Characterization of genomic alterations in Chinese LCNEC and SCLC via comprehensive genomic profiling.

1575 Background: LCNEC and SCLC are aggressive neuroendocrine carcinomas with overlap in clinical, histopathologic, morphologic and genomic features. Differential molecular features between the two subtypes have not been well elucidated, contributing the uncertainty for optimal clinical strategy for each subtype. Here we interrogated the genomic characteristics in LCNEC as compared to SCLC along with their histologically related subtypes: carcinoids and atypical carcinoids via comprehensive genomic profiling. Methods: FFPE samples from 31 LCNECs, 35 SCLCs, 14 carcinoids and 22 atypical carcinoids were sequenced in a CLIA-certified sequencing laboratory using 520-cancer-related gene panel, with an average sequencing depth of 1385×. Results: Comparative mutational analysis revealed that both LCNEC and SCLC sub-cohorts displayed higher rate of TP53 alterations than that of carcinoid (p < 0.001, p < 0.001). SCLC patients harbored more RB1 and PIK3CA mutations than LCNECs (p < 0.001, p = 0.014) and carcinoids (p < 0.001, p = 0.018). In addition, mutation frequencies of LRP1B, FAT1, PRKDC, NOTCH1, SPTA1, EPHA3 and KEAP1 in SCLC were significantly higher than that in carcinoid. Mutations in TP53 and RB1 occurred concurrently in 83% (29/35) SCLC patients, whereas in only 32.3% (10/31) LCNECs. We further investigated the distribution of mutations across KEGG pathways and found that mutation frequencies in both HIF-1 and Notch signaling pathways were lower in LCNEC than SCLC (p = 0.032, p = 0.025). Copy number variation (CNV) analysis revealed that LCNEC and SCLC had comparable CNVs which were significantly higher than carcinoid (p < 0.001, p < 0.001) and atypical carcinoid (p = 0.010, p = 0.028). TMB analysis also revealed a comparable TMB status of LCNEC (12.7/Mb) and SCLC (11.9/Mb), and relatively lower TMB in both carcinoid (2.4/Mb, p < 0.001, p < 0.001) and atypical carcinoid (5.6/Mb, p = 0.003, p = 0.009) than LCNEC and SCLC. Conclusions: We demonstrated the differential genomic characteristics in the four subtypes of neuroendocrine carcinomas. Compared with SCLC, LCNEC has lower mutation frequencies in RB1, PIK3CA, as well as HIF-1 and Notch signaling pathways. In addition, LCNEC and SCLC had comparable CNV and TMB status, which significantly higher than that of carcinoids and atypical carcinoid.

Download Full-text

Comprehensive genomic profiling reveals ubiquitous KRAS mutations and frequent PIK3CA mutations in ovarian seromucinous borderline tumor

Modern Pathology ◽

10.1038/s41379-020-0611-3 ◽

2020 ◽

Vol 33 (12) ◽

pp. 2534-2543

Author(s):

Ren-Chin Wu ◽

Shu-Jen Chen ◽

Hua-Chien Chen ◽

Kien Thiam Tan ◽

Shih-Ming Jung ◽

...

Keyword(s):

Borderline Tumor ◽

Genomic Profiling ◽

Kras Mutations ◽

Pik3ca Mutations ◽

Comprehensive Genomic Profiling

Download Full-text

Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System

Cancer Discovery ◽

10.1158/2159-8290.cd-21-0669 ◽

2021 ◽

pp. candisc.0669.2021

Author(s):

Shinichi Yachida ◽

Yasushi Totoki ◽

Michael Noe ◽

Yoichiro Nakatani ◽

Masafumi Horie ◽

...

Keyword(s):

Gastrointestinal System ◽

Genomic Profiling ◽

Comprehensive Genomic Profiling ◽

Neuroendocrine Carcinomas

Download Full-text

Genomic architecture of gallbladder cancer: Results of a first prospective study.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16628 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16628-e16628

Author(s):

Amol Patel ◽

H P Singh ◽

Suresh Pandalanghat ◽

Manish Kumar ◽

Bhupesh Guleria ◽

...

