AustralieFrV1, PascalFrancis, Corpus, bibRecord, 001586

RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors

Identifieur interne : 001586 ( PascalFrancis/Corpus ); précédent : 001585; suivant : 001587

RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors

Auteurs : Patrick A. Oberholzer ; Damien Kee ; Piotr Dziunycz ; Antje Sucker ; Nyam Kamsukom ; Robert Jones ; Christine Roden ; Clinton J. Chalk ; Kristin Ardlie ; Emanuele Palescandolo ; Adriano Piris ; Laura E. Macconaill ; Caroline Robert ; Günther F. L. Hofbauer ; Grant A. Mcarthur ; Dirk Schadendorf ; Levi A. Garraway

Source :

Journal of clinical oncology [ 0732-183X ] ; 2012.

RBID : Pascal:12-0103033

Descripteurs français

Pascal (Inist)
- Gène ras, Mutation, Multiplication cellulaire, Peau, Cellule tumorale, Homme, Traitement, Gène onc cellulaire, Protooncogène, Inhibiteur, Cancérologie, Gène raf.

English descriptors

KwdEn :
- C-Onc gene, Cancerology, Cell proliferation, Human, Inhibitor, Mutation, Protooncogene, Ras gene, Skin, Treatment, Tumor cell.

Abstract

Purpose RAF inhibitors are effective against melanomas with BRAF V600E mutations but may induce keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs). The potential of these agents to promote secondary malignancies is concerning. We analyzed cSCC and KA lesions for genetic mutations in an attempt to identify an underlying mechanism for their formation. Methods Four international centers contributed 237 KA or cSCC tumor samples from patients receiving an RAF inhibitor (either vemurafenib or sorafenib; n = 19) or immunosuppression therapy (n = 53) or tumors that developed spontaneously (n = 165). Each sample was profiled for 396 known somatic mutations across 33 cancer-related genes by using a mass spectrometric-based genotyping platform. Results Mutations were detected in 16% of tumors (38 of 237), with five tumors harboring two mutations. Mutations in TP53, CDKN2A, HRAS, KRAS, and PIK3CA were previously described in squamous cell tumors. Mutations in MYC, FGFR3, and VHL were identified for the first time. A higher frequency of activating RAS mutations was found in tumors from patients treated with an RAF inhibitor versus populations treated with a non-RAF inhibitor (21.1% v 3.2%; P < .01), although overall mutation rates between treatment groups were similar (RAF inhibitor, 21.1 % ; immunosuppression, 18.9%; and spontaneous, 17.6%; P= not significant). Tumor histology (KA v cSCC), tumor site (head and neck v other), patient age (≤ 70 v > 70 years), and sex had no significant impact on mutation rate or type. Conclusion Squamous cell tumors from patients treated with an RAF inhibitor have a distinct mutational profile that supports a mechanism of therapy-induced tumorigenesis in RAS-primed cells. Conceivably, cotargeting of MEK together with RAF may reduce or prevent formation of these tumors.

Notice en format standard (ISO 2709)

Pour connaître la documentation sur le format Inist Standard.

