POLD1 germline pathogenic variants in the exonuclease (proofreading) domain cause PPAP —...
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| ID | BMA-POLD1-GERMLINE-POLYMERASE-PROOFREADING |
|---|---|
| Тип | Клінічна застосовність |
| Статус | переглянуто 2026-05-18 | очікує клінічного підпису | потрібне рев’ю клінічної застосовності |
| Хвороби | DIS-CRC |
| Джерела | SRC-NCCN-GENETIC-FAMILIAL-CRC-2025 |
Дані про клінічну застосовність
| Біомаркер | BIO-POLD1-GERMLINE |
|---|---|
| Варіант | POLD1 germline exonuclease-domain pathogenic (PPAP — polymerase proofreading–associated polyposis) |
| Хвороба | DIS-CRC |
| Рівень ESCAT | IIA |
| Рекомендовані комбінації | colonoscopy q1-2y starting age 20-25 with polypectomy, endometrial sampling + TVUS q1-2y from age 30-35 (women); consider earlier given higher endometrial risk vs POLE, discussion of risk-reducing hysterectomy + BSO after childbearing (INTENSIFIED-track conversation), EGD q3y from age 30, annual urinalysis from age 30, for POLD1-mutant advanced disease: pembrolizumab 200 mg q3w — high response rate in TMB-H ultramutator setting |
| Підсумок доказів | POLD1 germline pathogenic variants in the exonuclease (proofreading) domain cause PPAP — similar to POLE-PPAP but with a stronger endometrial-cancer signal in women (lifetime endometrial risk ~50% per published cohorts). Phenotype includes attenuated polyposis with early-onset CRC, endometrial cancer, and CNS tumors in some families. Confirmed-carrier surveillance protocol (Lynch-like): colonoscopy q1-2y starting age 20-25, endometrial sampling + TVUS q1-2y from age 30-35 in women (consider earlier given higher endometrial risk than POLE), EGD q3y from age 30, urinalysis q1y from age 30. Tumor ultramutator phenotype (TMB high) suggests immunotherapy responsiveness in advanced disease; pembrolizumab FDA- approved for TMB-H solid tumors. Risk-reducing hysterectomy + BSO after childbearing is reasonable to discuss in POLD1 carriers (analogous to Lynch INTENSIFIED-track decision). ESCAT IIA. |
Нотатки
STUB — Wave A+B germline expansion. Linked Indication: IND-LYNCH-CARRIER- SURVEILLANCE used as closest-fit; no POLD1-specific Indication exists. Two-Clinical-Co-Lead signoff queued. Variant classification: only exonuclease-domain variants (Ser478Asn, Pro327Leu, Leu474Pro most common) drive PPAP. Endometrial-cancer risk in POLD1 carriers appears higher than POLE — supports earlier / denser endometrial surveillance + low-threshold risk-reducing surgery discussion at completion of childbearing.
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