Keyword(s):

Prospective Study ◽

Gallbladder Cancer ◽

Resistance Mechanisms ◽

Driver Mutations ◽

Genomic Profiling ◽

Female Ratio ◽

Pik3ca Mutations ◽

Phase 2 Trial ◽

Comprehensive Genomic Profiling

e16628 Background: Rarity in western countries precluded Gallbladder cancer (GBC) from prospective research. Comprehensive Genomic profiling carries potential to determine oncogenic pathways, driver mutations and possible resistance mechanisms. This study is evaluating the role of comprehensive genomic profiling and role of targeted therapies therein. Methods: This is a single center, prospective, study conducted from Aug2018-Dec2019. All consecutive patients of unresectable and/or metastatic GBC of age ≥18 years were enrolled. Hybrid capture based comprehensive genomic profiling was performed by Foundation Medicine CDx. Microsatellite instability and PDL1 expression were studied. Results: Median age was 56 years (range:26-83) with male to female ratio of 1:1.6. NGS information was available for 50 patients. ERBB pathway was aberrated in 44% of patients. ERBB2 & ERBB3 amplification was seen in 9(18%) and 2(4%) patients respectively. ERBB2 mutations were present concurrently with amplification in 3 patients. MET amplification was present in 3 (6%) PIK3CA mutations were seen in 14% of cases. PIK3CA mutations were independent of ERBB aberrations. FGFR2 mutation, FGFR2 and FGFR3 amplification was present in one patient each. NF1 and NF2 mutations were seen in three and two patients respectively. Median TMB (n = 39) was 5 mut/Mb with range of 1-14 mut/Mb. PDL1 (n = 31) of ≥ 1% was present in 32% of cases and it ranged from 1-100%. MSI (n = 39) was stable in all cases. Other somatic mutations and/or amplifications are shown in Table. Conclusions: GBC is enriched in 28% of patients with ERBB2 & ERBB3 amplifications and/or mutations. FGFR2 mutation is rare in GBC. PIK3CA aberrations are common. Phase 2 trial of frontline Trastuzumab combined with chemotherapy is ongoing. [Table: see text]

Download Full-text

107P Immune Checkpoint Inhibitor (ICPI) resistance genes STK11 and KEAP1: A comparative Comprehensive Genomic Profiling (CGP) study

Annals of Oncology ◽

10.1016/j.annonc.2020.08.228 ◽

2020 ◽

Vol 31 ◽

pp. S283-S284

Author(s):

B. Alexander ◽

E.S. Sokol ◽

N.A. Danziger ◽

D.C. Pavlick ◽

J. Elvin ◽

...

Keyword(s):

Resistance Genes ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Genomic Profiling ◽

Comprehensive Genomic Profiling

Download Full-text

A Combination of Targeted Therapy with Chemotherapy Backbone Induces Response in a Treatment-Resistant Triple-Negative MCL1-Amplified Metastatic Breast Cancer Patient

Case Reports in Oncology ◽

10.1159/000443371 ◽

2016 ◽

Vol 9 (1) ◽

pp. 112-118 ◽

Cited By ~ 3

Author(s):

Siraj M. Ali ◽

Jessica Watson ◽

Kai Wang ◽

Jon H. Chung ◽

Caitlin McMahon ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative ◽

Hospice Care ◽

Treatment Initiation ◽

Clinical Care ◽

Metastatic Breast ◽

Genomic Profiling ◽

Treatment Resistant ◽

Bcl2 Family ◽

Comprehensive Genomic Profiling

After failure of anthracycline- and platinum-based therapy, no effective therapies exist for management of metastatic triple-negative breast cancer (TNBC). We report a case of metastatic TNBC harboring MCL1 amplification, as identified by comprehensive genomic profiling in the course of clinical care. MCL1 is an antiapoptotic gene in the BCL2 family, and MCL1 amplification is common in TNBC (at least 20%). A personalized dose-reduced regimen centered on a combination of sorafenib and vorinostat was implemented, based on preclinical evidence demonstrating treatment synergy in the setting of MCL1 amplification. Although hospice care was being considered before treatment initiation, the personalized regimen yielded 6 additional months of life for this patient. Further rigorous studies are needed to confirm that this regimen or derivatives thereof can benefit the MCL1-amplified subset of TNBC patients.

Download Full-text

Making the Most of Complexity to Create Opportunities: Comprehensive Genomic Profiling and Molecular Tumor Board for Patients with Non-Small Cell Lung Cancer (NSCLC)

Cancers ◽

10.3390/cancers13040609 ◽

2021 ◽

Vol 13 (4) ◽

pp. 609

Author(s):

Caterina Fumagalli ◽

Elena Guerini-Rocco ◽

Massimo Barberis

Keyword(s):

Lung Cancer ◽

Small Cell ◽

Tumor Board ◽

Genomic Profiling ◽

Small Cell Lung ◽

Molecular Alterations ◽

Comprehensive Genomic Profiling ◽

Molecular Tumor Board ◽

Personalized Cancer Therapy ◽

Personalized Cancer

Personalized cancer therapy matches the plan of treatment with specific molecular alterations [...]