A01	`01`	`1`		`@0 0732-183X`
A03		`1`		`@0 J. clin. oncol.`
A05				`@2 30`
A06				`@2 3`
A08	`01`	`1`	`ENG`	`@1 RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors`
A11	`01`	`1`		`@1 OBERHOLZER (Patrick A.)`
A11	`02`	`1`		`@1 KEE (Damien)`
A11	`03`	`1`		`@1 DZIUNYCZ (Piotr)`
A11	`04`	`1`		`@1 SUCKER (Antje)`
A11	`05`	`1`		`@1 KAMSUKOM (Nyam)`
A11	`06`	`1`		`@1 JONES (Robert)`
A11	`07`	`1`		`@1 RODEN (Christine)`
A11	`08`	`1`		`@1 CHALK (Clinton J.)`
A11	`09`	`1`		`@1 ARDLIE (Kristin)`
A11	`10`	`1`		`@1 PALESCANDOLO (Emanuele)`
A11	`11`	`1`		`@1 PIRIS (Adriano)`
A11	`12`	`1`		`@1 MACCONAILL (Laura E.)`
A11	`13`	`1`		`@1 ROBERT (Caroline)`
A11	`14`	`1`		`@1 HOFBAUER (Günther F. L.)`
A11	`15`	`1`		`@1 MCARTHUR (Grant A.)`
A11	`16`	`1`		`@1 SCHADENDORF (Dirk)`
A11	`17`	`1`		`@1 GARRAWAY (Levi A.)`
A14	`01`			`@1 Broad Institute of Massachusetts Institute of Technology and Harvard @2 Cambridge @3 USA @Z 1 aut. @Z 8 aut. @Z 9 aut. @Z 12 aut. @Z 17 aut.`
A14	`02`			`@1 Emanuele Palescandolo, and Laura E. MacConaill, Dana-Farber Cancer Institute @3 USA @Z 1 aut. @Z 6 aut. @Z 7 aut. @Z 10 aut. @Z 12 aut.`
A14	`03`			`@1 Massachusetts General Hospital @3 USA @Z 11 aut.`
A14	`04`			`@1 Harvard Medical School @2 Boston, MA @3 USA @Z 11 aut.`
A14	`05`			`@1 Peter MacCallum Cancer Centre @2 East Melbourne @3 USA @Z 2 aut. @Z 15 aut.`
A14	`06`			`@1 University of Melbourne @2 Parkville @3 AUS @Z 2 aut.`
A14	`07`			`@1 University Hospital Zürich @2 Zürich @3 CHE @Z 3 aut. @Z 14 aut.`
A14	`08`			`@1 University Hospital Essen @2 Essen @3 DEU @Z 4 aut. @Z 16 aut.`
A14	`09`			`@1 Gustave Roussy Institute and L'Institut National de la Santé et de la Recherche Médicale (INSERM) U981 @2 Villejuif @3 FRA @Z 5 aut. @Z 13 aut.`
A20				`@1 316-321`
A21				`@1 2012`
A23	`01`			`@0 ENG`
A43	`01`			`@1 INIST @2 20094 @5 354000508870830160`
A44				`@0 0000 @1 © 2012 INIST-CNRS. All rights reserved.`
A45				`@0 47 ref.`
A47	`01`	`1`		`@0 12-0103033`
A60				`@1 P`
A61				`@0 A`
A64	`01`	`1`		`@0 Journal of clinical oncology`
A66	`01`			`@0 USA`
C01	`01`		`ENG`	@0 Purpose RAF inhibitors are effective against melanomas with BRAF V600E mutations but may induce keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs). The potential of these agents to promote secondary malignancies is concerning. We analyzed cSCC and KA lesions for genetic mutations in an attempt to identify an underlying mechanism for their formation. Methods Four international centers contributed 237 KA or cSCC tumor samples from patients receiving an RAF inhibitor (either vemurafenib or sorafenib; n = 19) or immunosuppression therapy (n = 53) or tumors that developed spontaneously (n = 165). Each sample was profiled for 396 known somatic mutations across 33 cancer-related genes by using a mass spectrometric-based genotyping platform. Results Mutations were detected in 16% of tumors (38 of 237), with five tumors harboring two mutations. Mutations in TP53, CDKN2A, HRAS, KRAS, and PIK3CA were previously described in squamous cell tumors. Mutations in MYC, FGFR3, and VHL were identified for the first time. A higher frequency of activating RAS mutations was found in tumors from patients treated with an RAF inhibitor versus populations treated with a non-RAF inhibitor (21.1% v 3.2%; P < .01), although overall mutation rates between treatment groups were similar (RAF inhibitor, 21.1 % ; immunosuppression, 18.9%; and spontaneous, 17.6%; P= not significant). Tumor histology (KA v cSCC), tumor site (head and neck v other), patient age (≤ 70 v > 70 years), and sex had no significant impact on mutation rate or type. Conclusion Squamous cell tumors from patients treated with an RAF inhibitor have a distinct mutational profile that supports a mechanism of therapy-induced tumorigenesis in RAS-primed cells. Conceivably, cotargeting of MEK together with RAF may reduce or prevent formation of these tumors.
C02	`01`	`X`		`@0 002B04`
C03	`01`	`X`	`FRE`	`@0 Gène ras @5 02`
C03	`01`	`X`	`ENG`	`@0 Ras gene @5 02`
C03	`01`	`X`	`SPA`	`@0 Gen ras @5 02`
C03	`02`	`X`	`FRE`	`@0 Mutation @5 03`
C03	`02`	`X`	`ENG`	`@0 Mutation @5 03`
C03	`02`	`X`	`SPA`	`@0 Mutación @5 03`
C03	`03`	`X`	`FRE`	`@0 Multiplication cellulaire @5 05`
C03	`03`	`X`	`ENG`	`@0 Cell proliferation @5 05`
C03	`03`	`X`	`SPA`	`@0 Multiplicación celular @5 05`
C03	`04`	`X`	`FRE`	`@0 Peau @5 06`
C03	`04`	`X`	`ENG`	`@0 Skin @5 06`
C03	`04`	`X`	`SPA`	`@0 Piel @5 06`
C03	`05`	`X`	`FRE`	`@0 Cellule tumorale @5 08`
C03	`05`	`X`	`ENG`	`@0 Tumor cell @5 08`
C03	`05`	`X`	`SPA`	`@0 Célula tumoral @5 08`
C03	`06`	`X`	`FRE`	`@0 Homme @5 09`
C03	`06`	`X`	`ENG`	`@0 Human @5 09`
C03	`06`	`X`	`SPA`	`@0 Hombre @5 09`
C03	`07`	`X`	`FRE`	`@0 Traitement @5 11`
C03	`07`	`X`	`ENG`	`@0 Treatment @5 11`
C03	`07`	`X`	`SPA`	`@0 Tratamiento @5 11`
C03	`08`	`X`	`FRE`	`@0 Gène onc cellulaire @5 12`
C03	`08`	`X`	`ENG`	`@0 C-Onc gene @5 12`
C03	`08`	`X`	`SPA`	`@0 Gen onc celular @5 12`
C03	`09`	`X`	`FRE`	`@0 Protooncogène @5 17`
C03	`09`	`X`	`ENG`	`@0 Protooncogene @5 17`
C03	`09`	`X`	`SPA`	`@0 Protooncogen @5 17`
C03	`10`	`X`	`FRE`	`@0 Inhibiteur @5 18`
C03	`10`	`X`	`ENG`	`@0 Inhibitor @5 18`
C03	`10`	`X`	`SPA`	`@0 Inhibidor @5 18`
C03	`11`	`X`	`FRE`	`@0 Cancérologie @5 19`
C03	`11`	`X`	`ENG`	`@0 Cancerology @5 19`
C03	`11`	`X`	`SPA`	`@0 Cancerología @5 19`
C03	`12`	`X`	`FRE`	`@0 Gène raf @4 INC @5 86`
N21				`@1 079`
N44	`01`			`@1 OTO`
N82				`@1 OTO`

