Abstract
Neuroendocrine tumors (NETs) have historically been subcategorized according to histologic features and the site of anatomic origin. Here, we characterize the genomic alterations in patients enrolled in three phase 3 clinical trials of NET of different anatomic origins and assess the potential correlation with clinical outcomes. Whole-exome and targeted panel sequencing was used to characterize 225 NET samples collected in the RADIANT series of clinical trials. Genomic profiling of NET was analyzed along with nongenomic biomarker data on the tumor grade and circulating chromogranin A (CgA) and neuron-specific enolase (NSE) levels from these patients enrolled in clinical trials. Our results highlight recurrent large-scale chromosomal alterations as a common theme among NET. Although the specific pattern of chromosomal alterations differed between tumor subtypes, the evidence for generalized chromosomal instability (CIN) was observed across all primary sites of NET. In pancreatic NET, although the P value was not significant, higher CIN suggests a trend toward longer survival (HR, 0.55, P = 0.077), whereas in the gastrointestinal NET, lower CIN was associated with longer survival (HR, 0.44, P = 0.0006). Our multivariate analyses demonstrated that when combined with other clinical data among patients with progressive advanced NETs, chromosomal level alteration adds important prognostic information. Large-scale CIN is a common feature of NET, and specific patterns of chromosomal gain and loss appeared to have independent prognostic value in NET subtypes. However, whether CIN in general has clinical significance in NET requires validation in larger patient cohort and warrants further mechanistic studies.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 391-403 |
| Number of pages | 13 |
| Journal | Endocrine-Related Cancer |
| Volume | 26 |
| Issue number | 4 |
| DOIs | |
| State | Published - Jan 1 2018 |
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Keywords
- Chromosomal instability
- Clinical biomarkers
- Everolimus
- Neuroendocrine tumors
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Oncology
- Endocrinology
- Cancer Research
Cite this
Genomic profiling of NETs : A comprehensive analysis of the RADIANT trials. / Yao, James; Garg, Abhishek; Chen, David; Capdevila, Jaume; Engstrom, Paul; Pommier, Rodney; Van Cutsem, Eric; Singh, Simron; Fazio, Nicola; He, Wei; Riester, Markus; Patel, Parul; Voi, Maurizio; Morrissey, Michael; Pavel, Marianne; Helmut Kulke, Matthew.
In: Endocrine-Related Cancer, Vol. 26, No. 4, 01.01.2018, p. 391-403.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Genomic profiling of NETs
T2 - A comprehensive analysis of the RADIANT trials
AU - Yao, James
AU - Garg, Abhishek
AU - Chen, David
AU - Capdevila, Jaume
AU - Engstrom, Paul
AU - Pommier, Rodney
AU - Van Cutsem, Eric
AU - Singh, Simron
AU - Fazio, Nicola
AU - He, Wei
AU - Riester, Markus
AU - Patel, Parul
AU - Voi, Maurizio
AU - Morrissey, Michael
AU - Pavel, Marianne
AU - Helmut Kulke, Matthew
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Neuroendocrine tumors (NETs) have historically been subcategorized according to histologic features and the site of anatomic origin. Here, we characterize the genomic alterations in patients enrolled in three phase 3 clinical trials of NET of different anatomic origins and assess the potential correlation with clinical outcomes. Whole-exome and targeted panel sequencing was used to characterize 225 NET samples collected in the RADIANT series of clinical trials. Genomic profiling of NET was analyzed along with nongenomic biomarker data on the tumor grade and circulating chromogranin A (CgA) and neuron-specific enolase (NSE) levels from these patients enrolled in clinical trials. Our results highlight recurrent large-scale chromosomal alterations as a common theme among NET. Although the specific pattern of chromosomal alterations differed between tumor subtypes, the evidence for generalized chromosomal instability (CIN) was observed across all primary sites of NET. In pancreatic NET, although the P value was not significant, higher CIN suggests a trend toward longer survival (HR, 0.55, P = 0.077), whereas in the gastrointestinal NET, lower CIN was associated with longer survival (HR, 0.44, P = 0.0006). Our multivariate analyses demonstrated that when combined with other clinical data among patients with progressive advanced NETs, chromosomal level alteration adds important prognostic information. Large-scale CIN is a common feature of NET, and specific patterns of chromosomal gain and loss appeared to have independent prognostic value in NET subtypes. However, whether CIN in general has clinical significance in NET requires validation in larger patient cohort and warrants further mechanistic studies.
AB - Neuroendocrine tumors (NETs) have historically been subcategorized according to histologic features and the site of anatomic origin. Here, we characterize the genomic alterations in patients enrolled in three phase 3 clinical trials of NET of different anatomic origins and assess the potential correlation with clinical outcomes. Whole-exome and targeted panel sequencing was used to characterize 225 NET samples collected in the RADIANT series of clinical trials. Genomic profiling of NET was analyzed along with nongenomic biomarker data on the tumor grade and circulating chromogranin A (CgA) and neuron-specific enolase (NSE) levels from these patients enrolled in clinical trials. Our results highlight recurrent large-scale chromosomal alterations as a common theme among NET. Although the specific pattern of chromosomal alterations differed between tumor subtypes, the evidence for generalized chromosomal instability (CIN) was observed across all primary sites of NET. In pancreatic NET, although the P value was not significant, higher CIN suggests a trend toward longer survival (HR, 0.55, P = 0.077), whereas in the gastrointestinal NET, lower CIN was associated with longer survival (HR, 0.44, P = 0.0006). Our multivariate analyses demonstrated that when combined with other clinical data among patients with progressive advanced NETs, chromosomal level alteration adds important prognostic information. Large-scale CIN is a common feature of NET, and specific patterns of chromosomal gain and loss appeared to have independent prognostic value in NET subtypes. However, whether CIN in general has clinical significance in NET requires validation in larger patient cohort and warrants further mechanistic studies.
KW - Chromosomal instability
KW - Clinical biomarkers
KW - Everolimus
KW - Neuroendocrine tumors
UR - http://www.scopus.com/inward/record.url?scp=85062810607&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062810607&partnerID=8YFLogxK
U2 - 10.1530/ERC-18-0332
DO - 10.1530/ERC-18-0332
M3 - Article
VL - 26
SP - 391
EP - 403
JO - Endocrine-Related Cancer
JF - Endocrine-Related Cancer
SN - 1351-0088
IS - 4
ER -