Table 1 Summary of molecular, clinical and histologic findings of 16 fusion-positive cases.

From: Identification of fusions with potential clinical significance in melanoma

	Rearrangement/Fusion^a Fusion partners (transcripts)	Fusion mechanism^b	TMB (score)	Site of tested specimen	Melanoma subtype^c histology of primary	Age (years)/ Gender	Clinical stage^d	Treatment	Outcome followup
1	AGAP3::BRAF AGAP3 exon10 BRAF exon 6	Inversion	High (27)	Metastasis, chest wall skin	Cutaneous Nodular, Clark level IV, depth 1.95 mm, non-ulcerated, mitoses >6/mm²	42/M	III	Surgery; Radiation IT: Pembro TT: Trametinib^CT, MEK^inhib IS: Infliximab, Prednisone	AWD 116 mo
2	AGK::BRAF AGK exon 2 BRAF exon 8	Inversion	Low (13)	Primary, right shoulder Metastasis, right scapula	Cutaneous NOS, epithelioid, Clark level IV, depth at least 8.0 mm, ulcerated, 46 mitoses per mm²	45/M	IV	IT: Ipi/Nivo IS: Prednisone	NED 23 mo
3	CDH3::BRAF CDH3 exon 15 BRAF exon 6	Translocation	Low (7)	Primary, left posterior shoulder	Cutaneous NOS, epithelioid, Clark level IV, depth 3.9 mm, ulcerated, 10 mitoses per mm²	76/F	IIB	Surgery	NED 13 mo
4	CCT8::BRAF CCT8 exon 14 BRAF exon 9	Translocation	Low (11)	Metastasis, left chest skin	Cutaneous Nodular, epithelioid, Clark level IV, 1.67 mm, ulcerated	53/F	IIA	Surgery; Radiation; Cryotherapy^CT IT: IFN^CT (adjuvant), Nivo/TAK-202^CT, Pembro, Ipi IS: Prednisone, Methylprednisolone	DOD 47 mo
5	DIP2B::BRAF DIP2B exon 19 BRAF exon 9	Translocation	Low (6)	Metastasis, inguinal lymph node	Cutaneous NM, epithelioid, Clark level IV, depth 1.4 mm, non-ulcerated, 5 mitoses per mm²	56/F	III	Surgery IT: Pembro, Nivo/anti-LAG3 mAb^CT, Ipi IS: Infliximab, Methylprednisolone, Prednisone	DOD 14 mo
6	EFNB1::RAF1 EFNB1 exon 5 RAF1 exon 9	Translocation	High (16)	Metastasis, brain	Cutaneous SSM, epithelioid, Clark level IV, depth 2.75 mm, non-ulcerated, 0 mitoses per mm²	56/M	IIA	Surgery IT: Ipi/Nivo IS: Methylprednisolone, Infliximab, Prednisone, Vedolizumab	DOD 58 mo
7	LRCH3::RAF1 LRCH3 exon 12 RAF1 exon 9	Inversion	Low (13)	Metastasis, brain	Cutaneous SSM, epithelioid, Clark level III, depth 0.45 mm, not ulcerated, 2 mitoses per mm²	73/M	IV	Surgery; Radiation IT: Pembro	AWD 12 mo
8	MAP4::RAF1 MAP4 exon 13 RAF1 exon 8	Deletion	Low (12)	Metastasis, lung	Cutaneous SSM, spindle, Clark level IV, depth of 0.62 mm, non-ulcerated, 3 mitoses per mm²	50/M	IA	Surgery IT: Pembro (adjuvant/neoadjuvant)	NED 173 mo
9	RUFY1::RAF1 RUFY1 exon 9 RAF1 exon 10	Translocation	Low (12)	Metastasis, lung Metastasis, brain	Cutaneous NM, epithelioid, Clark level IV, depth of 1.65 mm, non-ulcerated, 3 mitoses per mm²	51/M	III	Surgery IT: Pembro, Ipi/ Nivo TT: Binimetinib, MEK^inhib IS: Methylprednisolone, Infliximab	DOD 40 mo
10	EML4::ALK EML4 exon 5 ALK exon 20	Inversion	Low (11)	Primary, nasopharynx	Mucosal, Sinonasal Epithelioid, depth 4 mm, ulcerated, 3 mitoses per mm²	59/M	IIB	Surgery; Radiation IT: Ipi/Nivo^CT, Nivo/T-VEC TT: Alectinib, ALK inhibitor Chemotherapy: Carbo/Taxol Cell therapy: TCR-engineered T cells against the MAGE-A3/A6 antigens IS: Prednisone, Infliximab	DOD 41 mo
11	MLPH::ALK MLPH exon 12 ALK exon 20	Inversion	Low (9)	Primary, left foot	Acral ALM, epithelioid, Clark level IV, depth 1 mm, non-ulcerated, 2 mitoses per mm²	29/F	III	Surgery IT: IFN (adjuvant)	NED 53 mo
12	CANT1::ETV4 novel in melanoma CANT1 exon 3 ETV4 exon 7	Deletion	Low (6)	Primary, vulva	Mucosal MLM, epithelioid, Clark level IV, depth 6 mm, ulcerated, 16 mitoses per mm², lymphovascular invasion present	82/F	IIC	Surgery; Radiation IT: Pembro	DOD 20 mo
13	CCDC6::RET novel in melanoma CCDC6 exon 1 RET exon 12	Inversion	Low (12)	Primary, right knee	Cutaneous SSM, epithelioid, Clark level IV, depth 2.3 mm, non-ulcerated, 15 mitoses per mm²	72/M	III	Surgery	NED 25 mo
14	NOTCH1::GNB1^e novel NOTCH1 exon 2 GNB1 exon 2	Translocation	High (23)	Metastasis, intraparotid lymph node	Cutaneous - NA Metastasis - epithelioid	55/M	III	Surgery; Radiation IT: Pembro, Ipi/Nivo IS: Prednisone (s/p kidney transplant)	AWD 53 mo
15	ADCY2::TERT ADCY2 exon 20 TERT exon 2	Inversion	Low (13)	Metastasis, lung	Acral NOS, epithelioid and spindle, Clark level IV, depth of 1.9 mm, ulcerated, 8 mitoses per mm²	58/M	III	Surgery; Radiation; Cryotherapy^CT IT: Ipi (adjuvant)^CT, Pembro IS: Prednisone, Budesonide	AWD 73mo
16	NAG::MAST2 novel NAGS exon 6 MAST2 exon 5	Translocation	N/A	Metastasis, neck lymph node	Cutaneous NOS, epithelioid, Clark level IV, depth of 4.9 mm, non-ulcerated, 6 mitosis per mm²	56/M	III	Surgery IT: Nivo (adjuvant)	NED 42 mo