Format Inist (serveur)

NO :	PASCAL 12-0103033 INIST
ET :	RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors
AU :	OBERHOLZER (Patrick A.); KEE (Damien); DZIUNYCZ (Piotr); SUCKER (Antje); KAMSUKOM (Nyam); JONES (Robert); RODEN (Christine); CHALK (Clinton J.); ARDLIE (Kristin); PALESCANDOLO (Emanuele); PIRIS (Adriano); MACCONAILL (Laura E.); ROBERT (Caroline); HOFBAUER (Günther F. L.); MCARTHUR (Grant A.); SCHADENDORF (Dirk); GARRAWAY (Levi A.)
AF :	Broad Institute of Massachusetts Institute of Technology and Harvard/Cambridge/Etats-Unis (1 aut., 8 aut., 9 aut., 12 aut., 17 aut.); Emanuele Palescandolo, and Laura E. MacConaill, Dana-Farber Cancer Institute/Etats-Unis (1 aut., 6 aut., 7 aut., 10 aut., 12 aut.); Massachusetts General Hospital/Etats-Unis (11 aut.); Harvard Medical School/Boston, MA/Etats-Unis (11 aut.); Peter MacCallum Cancer Centre/East Melbourne/Etats-Unis (2 aut., 15 aut.); University of Melbourne/Parkville/Australie (2 aut.); University Hospital Zürich/Zürich/Suisse (3 aut., 14 aut.); University Hospital Essen/Essen/Allemagne (4 aut., 16 aut.); Gustave Roussy Institute and L'Institut National de la Santé et de la Recherche Médicale (INSERM) U981/Villejuif/France (5 aut., 13 aut.)
DT :	Publication en série; Niveau analytique
SO :	Journal of clinical oncology; ISSN 0732-183X; Etats-Unis; Da. 2012; Vol. 30; No. 3; Pp. 316-321; Bibl. 47 ref.
LA :	Anglais
EA :	Purpose RAF inhibitors are effective against melanomas with BRAF V600E mutations but may induce keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs). The potential of these agents to promote secondary malignancies is concerning. We analyzed cSCC and KA lesions for genetic mutations in an attempt to identify an underlying mechanism for their formation. Methods Four international centers contributed 237 KA or cSCC tumor samples from patients receiving an RAF inhibitor (either vemurafenib or sorafenib; n = 19) or immunosuppression therapy (n = 53) or tumors that developed spontaneously (n = 165). Each sample was profiled for 396 known somatic mutations across 33 cancer-related genes by using a mass spectrometric-based genotyping platform. Results Mutations were detected in 16% of tumors (38 of 237), with five tumors harboring two mutations. Mutations in TP53, CDKN2A, HRAS, KRAS, and PIK3CA were previously described in squamous cell tumors. Mutations in MYC, FGFR3, and VHL were identified for the first time. A higher frequency of activating RAS mutations was found in tumors from patients treated with an RAF inhibitor versus populations treated with a non-RAF inhibitor (21.1% v 3.2%; P < .01), although overall mutation rates between treatment groups were similar (RAF inhibitor, 21.1 % ; immunosuppression, 18.9%; and spontaneous, 17.6%; P= not significant). Tumor histology (KA v cSCC), tumor site (head and neck v other), patient age (≤ 70 v > 70 years), and sex had no significant impact on mutation rate or type. Conclusion Squamous cell tumors from patients treated with an RAF inhibitor have a distinct mutational profile that supports a mechanism of therapy-induced tumorigenesis in RAS-primed cells. Conceivably, cotargeting of MEK together with RAF may reduce or prevent formation of these tumors.
CC :	002B04
FD :	Gène ras; Mutation; Multiplication cellulaire; Peau; Cellule tumorale; Homme; Traitement; Gène onc cellulaire; Protooncogène; Inhibiteur; Cancérologie; Gène raf
ED :	Ras gene; Mutation; Cell proliferation; Skin; Tumor cell; Human; Treatment; C-Onc gene; Protooncogene; Inhibitor; Cancerology
SD :	Gen ras; Mutación; Multiplicación celular; Piel; Célula tumoral; Hombre; Tratamiento; Gen onc celular; Protooncogen; Inhibidor; Cancerología
LO :	INIST-20094.354000508870830160
ID :	12-0103033

