF V600E GA that predict benefit from ICPI and anti-BRAF therapies. Although both AM and CM feature MTOR pathway targets, AM does have higher PD-L1 expression than CM and is characterized by an array of potentially targetable kinase genes including KIT, PDGFRA, ERBB2 and to a lesser extent than CM, BRAF.[Table: see text]

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

Journal of Clinical Pathology ◽

10.1136/jclinpath-2015-203394 ◽

2015 ◽

Vol 69 (5) ◽

pp. 403-408 ◽

Cited By ~ 23

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.

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Pulmonary Sarcomatoid Carcinomas Commonly Harbor Either Potentially Targetable Genomic Alterations or High Tumor Mutational Burden as Observed by Comprehensive Genomic Profiling

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2017.03.005 ◽

2017 ◽

Vol 12 (6) ◽

pp. 932-942 ◽

Cited By ~ 49

Author(s):

Alexa B. Schrock ◽

Shuyu D. Li ◽

Garrett M. Frampton ◽

James Suh ◽

Eduardo Braun ◽

...

Keyword(s):

Genomic Profiling ◽

Genomic Alterations ◽

Mutational Burden ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden

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Novel synthetic lethality (SL) anti-cancer drug target in urothelial bladder cancer (UCB) based on MTAP genomic loss: Incidence and correlations in standard of care (SOC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.485 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 485-485

Author(s):

Gennady Bratslavsky ◽

Joseph M Jacob ◽

Andrea Necchi ◽

Petros Grivas ◽

Natalie Danziger ◽

...

Keyword(s):

Synthetic Lethality ◽

Standard Of Care ◽

Drug Benefit ◽

Cancer Drug ◽

Genomic Signatures ◽

Therapy Targets ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden ◽

Urothelial Bladder ◽

9P21 Locus

485 Background: When UCB presents or progresses to chemorefractory metastatic disease, the search for new therapy targets is paramount. Targeting PRMT5 arginine methyltransferase accumulation in tumors with MTAP (methylthioadenosine Phosphorylase) genomic loss has been proposed as a new SL based anti-tumor strategy and under consideration for development for UCB. We sought to evaluate the incidence of patients with candidate SL and correlate to treatment-guiding biomarkers currently evaluated in SOC. Methods: 2,683 cases of clinically advanced UCB underwent hybrid-capture based comprehensive genomic profiling in a standard of care setting using the F1CDx FDA-approved assay to evaluate all classes of genomic alterations (GA) among 324 genes. Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 650 (24%) of UCB feature MTAP loss (MTAP-) (Table). The gene and age distributions were similar MTAP intact (MTAP+) and MTAP- UCB. The GA/tumor was higher in MTAP- UCB likely reflecting the significant GA co-deletions of CDKN2A/ B at the 9p21 locus. Of potential therapeutic targets, FGFR3 and PTEN GA were more frequent in the MTAP- UCB. In contrast, biomarkers of immunotherapy (IO) response included higher frequencies of high TMB and high PD-L1 IHC staining in the MTAP+ UCB. Conclusions: When compared with MATP+ UCB, MTAP- UCB differs in genomic signatures including an increase in potential for targeted therapies but a lower potential for IO drug benefit. Thus, the genomic landscape in MTAP- UCB may play a significant role in the design of clinical trials incorporating SL strategies when targeting PRMT5 in MTAP deficient tumors. [Table: see text]

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Mining high-throughput screens for cancer drug targets-lessons from yeast chemical-genomic profiling and synthetic lethality

Wiley Interdisciplinary Reviews Data Mining and Knowledge Discovery ◽

10.1002/widm.1055 ◽

2012 ◽

Vol 2 (3) ◽

pp. 263-272 ◽

Cited By ~ 5

Author(s):

Marja A. Heiskanen ◽

Tero Aittokallio

Keyword(s):

High Throughput ◽

Drug Targets ◽

Synthetic Lethality ◽

Cancer Drug ◽

Genomic Profiling ◽

Chemical Genomic ◽

High Throughput Screens

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134P In search of novel Synthetic Lethality (SL) anti-cancer drug targets: MTAP Genomic Alterations (GA) in human malignancies

Annals of Oncology ◽

10.1016/j.annonc.2020.08.255 ◽

2020 ◽

Vol 31 ◽

pp. S293

Author(s):

E.S. Sokol ◽

R. Madison ◽

D.C. Pavlick ◽

N.A. Danziger ◽

A.B. Schrock ◽

...

Keyword(s):

Drug Targets ◽

Synthetic Lethality ◽

Cancer Drug ◽

Genomic Alterations ◽

Anti Cancer

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Profiling of 3,634 cholangiocarcinomas (CCA) to identify genomic alterations (GA), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4087 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4087-4087 ◽

Cited By ~ 8

Author(s):

Milind M. Javle ◽

Karthikeyan Murugesan ◽

Rachna T. Shroff ◽

Mitesh J. Borad ◽

Reham Abdel-Wahab ◽

...

