Variantes patogênicas da linha germinal POLE no domínio da exonuclease (leitura de prova) causam polimeras...
Visão determinística da entidade fonte YAML. A autoridade clínica permanece com os IDs de fonte citados e estado de assinatura do revisor.
| ID | BMA-POLE-GERMLINE-POLYMERASE-PROOFREADING |
|---|---|
| Tipo | Relevância terapêutica |
| Estado | reviewed 2026-05-18 | pending_clinical_signoff | actionability review required |
| Doenças | DIS-CRC |
| Fontes | SRC-NCCN-GENETIC-FAMILIAL-CRC-2025 |
Fatos de ação
| Biomarcador | BIO-POLE-GERMLINE |
|---|---|
| Variante | POLE germline exonuclease-domain pathogenic (PPAP — polymerase proofreading–associated polyposis) |
| Doença | DIS-CRC |
| Nível ESCAT | IIA |
| Combinações recomendadas | colonoscopy q1-2y starting age 20-25 with polypectomy, EGD q3y from age 30, endometrial sampling + TVUS q1-2y from age 30-35 (women), annual urinalysis from age 30, for POLE-mutant advanced CRC / endometrial: pembrolizumab 200 mg q3w — high response rate in ultramutator setting (NCCN Category 1 for TMB-H or MSI-H), cascade testing to first-degree relatives; specific to exonuclease-domain variants (Pro286Arg, Val411Leu most common) |
| Resumo das provas | POLE germline pathogenic variants in the exonuclease (proofreading) domain cause polymerase proofreading–associated polyposis (PPAP) — characterized by attenuated/oligo-polyposis (typically <100 adenomas), early-onset colorectal cancer, elevated endometrial cancer risk in women, and characteristic ultramutator tumor phenotype (TMB >100 mut/Mb) with potential immunotherapy responsiveness. Confirmed-carrier surveillance protocol (Lynch-like; per NCCN Genetic/Familial CRC 2025): colonoscopy q1-2y starting age 20-25, EGD q3y from age 30, endometrial sampling + TVUS q1-2y from age 30-35 in women, urinalysis annual from 30 (overlap with Lynch organ spectrum). The ultramutator phenotype in POLE-mutant tumors predicts immunotherapy benefit (high TMB) — pembrolizumab is FDA- approved for TMB-high (≥10 mut/Mb) advanced solid tumors regardless of tissue; POLE-mutant CRC and endometrial benefit appears substantial in small series. ESCAT IIA (predisposition + tumor-phenotype actionability). |
Notas
STUB — Wave A+B germline expansion. Linked Indication: IND-LYNCH-CARRIER- SURVEILLANCE used as closest-fit (POLE-specific Indication does not yet exist; PPAP overlaps Lynch surveillance for CRC + endometrial). Note that IND-ENDOMETRIAL-STAGE-I-POLE-OBSERVATION exists for the somatic-POLE endometrial-treatment context — distinct from germline-carrier surveillance handled here. Two-Clinical-Co-Lead signoff queued. Variant classification matters: only exonuclease-domain variants (Pro286Arg, Val411Leu, Ser297Phe) drive PPAP — non-exonuclease variants are usually uncertain significance.
Usado por
Não há referências reversas encontradas no corpus YAML.