Links to Exploration step

Pascal:12-0103033

Le document en format XML

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<author><name sortKey="Robert, Caroline" sort="Robert, Caroline" uniqKey="Robert C" first="Caroline" last="Robert">Caroline Robert</name>
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<author><name sortKey="Hofbauer, Gunther F L" sort="Hofbauer, Gunther F L" uniqKey="Hofbauer G" first="Günther F. L." last="Hofbauer">Günther F. L. Hofbauer</name>
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<author><name sortKey="Schadendorf, Dirk" sort="Schadendorf, Dirk" uniqKey="Schadendorf D" first="Dirk" last="Schadendorf">Dirk Schadendorf</name>
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<author><name sortKey="Garraway, Levi A" sort="Garraway, Levi A" uniqKey="Garraway L" first="Levi A." last="Garraway">Levi A. Garraway</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors</title>
<author><name sortKey="Oberholzer, Patrick A" sort="Oberholzer, Patrick A" uniqKey="Oberholzer P" first="Patrick A." last="Oberholzer">Patrick A. Oberholzer</name>
<affiliation><inist:fA14 i1="01"><s1>Broad Institute of Massachusetts Institute of Technology and Harvard</s1>
<s2>Cambridge</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
</affiliation>
<affiliation><inist:fA14 i1="02"><s1>Emanuele Palescandolo, and Laura E. MacConaill, Dana-Farber Cancer Institute</s1>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Kee, Damien" sort="Kee, Damien" uniqKey="Kee D" first="Damien" last="Kee">Damien Kee</name>
<affiliation><inist:fA14 i1="05"><s1>Peter MacCallum Cancer Centre</s1>
<s2>East Melbourne</s2>
<s3>USA</s3>
<sZ>2 aut.</sZ>
<sZ>15 aut.</sZ>
</inist:fA14>
</affiliation>
<affiliation><inist:fA14 i1="06"><s1>University of Melbourne</s1>
<s2>Parkville</s2>
<s3>AUS</s3>
<sZ>2 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Dziunycz, Piotr" sort="Dziunycz, Piotr" uniqKey="Dziunycz P" first="Piotr" last="Dziunycz">Piotr Dziunycz</name>
<affiliation><inist:fA14 i1="07"><s1>University Hospital Zürich</s1>
<s2>Zürich</s2>
<s3>CHE</s3>
<sZ>3 aut.</sZ>
<sZ>14 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Sucker, Antje" sort="Sucker, Antje" uniqKey="Sucker A" first="Antje" last="Sucker">Antje Sucker</name>
<affiliation><inist:fA14 i1="08"><s1>University Hospital Essen</s1>
<s2>Essen</s2>
<s3>DEU</s3>
<sZ>4 aut.</sZ>
<sZ>16 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Kamsukom, Nyam" sort="Kamsukom, Nyam" uniqKey="Kamsukom N" first="Nyam" last="Kamsukom">Nyam Kamsukom</name>
<affiliation><inist:fA14 i1="09"><s1>Gustave Roussy Institute and L'Institut National de la Santé et de la Recherche Médicale (INSERM) U981</s1>
<s2>Villejuif</s2>
<s3>FRA</s3>
<sZ>5 aut.</sZ>
<sZ>13 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Jones, Robert" sort="Jones, Robert" uniqKey="Jones R" first="Robert" last="Jones">Robert Jones</name>
<affiliation><inist:fA14 i1="02"><s1>Emanuele Palescandolo, and Laura E. MacConaill, Dana-Farber Cancer Institute</s1>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Roden, Christine" sort="Roden, Christine" uniqKey="Roden C" first="Christine" last="Roden">Christine Roden</name>
<affiliation><inist:fA14 i1="02"><s1>Emanuele Palescandolo, and Laura E. MacConaill, Dana-Farber Cancer Institute</s1>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Chalk, Clinton J" sort="Chalk, Clinton J" uniqKey="Chalk C" first="Clinton J." last="Chalk">Clinton J. Chalk</name>
<affiliation><inist:fA14 i1="01"><s1>Broad Institute of Massachusetts Institute of Technology and Harvard</s1>
<s2>Cambridge</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Ardlie, Kristin" sort="Ardlie, Kristin" uniqKey="Ardlie K" first="Kristin" last="Ardlie">Kristin Ardlie</name>
<affiliation><inist:fA14 i1="01"><s1>Broad Institute of Massachusetts Institute of Technology and Harvard</s1>