Keyword(s):

Lymph Node ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Parp Inhibitors ◽

Genomic Profiling ◽

Genomic Alterations ◽

Hybrid Capture ◽

Mutational Burden ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden

4087 Background: The management of CCA has evolved as targeted and immune checkpoint inhibitor (ICPI) therapies have emerged. We used comprehensive genomic profiling (CGP) to characterize the genomic alterations (GA) that have potential to personalize therapy for CCA. Methods: 3634 CCA underwent hybrid capture based CGP on 0.8-1.1 Mb of the coding genome to identify GAs in exons and select introns in up to 404 genes, TMB, microsatellite status (MSI) and % monoallelic genome (gLOH). PD-L1 expression was determined by IHC (Dako 22C3). Results: 52% of CCA were female with a median age of 62 years (range 16 - > 89). The most common biopsy sites were liver (74%), lymph node (4%), bile duct (3.3%), and lung (2%). MSI-high was rare (1%), 118 and 47 cases had TMB > 10 and > 20 mut/mb respectively. Of the latter, 51% (24/47) were MSI-H. PD-L1 amplification (AMP) was present in 0.27%. Of 490 CCA tested, 43 (9%) were positive for PD-L1 expression. 11% of cases had gLOH > 16%, only 2 cases had both TMB > 20 and gLOH > 16%. GA were most common in TP53 (31%), CDKN2A (29%), KRAS (20%) and ARID1A (17%). Potentially targetable GAs included FGFR2 (11%, 85% fusions), BRAF (5%, 50% V600E), ERBB2 (5%, 72% AMP), MET (2%, 90% AMP), EGFR (0.52%) and rarer ( < 0.5%) FGFR3, RET, FGFR1, ALK, and ROS1 fusions. The FGFR2 fusions had 128 unique 3’ partner genes including BICC1 (26%), CCDC6 (3.2%), AHCYL1 (2.6%) and KIAA1217 (2.6%). FGFR2 fusions occurred in a mutually exclusive fashion from high gLOH (p < 0.002), but not high TMB. GA in IDH1 (15%) were mutually exclusive of FGFR2 fusions (p < 1e-13), but co-occurred with PBRM1 GA (23%, p < 1e-21), ARID1A (26% p < 1e-10). IDH1 GA had gLOH similar to the overall CCA population but were enriched for low TMB (p < 1e-3). Conclusions: Nearly 20% of CCA cases harbor targetable kinase GA, half of which were FGFR2 fusions. Independently, an additional 10% (gLOH) and 1% (high TMB, MSI and/or PD-L1 AMP) may benefit from PARP inhibitors and ICPI respectively. Independently, co-mutation of IDH1 and PBRM1/ARID1A defines a class of CCA that warrants further investigation for sensitivity to PARP inhibitors and may serve as a paradigm for other tumors (ie. gliomas) with a similar co-occurrence landscape.

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Genomic landscape of non-small cell lung cancer (NSCLC) with methylthioadenosine phosphorylase (MTAP) deletion.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9116 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9116-9116

Author(s):

Stephen L. Graziano ◽

Dean C. Pavlick ◽

Ethan Sokol ◽

Shakti H. Ramkissoon ◽

Eric Allan Severson ◽

...

Keyword(s):

Tumor Cell ◽

Synthetic Lethality ◽

Checkpoint Inhibitors ◽

Large Cell ◽

Combination Strategies ◽

Genomic Landscape ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden ◽

Cell Expression ◽

The Impact

9116 Background: NSCLC remains a major cause of cancer-associated mortality despite major advancements in treatments. In addition to immune checkpoint inhibitors (ICPI), new strategies for clinically advanced NSCLC now include the development of new synthetic lethality targets focused on protein arginine methyl transferases such as PRMT5 that exploit the impact of tumor cell genomic loss of MTAP. Methods: 29,379 advanced/metastatic NSCLC cases underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 tumor cell expression was determined by DAKO 22C3 immunohistochemistry (IHC); low positive was a tumor proportion score (TPS) 1-49% and high positive was a TPS ≥50%. Results: 3,928 NSCLC exhibited MTAP homozygous loss. Cases had the following subtypes: adenocarcinoma (59%), squamous cell ca (22%), NSCLC NOS (16%), and large cell neuroendocrine, sarcomatoid, adenosquamous ca (all 1%). GA/tumor were similar when CDKN2A/B losses associated with 9p21 co-deletion with MTAP loss are excluded. Significant differences in currently targetable GA included KRAS G12C higher in MTAP-intact NSCLC (P =.0003) and EGFR short variant mutations higher in MTAP-deleted NSCLC (P <.0001). MTAP-intact NSCLC had higher frequencies of GAs in TP53 (P <.0001) and RB1 and a lower frequency of SMARCA4 (P <.0001). GAs frequencies in ERBB2, MET, ALK, ROS1 and NTRK1 were similar. Biomarkers for potential ICPI efficacy were higher in MTAP-intact including TMB ≥10mut/Mb (P =.0002) and low and high PD-L1 IHC staining (P =.01). Biomarkers potentially predictive of ICPI resistance ( STK11 and KEAP1) were similar in both groups. Conclusions: MTAP loss occurs in 13% of NSCLC, supporting the development of novel targeted therapies designed to exploit PRMT5 hyper-dependence in these tumors. MTAP loss in NSCLC is accompanied by differences in targeted and ICPI options for these patients which may impact future combination strategies. Further study of anti-PRMT5 drugs that are enabled by MTAP loss in NSCLC appears warranted.[Table: see text]

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