Uveal (intraocular — choroidal, ciliary-body, iris) melanoma with somatic BAP1 loss-of-fu...

Детермінований перегляд YAML-сутності з джерельної бази. Клінічний авторитет лишається за вказаними source ID та статусом клінічного sign-off.

ID	`RF-UVEAL-MELANOMA-BAP1-MUT-CANDIDATE`
Тип	Тривожна ознака
Статус	переглянуто 2026-04-29 \| очікує клінічного підпису
Хвороби	`DIS-MELANOMA`
Джерела	`SRC-CIVIC` `SRC-NCCN-MELANOMA-2025`

Походження тривожної ознаки

Визначення	Uveal (intraocular — choroidal, ciliary-body, iris) melanoma with somatic BAP1 loss-of-function mutation OR loss of BAP1 nuclear staining by IHC. BAP1-loss in uveal melanoma is the strongest single prognostic marker for metastasis-prone disease — class-2 GEP (gene-expression profile) tumors per Harbour 2010 / Onken 2010 carry ~70-80% 5-year metastasis rate vs. ~5% for class-1 (BAP1- intact) tumors. Metastatic uveal melanoma was historically unresponsive to ICI (ORR <5% with anti-PD-1 mono; ORR ~12-18% with ipi/nivo combo) due to low TMB; tebentafusp (gp100 × CD3 ImmTAC, IMCgp100-202 phase 3, Nathan NEJM 2021) is the first approved systemic therapy for HLA-A*02:01+ metastatic uveal melanoma, with mOS 21.7 vs 16.0 mo vs investigator-choice. Informational at MVP: uveal melanoma is not a separately-modeled disease (DIS-UVEAL not defined); RF surfaces (a) the BAP1-loss → high-metastasis-risk...
Клінічний напрям	investigate
Категорія	high-risk-biology

Логіка спрацьовування

{
  "all_of": [
    {
      "any_of": [
        {
          "finding": "tumor_subtype",
          "value": "uveal_melanoma"
        },
        {
          "finding": "tumor_subtype",
          "value": "uveal"
        },
        {
          "finding": "anatomic_site",
          "value": "uveal"
        },
        {
          "finding": "anatomic_site",
          "value": "choroid"
        },
        {
          "finding": "anatomic_site",
          "value": "ciliary_body"
        },
        {
          "finding": "anatomic_site",
          "value": "iris"
        }
      ]
    },
    {
      "any_of": [
        {
          "finding": "bap1_mutation",
          "value": "pathogenic"
        },
        {
          "finding": "bap1_mutation",
          "value": true
        },
        {
          "finding": "bap1_status",
          "value": "loss_of_function"
        },
        {
          "finding": "bap1_ihc",
          "value": "loss"
        },
        {
          "finding": "bap1_nuclear_staining",
          "value": "lost"
        }
      ]
    }
  ],
  "type": "biomarker"
}

Нотатки

**Why uveal melanoma is biologically distinct from cutaneous:** Uveal arises from choroidal/ciliary/iris melanocytes (neural-crest origin, post-migration to the eye), drivers are GNAQ / GNA11 / CYSLTR2 / PLCB4 (Gαq-pathway, ~95%), NOT BRAF / NRAS / NF1. Mutational burden is ~10× lower than cutaneous (low TMB → poor ICI substrate). BAP1 (3p21) is the second hit in ~50% of metastatic-prone uveal — the seminal Harbour Science 2010 finding that linked BAP1-loss to class-2 GEP and metastatic dissemination. **Prognostic stratification (uveal-specific):** - Class-1A GEP (BAP1-intact, low PRAME): 5-yr metastasis ~2-5% - Class-1B GEP (BAP1-intact, high PRAME): 5-yr metastasis ~20% - Class-2 GEP (BAP1-loss): 5-yr metastasis 70-80% Liver is the dominant metastatic site (>90% of metastases involve liver as first site). **Therapeutic implications (metastatic uveal):** - HLA-A*02:01-positive: tebentafusp (FDA-approved 2022) — required HLA testing before treatment selection. mOS 21.7 mo (IMCgp100-202). Cytokine-release toxicity dominates — initial inpatient or monitored-outpatient escalation per protocol. - HLA-A*02:01-negative: ipilimumab + nivolumab off-label (per GEM1402 / single-arm phase 2...

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