<s2>Cambridge</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Palescandolo, Emanuele" sort="Palescandolo, Emanuele" uniqKey="Palescandolo E" first="Emanuele" last="Palescandolo">Emanuele Palescandolo</name>
<affiliation><inist:fA14 i1="02"><s1>Emanuele Palescandolo, and Laura E. MacConaill, Dana-Farber Cancer Institute</s1>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Piris, Adriano" sort="Piris, Adriano" uniqKey="Piris A" first="Adriano" last="Piris">Adriano Piris</name>
<affiliation><inist:fA14 i1="03"><s1>Massachusetts General Hospital</s1>
<s3>USA</s3>
<sZ>11 aut.</sZ>
</inist:fA14>
</affiliation>
<affiliation><inist:fA14 i1="04"><s1>Harvard Medical School</s1>
<s2>Boston, MA</s2>
<s3>USA</s3>
<sZ>11 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Macconaill, Laura E" sort="Macconaill, Laura E" uniqKey="Macconaill L" first="Laura E." last="Macconaill">Laura E. Macconaill</name>
<affiliation><inist:fA14 i1="01"><s1>Broad Institute of Massachusetts Institute of Technology and Harvard</s1>
<s2>Cambridge</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
</affiliation>
<affiliation><inist:fA14 i1="02"><s1>Emanuele Palescandolo, and Laura E. MacConaill, Dana-Farber Cancer Institute</s1>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Robert, Caroline" sort="Robert, Caroline" uniqKey="Robert C" first="Caroline" last="Robert">Caroline Robert</name>
<affiliation><inist:fA14 i1="09"><s1>Gustave Roussy Institute and L'Institut National de la Santé et de la Recherche Médicale (INSERM) U981</s1>
<s2>Villejuif</s2>
<s3>FRA</s3>
<sZ>5 aut.</sZ>
<sZ>13 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Hofbauer, Gunther F L" sort="Hofbauer, Gunther F L" uniqKey="Hofbauer G" first="Günther F. L." last="Hofbauer">Günther F. L. Hofbauer</name>
<affiliation><inist:fA14 i1="07"><s1>University Hospital Zürich</s1>
<s2>Zürich</s2>
<s3>CHE</s3>
<sZ>3 aut.</sZ>
<sZ>14 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Mcarthur, Grant A" sort="Mcarthur, Grant A" uniqKey="Mcarthur G" first="Grant A." last="Mcarthur">Grant A. Mcarthur</name>
<affiliation><inist:fA14 i1="05"><s1>Peter MacCallum Cancer Centre</s1>
<s2>East Melbourne</s2>
<s3>USA</s3>
<sZ>2 aut.</sZ>
<sZ>15 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Schadendorf, Dirk" sort="Schadendorf, Dirk" uniqKey="Schadendorf D" first="Dirk" last="Schadendorf">Dirk Schadendorf</name>
<affiliation><inist:fA14 i1="08"><s1>University Hospital Essen</s1>
<s2>Essen</s2>
<s3>DEU</s3>
<sZ>4 aut.</sZ>
<sZ>16 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Garraway, Levi A" sort="Garraway, Levi A" uniqKey="Garraway L" first="Levi A." last="Garraway">Levi A. Garraway</name>
<affiliation><inist:fA14 i1="01"><s1>Broad Institute of Massachusetts Institute of Technology and Harvard</s1>
<s2>Cambridge</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>17 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
</analytic>
<series><title level="j" type="main">Journal of clinical oncology</title>
<title level="j" type="abbreviated">J. clin. oncol.</title>
<idno type="ISSN">0732-183X</idno>
<imprint><date when="2012">2012</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt><title level="j" type="main">Journal of clinical oncology</title>
<title level="j" type="abbreviated">J. clin. oncol.</title>
<idno type="ISSN">0732-183X</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>C-Onc gene</term>
<term>Cancerology</term>
<term>Cell proliferation</term>
<term>Human</term>
<term>Inhibitor</term>
<term>Mutation</term>
<term>Protooncogene</term>
<term>Ras gene</term>
<term>Skin</term>
<term>Treatment</term>
<term>Tumor cell</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Gène ras</term>
<term>Mutation</term>
<term>Multiplication cellulaire</term>
<term>Peau</term>
<term>Cellule tumorale</term>
<term>Homme</term>
<term>Traitement</term>
<term>Gène onc cellulaire</term>
<term>Protooncogène</term>
<term>Inhibiteur</term>
