Table 3. Potential therapies for genomic aberrations in each of 17 patients with Merkel cell carcinoma [34–72] ^[a].

C	Aberrations	Examples of potential cognate targeted therapies
1	NF1 L937*	NF1 may be targeted with the mTOR inhibitor everolimus [34, 35] and /or the MEK inhibitor trametinib [36]
	RB1 Q685*TP53 H179Y	Longer progression free survival with bevacizumab in patient with TP53 mutations [37, 38]
2	RICTOR amplification	RICTOR amplification is targetable by investigational mTORC1/mTORC2 inhibiotrs (such as AZD8055 and MLN0128) [39–41]
3	CDKN2C lossPIK3R1 Q221*	PIK3R1 mutation targeted with mTOR inhibitor everolimus [42, 43]
4	BAP1 G422fs*8	BAP1 targeted with PARP inhibitor olaparib [44–47]
	BRCA2 K3326*	BRCA2 targeted with PARP inhibitor olaparib [44, 45, 48, 49]
	PDGFRB L986F [b]	PDGFRB targeted by dovitinib [50] and sorafenib [51]
	RB1 Q257*TP53 C275W	Longer progression free survival with bevacizumab in patient with TP53 mutations [37, 38]
5	ARID1A loss
6	MYC amplificationNTRK3 K461R [b]	NTRK3 inhibitors in development; also targeted by crizotinib [52, 53]
	RB1 Q93*TP53 K120*	Longer progression free survival with bevacizumab in patient with TP53 mutations [37, 38]
7	AKT2 amplification	AKT2 may be targeted with AKT or mTOR inhibitors [54] or MEK inhibitors [55]
	RB1 Q93*TP53 Q331*	Longer progression free survival with bevacizumab in patient with TP53 mutations [37, 38]
8	CDKN2A/B loss	CDKN2A/B loss leads to activation of the CDK4/6 pathway which can be targeted with CDK4/6 inhibitor palbociclib [56]
	EGFR E282K [b]	EGFR targeted with erlotinib or cetuximab [57]
9	BAP1 Q729*	BAP1 may theoretically be targeted by olaparib and platinums [44–47]
	FANCA T1161M [b]	FANCA may theoretically be targeted by PARP inhibitors and platinums [44–47, 58, 59]
	MLH1 E694*	MLH1 mutations may be targeted by PARP inhibitors and Top1 inhibitor (irinotecan) [60] or antiPD1 agents [61]
	RB1 splice site 1499 – 2A > GRB1 splice site 2489 + 1G > ATP53 R248W	Longer progression free survival with bevacizumab in patient with TP53 mutations [37, 38]
10	FBXW7 Q95*	FBXW7 may be targeted by mTOR inhibitors [62, 63]
	NOTCH1 splice site 4586 + 1G > A [c]	NOTCH1 is potentially targetable with gamma-secretase inhibitor [64, 65]; this alteration is unlikely to be activating
	RB1 splice site 1422–1G > ASMARCA4 R1192C1TP53 R280K	Longer progression free survival with bevacizumab in patient with TP53 mutations [37, 38]
11	KMT2D truncation, exon 4NOTCH1 splice site 5168–1G > A [c]	NOTCH1 is potentially targetable with gamma-secretase inhibitor [64, 65]; this alteration is unlikely to be activating
	RB1 A392fs*5TP53 R175H	Longer progression free survival with bevacizumab in patient with TP53 mutations [37, 38]
12	ATM R2993*NOTCH1 E256* [c]	ATM mutation targeted with olaparib [66] NOTCH1 is potentially targetable with gamma-secretase inhibitor [64,65]; this alteration is unlikely to be activating
	RB1 S249*TP53 R282W	Longer progression free survival with bevacizumab in patient with TP53 mutations [37, 38]
13	BRCA1 Q1756*PIK3CA E542K	BRCA1 targeted with PARP inhibitor olaparib [48] PIK3CA mutations may be targeted with the mTOR inhibitor everolimus [42, 43]
	PTEN splice site 635–1G > A	PTEN mutations may be targeted with the mTOR inhibitor everolimus [43]
	TP53 E339KTP53 G187STP53 R202fs*45	Longer progression free survival with bevacizumab in patient with TP53 mutations [37, 38]
14	ALK F1174C	ALK targeted with crizotinib [67]
	RET E511K	RET targeted with cabozantinib [68]
15	CHEK2 R346G [b]PIK3CA R88Q	CHEK2 may be targeted by olaparib and platinums [44–47, 69] PIK3CA mutations may be targeted with the mTOR inhibitor everolimus [42, 43]
	TP53 P177L	Longer progression free survival with bevacizumab in patient with TP53 mutations [37, 38]
16	PIK3CA G1049R	PIK3CA mutations may be targeted with the mTOR inhibitor everolimus [42, 43]
	PTCH1 P369L [b]	PTCH1 mutation targetable with vismodegib [70]
	RB1 M386fs*1TP53 R224HTP53 Y220*	Longer progression free survival with bevacizumab in patient with TP53 mutations [37, 38]
17	APC W2612*	APC may be targeted with sulindac [71, 72]
	EPHA5 R417Q [b]
	NF1 splice site 5609 + 1G > A	NF1 may be targeted with the mTOR inhibitor everolimus [34, 35] and/or the MEK inhibitor trametinib [36]
	RB1 W99*TP53 P151STP53 R248W	Longer progression free survival with bevacizumab in patient with TP53 mutations [37, 38]

Abbreviations: C, case.

^[a]Many of these therapies have not been validated as effective in patients.

^[b]Aberration is of uncertain clinical significance and relevance of therapeutic strategies is unknown.

^[c]Aberration is an inactivating alteration and therapeutic strategies are not expected to be relevant.