Pan-tumor landscape of fibroblast growth factor receptor 1-4 genomic alterations

K Murugesan; A Necchi; T C Burn; O Gjoerup; R Greenstein; M Krook; J A López; M Montesion; H Nimeiri; A R Parikh; S Roychowdhury; S Schwemmers; I M Silverman; A Vogel

doi:10.1016/j.esmoop.2022.100641

Pan-tumor landscape of fibroblast growth factor receptor 1-4 genomic alterations

K Murugesan, A Necchi, T C Burn, O Gjoerup, R Greenstein, M Krook, J A López, M Montesion, H Nimeiri, A R Parikh, S Roychowdhury, S Schwemmers, I M Silverman, A Vogel

Producción científica: Article › revisión exhaustiva

19 Citas (Scopus)

Resumen

BACKGROUND: Selective tyrosine kinase inhibitors targeting fibroblast growth factor receptor (FGFR) 1-4 genomic alterations are in development or have been approved for FGFR-altered cancers (e.g. bladder cancer and advanced intrahepatic cholangiocarcinoma). Understanding FGFR inhibitor-resistance mechanisms is increasingly relevant; we surveyed the pan-tumor landscape of FGFR1-4 genomic alterations [short variants (SVs), gene rearrangements (REs), and copy number alterations (CNAs)], including their association with tumor mutational burden (TMB) and the genomic comutational landscape.

PATIENTS AND METHODS: Comprehensive genomic profiling of 355 813 solid tumor clinical cases was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc.) to identify genomic alterations in >300 cancer-associated genes and TMB (determined on ≤1.1 megabases of sequenced DNA).

RESULTS: FGFR1-4 SVs and REs occurred in 9603/355 813 (2.7%), and CNAs in 15 078/355 813 (4.2%) samples. Most common FGFR alterations for bladder cancer, intrahepatic cholangiocarcinoma, and glioma were FGFR3 SVs (1051/7739, 13.6%), FGFR2 REs (618/6641, 9.3%), and FGFR1 SVs (239/11 550, 2.1%), respectively. We found several, potentially clinically relevant, tumor-specific associations between FGFR1-4 genomic alterations and other genomic markers. FGFR3 SV-altered bladder cancers and FGFR1 SV-altered gliomas were significantly less likely to be TMB-high versus unaltered samples. FGFR3 SVs in bladder cancer significantly co-occurred with TERT and CDKN2A/B alterations; TP53 and RB1 alterations were mutually exclusive. In intrahepatic cholangiocarcinoma, FGFR2 REs significantly co-occurred with BAP1 alterations, whereas KRAS, TP53, IDH1, and ARID1A alterations were mutually exclusive. FGFR1 SVs in gliomas significantly co-occurred with H3-3A and PTPN11 alterations, but were mutually exclusive with TERT, EGFR, TP53, and CDKN2A/B alterations.

CONCLUSIONS: Overall, our hypothesis-generating findings may help to stratify patients in clinical trials and guide optimal targeted therapy in those with FGFR alterations.

Idioma original	English (US)
Páginas (desde-hasta)	100641
Publicación	ESMO Open
Volumen	7
N.º	6
DOI	https://doi.org/10.1016/j.esmoop.2022.100641
Estado	Published - dic 2022

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@article{d75deebb441b4c80b55b78e895f8ed54,

title = "Pan-tumor landscape of fibroblast growth factor receptor 1-4 genomic alterations",