<term>Cancérologie</term>
<term>Gène raf</term>
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<front><div type="abstract" xml:lang="en">Purpose RAF inhibitors are effective against melanomas with BRAF V600E mutations but may induce keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs). The potential of these agents to promote secondary malignancies is concerning. We analyzed cSCC and KA lesions for genetic mutations in an attempt to identify an underlying mechanism for their formation. Methods Four international centers contributed 237 KA or cSCC tumor samples from patients receiving an RAF inhibitor (either vemurafenib or sorafenib; n = 19) or immunosuppression therapy (n = 53) or tumors that developed spontaneously (n = 165). Each sample was profiled for 396 known somatic mutations across 33 cancer-related genes by using a mass spectrometric-based genotyping platform. Results Mutations were detected in 16% of tumors (38 of 237), with five tumors harboring two mutations. Mutations in TP53, CDKN2A, HRAS, KRAS, and PIK3CA were previously described in squamous cell tumors. Mutations in MYC, FGFR3, and VHL were identified for the first time. A higher frequency of activating RAS mutations was found in tumors from patients treated with an RAF inhibitor versus populations treated with a non-RAF inhibitor (21.1% v 3.2%; P < .01), although overall mutation rates between treatment groups were similar (RAF inhibitor, 21.1 % ; immunosuppression, 18.9%; and spontaneous, 17.6%; P= not significant). Tumor histology (KA v cSCC), tumor site (head and neck v other), patient age (≤ 70 v > 70 years), and sex had no significant impact on mutation rate or type. Conclusion Squamous cell tumors from patients treated with an RAF inhibitor have a distinct mutational profile that supports a mechanism of therapy-induced tumorigenesis in RAS-primed cells. Conceivably, cotargeting of MEK together with RAF may reduce or prevent formation of these tumors.</div>
</front>
</TEI>
<inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0732-183X</s0>
</fA01>
<fA03 i2="1"><s0>J. clin. oncol.</s0>
</fA03>
<fA05><s2>30</s2>
</fA05>
<fA06><s2>3</s2>
</fA06>
<fA08 i1="01" i2="1" l="ENG"><s1>RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors</s1>
</fA08>
<fA11 i1="01" i2="1"><s1>OBERHOLZER (Patrick A.)</s1>
</fA11>
<fA11 i1="02" i2="1"><s1>KEE (Damien)</s1>
</fA11>
<fA11 i1="03" i2="1"><s1>DZIUNYCZ (Piotr)</s1>
</fA11>
<fA11 i1="04" i2="1"><s1>SUCKER (Antje)</s1>
</fA11>
<fA11 i1="05" i2="1"><s1>KAMSUKOM (Nyam)</s1>
</fA11>
<fA11 i1="06" i2="1"><s1>JONES (Robert)</s1>
</fA11>
<fA11 i1="07" i2="1"><s1>RODEN (Christine)</s1>
</fA11>
<fA11 i1="08" i2="1"><s1>CHALK (Clinton J.)</s1>
</fA11>
<fA11 i1="09" i2="1"><s1>ARDLIE (Kristin)</s1>
</fA11>
<fA11 i1="10" i2="1"><s1>PALESCANDOLO (Emanuele)</s1>
</fA11>
<fA11 i1="11" i2="1"><s1>PIRIS (Adriano)</s1>
</fA11>
<fA11 i1="12" i2="1"><s1>MACCONAILL (Laura E.)</s1>
</fA11>
<fA11 i1="13" i2="1"><s1>ROBERT (Caroline)</s1>
</fA11>
<fA11 i1="14" i2="1"><s1>HOFBAUER (Günther F. L.)</s1>
</fA11>
<fA11 i1="15" i2="1"><s1>MCARTHUR (Grant A.)</s1>
</fA11>
<fA11 i1="16" i2="1"><s1>SCHADENDORF (Dirk)</s1>
</fA11>
<fA11 i1="17" i2="1"><s1>GARRAWAY (Levi A.)</s1>
</fA11>
<fA14 i1="01"><s1>Broad Institute of Massachusetts Institute of Technology and Harvard</s1>
<s2>Cambridge</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>12 aut.</sZ>
<sZ>17 aut.</sZ>
</fA14>
<fA14 i1="02"><s1>Emanuele Palescandolo, and Laura E. MacConaill, Dana-Farber Cancer Institute</s1>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>12 aut.</sZ>
</fA14>
<fA14 i1="03"><s1>Massachusetts General Hospital</s1>
<s3>USA</s3>
<sZ>11 aut.</sZ>
</fA14>
<fA14 i1="04"><s1>Harvard Medical School</s1>
<s2>Boston, MA</s2>
<s3>USA</s3>
<sZ>11 aut.</sZ>
</fA14>
<fA14 i1="05"><s1>Peter MacCallum Cancer Centre</s1>
<s2>East Melbourne</s2>
<s3>USA</s3>
<sZ>2 aut.</sZ>