Download Full-text

PCN139 Value Frameworks and Innovative Contracting for Comprehensive Genomic Profiling

Value in Health ◽

10.1016/j.jval.2021.04.231 ◽

2021 ◽

Vol 24 ◽

pp. S44-S45

Author(s):

W. Lee ◽

J. Grueger ◽

S. Spencer ◽

D.L. Veenstra ◽

J. Carlson

Keyword(s):

Genomic Profiling ◽

Comprehensive Genomic Profiling ◽

Innovative Contracting

Download Full-text

Dominant Enhancers of Egfr in Drosophila melanogaster: Genetic Links Between the Notch and Egfr Signaling Pathways

Genetics ◽

10.1093/genetics/147.3.1139 ◽

1997 ◽

Vol 147 (3) ◽

pp. 1139-1153 ◽

Cited By ~ 3

Author(s):

James V Price ◽

Edward D Savenye ◽

David Lum ◽

Ashton Breitkreutz

Keyword(s):

Notch Signaling ◽

Signaling Pathways ◽

Growth Factor Receptor ◽

Compound Eyes ◽

Egfr Signaling ◽

Wing Vein ◽

Developmental Context ◽

Epidermal Growth ◽

Hypomorphic Alleles ◽

Complex Signaling

The Drosophila epidermal growth factor receptor (EGFR) is a key component of a complex signaling pathway that participates in multiple developmental processes. We have performed and F1 screen for mutations that cause dominant enhancement of wing vein phenotypes associated with mutations in Egfr. With this screen, we have recovered mutations in Hairless (H), vein, groucho (gro), and three apparently novel loci. All of the E(Egfr)s we have identified show dominant interactions in transheterozygous combinations with each other and with alleles of N or Su(H), suggesting that they are involved in cross-talk between the N and EGFR signaling pathways. Further examination of the phenotypic interactions between Egfr, H, and gro revealed that reductions in Egfr activity enhanced both the bristle loss associated with H mutations, and the bristle hyperplasia and ocellar hypertrophy associated with gro mutations. Double mutant combinations of Egfr and gro hypomorphic alleles led to the formation of ectopic compound eyes in a dosage sensitive manner. Our findings suggest that these E(Egfr)s represent links between the Egfr and Notch signaling pathways, and that Egfr activity can either promote or suppress Notch signaling, depending on its developmental context.

Download Full-text

Clinical utility of comprehensive genomic profiling in central nervous system tumors of children and young adults

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab037 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

Jianling Ji ◽

Kristiyana Kaneva ◽

Matthew C Hiemenz ◽

Girish Dhall ◽

Tom Belle Davidson ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Clinical Utility ◽

Adolescent And Young Adult ◽

Cns Tumors ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Genomic Profiling ◽

Comprehensive Genomic Profiling ◽

Clinically Significant

Abstract Background Recent large-scale genomic studies have revealed a spectrum of genetic variants associated with specific subtypes of central nervous system (CNS) tumors. The aim of this study was to determine the clinical utility of comprehensive genomic profiling of pediatric, adolescent and young adult (AYA) CNS tumors in a prospective setting, including detection of DNA sequence variants, gene fusions, copy number alterations (CNAs), and loss of heterozygosity. Methods OncoKids, a comprehensive DNA- and RNA-based next-generation sequencing (NGS) panel, in conjunction with chromosomal microarray analysis (CMA) was employed to detect diagnostic, prognostic, and therapeutic markers. NGS was performed on 222 specimens from 212 patients. Clinical CMA data were analyzed in parallel for 66% (146/222) of cases. Results NGS demonstrated clinically significant alterations in 66% (147/222) of cases. Diagnostic markers were identified in 62% (138/222) of cases. Prognostic information and targetable genomic alterations were identified in 22% (49/222) and 18% (41/222) of cases, respectively. Diagnostic or prognostic CNAs were revealed by CMA in 69% (101/146) of cases. Importantly, clinically significant CNAs were detected in 57% (34/60) of cases with noncontributory NGS results. Germline cancer predisposition testing was indicated for 27% (57/212) of patients. Follow-up germline testing was performed for 20 patients which confirmed a germline pathogenic/likely pathogenic variant in 9 cases: TP53 (2), NF1 (2), SMARCB1 (1), NF2 (1), MSH6 (1), PMS2 (1), and a patient with 47,XXY Klinefelter syndrome. Conclusions Our results demonstrate the significant clinical utility of integrating genomic profiling into routine clinical testing for pediatric and AYA patients with CNS tumors.

Download Full-text