Characterization of VHL missense mutations in sporadic clear cell renal cell carcinoma: hotspots, affected binding domains, functional impact on pVHL and therapeutic relevance

Razafinjatovo, Caroline; Bihr, Svenja; Mischo, Axel; Vogl, Ursula; Schmidinger, Manuela; Moch, Holger; Schraml, Peter

doi:10.1186/s12885-016-2688-0

Table 3 Treatment, response, and VHL mutation status of the patients treated with anti-angiogenic therapies

From: Characterization of VHL missense mutations in sporadic clear cell renal cell carcinoma: hotspots, affected binding domains, functional impact on pVHL and therapeutic relevance

Mutation	Mutation consequence	Functionality prediction	Interacting partners	Disease progression status	Treatment	pT stage	Fuhrman grade
c.163delG/p.Glu55ArgfsX11	fs	LOF		PD	Pazopanib > Everolimus	3	3
c172delC/p.Arg58GlyfsX9	fs	LOF		PD	IFNa > Pazopanib
c.194C > T/p.Ser65Leu	missense	stabilizing	HIF1αN/VDU1/USP33/VDU2/USP20/RPB7/VHLAK/BCL2L11/RPB1	PD	Sunitinib
c.240 T > A/p.Ser80Arg	missense	destabilizing	HIF1αN/VDU1/USP33/VDU2/USP20/RPB7/VHLAK/BCL2L11/HIF1α/EPAS1/RPB1	PD	IFNa > Sorafenib	1
c. 262 T > A/p.Trp88Arg	missense	highly destabilizing	HIF1αN/RPB7/VHLAK/BCL2L11/HIF1α/EPAS1/RPB1/PRKCZ	PD	Sunitinib	3	3
c.268_273del/p.Asn90_Phe91del	in frame	LOF		PD	Sunitinib		3
c.IVS1 + 1G > A (c.340 + 1G > A)	splice mut	LOF		PD	Sorafenib > Sunitinib > Everolimus
c.345_364del/p.Leu116ArgfsX9	fs	LOF		PD	IFNa > Sorafenib
c.349delT/p.Trp117GlyfsX42	fs	LOF		PD	Sunitinib	3	3
c.484 T > C/p.Cys162Arg	missense	neutral	VHLAK/p53/Nur77/EloC/HuR	PD	Sunitinib > Sorafenib > Everolimus > Pazopanib	3	3
c.497_505del9/p.Arg167ValdelSerLeu	in frame	LOF		PD	Sunitinib	3	3
C.580_583delinsAA/p.Val194LysfsX61	fs	LOF		PD	Sunitinib > Sorafenib
c.586A > T/p.Lys196X	nonsense	LOF		PD	Sunitinib > Sorafenib > Everolimus	1
	wild-type	wild-type		PD	Pazopanib	3	4
	wild-type	wild-type		PD	Sunitinib > Pazopanib > Sorafenib > Everolimus	4	3
	wild-type	wild-type		PD	Sunitinib	2	3
c.161_162delTG/p.Met54ArgfsX77	fs	LOF		SD	Sunitinib	3	4
c.203C > A/p.Ser68X	nonsense	LOF		SD	Sorafenib > Pazopanib > Everolimus	3	4
c.327insA/p.His110ProfsX22	fs	LOF		SD	Sunitinib > Sorafenib	1	4
c.IVS1 + 2 T > A (c.340 + 2 T > A)	splice mut	LOF		SD	Pazopanib > Axitinib	3	3
c.345insC/p.Leu116ProfsX15	fs	LOF		SD	Bevacizumab > IFNa > Pazopanib	3	4
c.350delG/p.Trp117CysfsX42	fs	LOF		SD	IFNa/Bevacizumab	1	3
c.481C > T/p.Arg161X	nonsense	LOF		SD	Sorafenib	2	2
	wild-type	wild-type		SD	Sunitinib > Sorafenib > Everolimus
c.167_168delCC/p.Ala56GlyfsX75	fs	LOF		RD	Sorafenib	3	1
c.227_229del3/p.Phe76del	in frame	LOF		RD	Pazopanib > Sunitinib	1	3
c.340G > T/p.Gly114Cys	missense	neutral	HIF1αN/VHLAK/BCL2L11/HIF1α/EPAS1/RPB1/PRKCZ/CARD9/TUBA4A/KIF3A/SP1/JADE1/PRKCD/aPKC-λ/ι/EEF1A1	RD	IFNa > Bevacizumab	2	3
c.383 T > C/p.Leu128Pro ^a	missense	higly destabilizing	HIF1αN/VHLAK/BCL2L11/EEF1A1	RD	Pazopanib	3	4
c.430G > T/p.Gly144X ^a	nonsense	LOF		RD	Pazopanib	3	4
c.458 T > C/p.Leu153Pro	missense	destabilizing	HIF1αN/VHLAK/PRKCD/CCT-ζ-2/TBP1	RD	Sunitinib	2	3
	wild-type	wild-type		RD	Pazopanib > Everolimus	3	3

PD progressive disease, SD Stable disease, RD Regressive disease, LOF loss-of-function, fs frameshift
^aone patient with two mutations

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