<sZ>15 aut.</sZ>
</fA14>
<fA14 i1="06"><s1>University of Melbourne</s1>
<s2>Parkville</s2>
<s3>AUS</s3>
<sZ>2 aut.</sZ>
</fA14>
<fA14 i1="07"><s1>University Hospital Zürich</s1>
<s2>Zürich</s2>
<s3>CHE</s3>
<sZ>3 aut.</sZ>
<sZ>14 aut.</sZ>
</fA14>
<fA14 i1="08"><s1>University Hospital Essen</s1>
<s2>Essen</s2>
<s3>DEU</s3>
<sZ>4 aut.</sZ>
<sZ>16 aut.</sZ>
</fA14>
<fA14 i1="09"><s1>Gustave Roussy Institute and L'Institut National de la Santé et de la Recherche Médicale (INSERM) U981</s1>
<s2>Villejuif</s2>
<s3>FRA</s3>
<sZ>5 aut.</sZ>
<sZ>13 aut.</sZ>
</fA14>
<fA20><s1>316-321</s1>
</fA20>
<fA21><s1>2012</s1>
</fA21>
<fA23 i1="01"><s0>ENG</s0>
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<fA43 i1="01"><s1>INIST</s1>
<s2>20094</s2>
<s5>354000508870830160</s5>
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<fA44><s0>0000</s0>
<s1>© 2012 INIST-CNRS. All rights reserved.</s1>
</fA44>
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</fA45>
<fA47 i1="01" i2="1"><s0>12-0103033</s0>
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<fA60><s1>P</s1>
</fA60>
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<fA64 i1="01" i2="1"><s0>Journal of clinical oncology</s0>
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<fA66 i1="01"><s0>USA</s0>
</fA66>
<fC01 i1="01" l="ENG"><s0>Purpose RAF inhibitors are effective against melanomas with BRAF V600E mutations but may induce keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs). The potential of these agents to promote secondary malignancies is concerning. We analyzed cSCC and KA lesions for genetic mutations in an attempt to identify an underlying mechanism for their formation. Methods Four international centers contributed 237 KA or cSCC tumor samples from patients receiving an RAF inhibitor (either vemurafenib or sorafenib; n = 19) or immunosuppression therapy (n = 53) or tumors that developed spontaneously (n = 165). Each sample was profiled for 396 known somatic mutations across 33 cancer-related genes by using a mass spectrometric-based genotyping platform. Results Mutations were detected in 16% of tumors (38 of 237), with five tumors harboring two mutations. Mutations in TP53, CDKN2A, HRAS, KRAS, and PIK3CA were previously described in squamous cell tumors. Mutations in MYC, FGFR3, and VHL were identified for the first time. A higher frequency of activating RAS mutations was found in tumors from patients treated with an RAF inhibitor versus populations treated with a non-RAF inhibitor (21.1% v 3.2%; P < .01), although overall mutation rates between treatment groups were similar (RAF inhibitor, 21.1 % ; immunosuppression, 18.9%; and spontaneous, 17.6%; P= not significant). Tumor histology (KA v cSCC), tumor site (head and neck v other), patient age (≤ 70 v > 70 years), and sex had no significant impact on mutation rate or type. Conclusion Squamous cell tumors from patients treated with an RAF inhibitor have a distinct mutational profile that supports a mechanism of therapy-induced tumorigenesis in RAS-primed cells. Conceivably, cotargeting of MEK together with RAF may reduce or prevent formation of these tumors.</s0>
</fC01>
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<s5>09</s5>
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<fC03 i1="10" i2="X" l="ENG"><s0>Inhibitor</s0>
<s5>18</s5>
</fC03>
<fC03 i1="10" i2="X" l="SPA"><s0>Inhibidor</s0>
<s5>18</s5>
</fC03>
<fC03 i1="11" i2="X" l="FRE"><s0>Cancérologie</s0>
<s5>19</s5>
</fC03>
<fC03 i1="11" i2="X" l="ENG"><s0>Cancerology</s0>
<s5>19</s5>
</fC03>
<fC03 i1="11" i2="X" l="SPA"><s0>Cancerología</s0>
<s5>19</s5>
</fC03>
<fC03 i1="12" i2="X" l="FRE"><s0>Gène raf</s0>
<s4>INC</s4>
<s5>86</s5>
</fC03>
<fN21><s1>079</s1>
</fN21>
<fN44 i1="01"><s1>OTO</s1>
</fN44>
<fN82><s1>OTO</s1>
</fN82>
</pA>
</standard>
<server><NO>PASCAL 12-0103033 INIST</NO>
<ET>RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors</ET>