AWD alive with disease, NED no evidence of disease, DOD died of disease, N/A not available, M male, F female, mo months, inhib inhibitor, IT immunotherapy/immuno checkpoint inhibitors, TT targeted therapy, IS immunosuppressants, Pembro Pembrolizumab, Ipi Ipilimumab, Nivo Nivolumab, IFN interferon, CT clinical trial, MLM mucosal lentiginous melanoma, SSM superficial spreading melanoma, NM nodular melanoma, ALM acral lentiginous melanoma, LMM lentigo maligna melanoma, NOS unclassified.
^aPotentially targetable fusions are shown in bold.
^bWhen the two partners are on the same chromosome, the presumed fusion mechanisms are inversions or deletions, depending on the orientation of their coding sequences. However, these fusions could result from more complex rearrangements.
^cIn addition to melanoma, patient 6 had mantle cell lymphoma and patient 13 had thymoma.
^dClinical stage at presentation, according to the 8th edition of the American Joint Committee on Cancer (AJCC) melanoma staging system (2018).
^eThe NOTCH1::GNB1 rearrangement is not expected to produce a chimeric fusion protein involving NOTCH1 and GNB1. Instead, as detailed in the text, this rearrangement may activate expression of the full-length GNB1 protein, under the control of the NOTCH1 promoter.

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Table 1 Summary of molecular, clinical and histologic findings of 16 fusion-positive cases.

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