abstract = "BACKGROUND: Selective tyrosine kinase inhibitors targeting fibroblast growth factor receptor (FGFR) 1-4 genomic alterations are in development or have been approved for FGFR-altered cancers (e.g. bladder cancer and advanced intrahepatic cholangiocarcinoma). Understanding FGFR inhibitor-resistance mechanisms is increasingly relevant; we surveyed the pan-tumor landscape of FGFR1-4 genomic alterations [short variants (SVs), gene rearrangements (REs), and copy number alterations (CNAs)], including their association with tumor mutational burden (TMB) and the genomic comutational landscape.PATIENTS AND METHODS: Comprehensive genomic profiling of 355 813 solid tumor clinical cases was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc.) to identify genomic alterations in >300 cancer-associated genes and TMB (determined on ≤1.1 megabases of sequenced DNA).RESULTS: FGFR1-4 SVs and REs occurred in 9603/355 813 (2.7%), and CNAs in 15 078/355 813 (4.2%) samples. Most common FGFR alterations for bladder cancer, intrahepatic cholangiocarcinoma, and glioma were FGFR3 SVs (1051/7739, 13.6%), FGFR2 REs (618/6641, 9.3%), and FGFR1 SVs (239/11 550, 2.1%), respectively. We found several, potentially clinically relevant, tumor-specific associations between FGFR1-4 genomic alterations and other genomic markers. FGFR3 SV-altered bladder cancers and FGFR1 SV-altered gliomas were significantly less likely to be TMB-high versus unaltered samples. FGFR3 SVs in bladder cancer significantly co-occurred with TERT and CDKN2A/B alterations; TP53 and RB1 alterations were mutually exclusive. In intrahepatic cholangiocarcinoma, FGFR2 REs significantly co-occurred with BAP1 alterations, whereas KRAS, TP53, IDH1, and ARID1A alterations were mutually exclusive. FGFR1 SVs in gliomas significantly co-occurred with H3-3A and PTPN11 alterations, but were mutually exclusive with TERT, EGFR, TP53, and CDKN2A/B alterations.CONCLUSIONS: Overall, our hypothesis-generating findings may help to stratify patients in clinical trials and guide optimal targeted therapy in those with FGFR alterations.",

keywords = "Humans, Bile Duct Neoplasms, Bile Ducts, Intrahepatic, Biomarkers, Tumor/genetics, Cholangiocarcinoma/genetics, Genomics, Glioma/genetics, Receptor, Fibroblast Growth Factor, Type 1/genetics, Urinary Bladder Neoplasms/drug therapy, Receptor Protein-Tyrosine Kinases/metabolism",

author = "K Murugesan and A Necchi and Burn, {T C} and O Gjoerup and R Greenstein and M Krook and L{\'o}pez, {J A} and M Montesion and H Nimeiri and Parikh, {A R} and S Roychowdhury and S Schwemmers and Silverman, {I M} and A Vogel",

year = "2022",

month = dec,

doi = "10.1016/j.esmoop.2022.100641",

language = "English (US)",

volume = "7",

pages = "100641",

journal = "ESMO Open",

issn = "2059-7029",

publisher = "Elsevier B.V.",

number = "6",

}

TY - JOUR

T1 - Pan-tumor landscape of fibroblast growth factor receptor 1-4 genomic alterations

AU - Murugesan, K

AU - Necchi, A

AU - Burn, T C

AU - Gjoerup, O

AU - Greenstein, R

AU - Krook, M

AU - López, J A

AU - Montesion, M

AU - Nimeiri, H

AU - Parikh, A R

AU - Roychowdhury, S

AU - Schwemmers, S

AU - Silverman, I M

AU - Vogel, A

PY - 2022/12

Y1 - 2022/12

N2 - BACKGROUND: Selective tyrosine kinase inhibitors targeting fibroblast growth factor receptor (FGFR) 1-4 genomic alterations are in development or have been approved for FGFR-altered cancers (e.g. bladder cancer and advanced intrahepatic cholangiocarcinoma). Understanding FGFR inhibitor-resistance mechanisms is increasingly relevant; we surveyed the pan-tumor landscape of FGFR1-4 genomic alterations [short variants (SVs), gene rearrangements (REs), and copy number alterations (CNAs)], including their association with tumor mutational burden (TMB) and the genomic comutational landscape.PATIENTS AND METHODS: Comprehensive genomic profiling of 355 813 solid tumor clinical cases was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc.) to identify genomic alterations in >300 cancer-associated genes and TMB (determined on ≤1.1 megabases of sequenced DNA).RESULTS: FGFR1-4 SVs and REs occurred in 9603/355 813 (2.7%), and CNAs in 15 078/355 813 (4.2%) samples. Most common FGFR alterations for bladder cancer, intrahepatic cholangiocarcinoma, and glioma were FGFR3 SVs (1051/7739, 13.6%), FGFR2 REs (618/6641, 9.3%), and FGFR1 SVs (239/11 550, 2.1%), respectively. We found several, potentially clinically relevant, tumor-specific associations between FGFR1-4 genomic alterations and other genomic markers. FGFR3 SV-altered bladder cancers and FGFR1 SV-altered gliomas were significantly less likely to be TMB-high versus unaltered samples. FGFR3 SVs in bladder cancer significantly co-occurred with TERT and CDKN2A/B alterations; TP53 and RB1 alterations were mutually exclusive. In intrahepatic cholangiocarcinoma, FGFR2 REs significantly co-occurred with BAP1 alterations, whereas KRAS, TP53, IDH1, and ARID1A alterations were mutually exclusive. FGFR1 SVs in gliomas significantly co-occurred with H3-3A and PTPN11 alterations, but were mutually exclusive with TERT, EGFR, TP53, and CDKN2A/B alterations.CONCLUSIONS: Overall, our hypothesis-generating findings may help to stratify patients in clinical trials and guide optimal targeted therapy in those with FGFR alterations.