<AU>OBERHOLZER (Patrick A.); KEE (Damien); DZIUNYCZ (Piotr); SUCKER (Antje); KAMSUKOM (Nyam); JONES (Robert); RODEN (Christine); CHALK (Clinton J.); ARDLIE (Kristin); PALESCANDOLO (Emanuele); PIRIS (Adriano); MACCONAILL (Laura E.); ROBERT (Caroline); HOFBAUER (Günther F. L.); MCARTHUR (Grant A.); SCHADENDORF (Dirk); GARRAWAY (Levi A.)</AU>
<AF>Broad Institute of Massachusetts Institute of Technology and Harvard/Cambridge/Etats-Unis (1 aut., 8 aut., 9 aut., 12 aut., 17 aut.); Emanuele Palescandolo, and Laura E. MacConaill, Dana-Farber Cancer Institute/Etats-Unis (1 aut., 6 aut., 7 aut., 10 aut., 12 aut.); Massachusetts General Hospital/Etats-Unis (11 aut.); Harvard Medical School/Boston, MA/Etats-Unis (11 aut.); Peter MacCallum Cancer Centre/East Melbourne/Etats-Unis (2 aut., 15 aut.); University of Melbourne/Parkville/Australie (2 aut.); University Hospital Zürich/Zürich/Suisse (3 aut., 14 aut.); University Hospital Essen/Essen/Allemagne (4 aut., 16 aut.); Gustave Roussy Institute and L'Institut National de la Santé et de la Recherche Médicale (INSERM) U981/Villejuif/France (5 aut., 13 aut.)</AF>
<DT>Publication en série; Niveau analytique</DT>
<SO>Journal of clinical oncology; ISSN 0732-183X; Etats-Unis; Da. 2012; Vol. 30; No. 3; Pp. 316-321; Bibl. 47 ref.</SO>
<LA>Anglais</LA>
<EA>Purpose RAF inhibitors are effective against melanomas with BRAF V600E mutations but may induce keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs). The potential of these agents to promote secondary malignancies is concerning. We analyzed cSCC and KA lesions for genetic mutations in an attempt to identify an underlying mechanism for their formation. Methods Four international centers contributed 237 KA or cSCC tumor samples from patients receiving an RAF inhibitor (either vemurafenib or sorafenib; n = 19) or immunosuppression therapy (n = 53) or tumors that developed spontaneously (n = 165). Each sample was profiled for 396 known somatic mutations across 33 cancer-related genes by using a mass spectrometric-based genotyping platform. Results Mutations were detected in 16% of tumors (38 of 237), with five tumors harboring two mutations. Mutations in TP53, CDKN2A, HRAS, KRAS, and PIK3CA were previously described in squamous cell tumors. Mutations in MYC, FGFR3, and VHL were identified for the first time. A higher frequency of activating RAS mutations was found in tumors from patients treated with an RAF inhibitor versus populations treated with a non-RAF inhibitor (21.1% v 3.2%; P < .01), although overall mutation rates between treatment groups were similar (RAF inhibitor, 21.1 % ; immunosuppression, 18.9%; and spontaneous, 17.6%; P= not significant). Tumor histology (KA v cSCC), tumor site (head and neck v other), patient age (≤ 70 v > 70 years), and sex had no significant impact on mutation rate or type. Conclusion Squamous cell tumors from patients treated with an RAF inhibitor have a distinct mutational profile that supports a mechanism of therapy-induced tumorigenesis in RAS-primed cells. Conceivably, cotargeting of MEK together with RAF may reduce or prevent formation of these tumors.</EA>
<CC>002B04</CC>
<FD>Gène ras; Mutation; Multiplication cellulaire; Peau; Cellule tumorale; Homme; Traitement; Gène onc cellulaire; Protooncogène; Inhibiteur; Cancérologie; Gène raf</FD>
<ED>Ras gene; Mutation; Cell proliferation; Skin; Tumor cell; Human; Treatment; C-Onc gene; Protooncogene; Inhibitor; Cancerology</ED>
<SD>Gen ras; Mutación; Multiplicación celular; Piel; Célula tumoral; Hombre; Tratamiento; Gen onc celular; Protooncogen; Inhibidor; Cancerología</SD>
<LO>INIST-20094.354000508870830160</LO>
<ID>12-0103033</ID>
</server>
</inist>
</record>

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RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors

RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors

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