Cutaneous melanoma with somatic NF1 loss-of-function mutation (frameshift / nonsense / sp...

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ID	`RF-MELANOMA-NF1-MUT-CANDIDATE`
Тип	Тривожна ознака
Статус	переглянуто 2026-04-29 \| очікує клінічного підпису
Хвороби	`DIS-MELANOMA`
Джерела	`SRC-CIVIC` `SRC-ESMO-MELANOMA-2024` `SRC-NCCN-MELANOMA-2025`

Походження тривожної ознаки

Визначення	Cutaneous melanoma with somatic NF1 loss-of-function mutation (frameshift / nonsense / splice / large deletion) and absent canonical BRAF V600 / NRAS Q61 driver — corresponds to the NF1 subtype of the TCGA Cell 2015 four-genome classification (~14% of cutaneous melanomas). Informational only at MVP: there is no FDA-approved NF1-directed targeted therapy in melanoma (2026); MEK inhibitor monotherapy (selumetinib, trametinib) has shown activity in RASopathy-associated MPNST and plexiform neurofibroma but is not approved for NF1-mutant melanoma. Phenotype: high-UV-mutational-burden, sun-exposed sites, often older patients — typically excellent candidates for ICI (anti-PD-1 monotherapy or ipi/nivo) given the high TMB. Flag exists to surface (a) trial-eligibility for MEK / SHP2 / RAS inhibitor studies and (b) the implicit "no BRAF / NRAS driver" status that pre-empts targeted-therapy first-l...
Клінічний напрям	investigate
Категорія	high-risk-biology

Логіка спрацьовування

{
  "all_of": [
    {
      "any_of": [
        {
          "finding": "nf1_mutation",
          "value": "pathogenic"
        },
        {
          "finding": "nf1_mutation",
          "value": true
        },
        {
          "finding": "nf1_status",
          "value": "loss_of_function"
        },
        {
          "finding": "nf1_lof",
          "value": true
        }
      ]
    },
    {
      "any_of": [
        {
          "finding": "braf_v600",
          "value": false
        },
        {
          "finding": "braf_v600_status",
          "value": "wild_type"
        },
        {
          "finding": "braf_mutation",
          "value": false
        }
      ]
    },
    {
      "any_of": [
        {
          "finding": "nras_q61",
          "value": false
        },
        {
          "finding": "nras_status",
          "value": "wild_type"
        },
        {
          "finding": "nras_mutation",
          "value": false
        }
      ]
    }
  ],
  "type": "biomarker"
}

Нотатки

TCGA cutaneous-melanoma subtype assignment (Cell 2015): BRAF-mut (~50%), RAS-mut (~28%), NF1-mut (~14%), triple-WT (~9%). NF1-mut melanomas often co-occur with secondary RAS-pathway alterations (RASA2, PTPN11) but the canonical hot-spots BRAF V600 and NRAS Q61 are typically absent. UV-signature mutational burden is among the highest of the four subtypes — translates to ICI sensitivity. **Therapeutic implications (MVP-conservative):** - First-line: anti-PD-1 monotherapy (pembrolizumab / nivolumab) OR ipilimumab + nivolumab combo (CheckMate-067) per fitness and brain-met status — same as for triple-WT or general ICI-eligible melanoma. - No BRAF/MEK targeted-therapy indication (BRAF V600 absent). Trametinib monotherapy off-label for NF1-mut melanoma has shown limited single- agent activity (case series, ORR <20%) and is not endorsed by NCCN / ESMO 2024. - Trial-eligibility: SHP2 inhibitors (e.g., RMC-4630, TNO155), pan-RAS inhibitors (e.g., RMC-6236), MEK + SHP2 combinations are in early-phase trials enrolling NF1-LOF tumors. **Why a separate RF (vs. just "no driver"):** NF1-LOF carries an implicit RAS-pathway-active state that argues against future single- agent MEK-inhibitor compas...

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