AB - BACKGROUND: Selective tyrosine kinase inhibitors targeting fibroblast growth factor receptor (FGFR) 1-4 genomic alterations are in development or have been approved for FGFR-altered cancers (e.g. bladder cancer and advanced intrahepatic cholangiocarcinoma). Understanding FGFR inhibitor-resistance mechanisms is increasingly relevant; we surveyed the pan-tumor landscape of FGFR1-4 genomic alterations [short variants (SVs), gene rearrangements (REs), and copy number alterations (CNAs)], including their association with tumor mutational burden (TMB) and the genomic comutational landscape.PATIENTS AND METHODS: Comprehensive genomic profiling of 355 813 solid tumor clinical cases was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc.) to identify genomic alterations in >300 cancer-associated genes and TMB (determined on ≤1.1 megabases of sequenced DNA).RESULTS: FGFR1-4 SVs and REs occurred in 9603/355 813 (2.7%), and CNAs in 15 078/355 813 (4.2%) samples. Most common FGFR alterations for bladder cancer, intrahepatic cholangiocarcinoma, and glioma were FGFR3 SVs (1051/7739, 13.6%), FGFR2 REs (618/6641, 9.3%), and FGFR1 SVs (239/11 550, 2.1%), respectively. We found several, potentially clinically relevant, tumor-specific associations between FGFR1-4 genomic alterations and other genomic markers. FGFR3 SV-altered bladder cancers and FGFR1 SV-altered gliomas were significantly less likely to be TMB-high versus unaltered samples. FGFR3 SVs in bladder cancer significantly co-occurred with TERT and CDKN2A/B alterations; TP53 and RB1 alterations were mutually exclusive. In intrahepatic cholangiocarcinoma, FGFR2 REs significantly co-occurred with BAP1 alterations, whereas KRAS, TP53, IDH1, and ARID1A alterations were mutually exclusive. FGFR1 SVs in gliomas significantly co-occurred with H3-3A and PTPN11 alterations, but were mutually exclusive with TERT, EGFR, TP53, and CDKN2A/B alterations.CONCLUSIONS: Overall, our hypothesis-generating findings may help to stratify patients in clinical trials and guide optimal targeted therapy in those with FGFR alterations.

KW - Humans

KW - Bile Duct Neoplasms

KW - Bile Ducts, Intrahepatic

KW - Biomarkers, Tumor/genetics

KW - Cholangiocarcinoma/genetics

KW - Genomics

KW - Glioma/genetics

KW - Receptor, Fibroblast Growth Factor, Type 1/genetics

KW - Urinary Bladder Neoplasms/drug therapy

KW - Receptor Protein-Tyrosine Kinases/metabolism

U2 - 10.1016/j.esmoop.2022.100641

DO - 10.1016/j.esmoop.2022.100641

M3 - Article

C2 - 36462464

SN - 2059-7029

VL - 7

SP - 100641

JO - ESMO Open

JF - ESMO Open

IS - 6

ER -

Pan-tumor landscape of fibroblast growth factor receptor 1-4 genomic alterations

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