BRCA2

BRCA2 (Breast Cancer 2 / FANCD1)

一行要約

BRCA2 は homologous recombination repair (HRR) の central tumor suppressor で、RAD51 を DNA double-strand break (DSB) site に loading させて HR を媒介する。Germline / somatic BRCA2 loss-of-function は HRD (homologous recombination deficiency) phenotype を生み、PARP inhibitor の synthetic lethality 標的の代表例。NSCLC では BRCA2 mutation 頻度は低い (約1-2%) が、ATM / BRCA1 / その他 HRR 遺伝子と合わせた HRD signature は化学療法 / IO 応答 biomarker として研究進行中。Lung cancer + BRCA2 germline carrier の cancer susceptibility / treatment selection も Mendelian randomization 含めて検討対象。

主要エビデンス

• Synthetic lethality with PARP inhibitor: Bryant et al. Nature 2005 / Farmer et al. Nature 2005 が BRCA1/2 deficient cell の PARP inhibitor 高感受性を確立、olaparib 等の clinical 開発の foundation
• PROfound (mCRPC): olaparib が BRCA1/2 mutant prostate で OS benefit、HRR mutation 範疇承認
• OlympiAD / SOLO-1 / 2 (breast / ovarian): gBRCA mutation で PARP inhibitor benefit
• NSCLC HRD: BRCA2 mutation 頻度 約1%、ATM / BRCA1 含む HRR signature が platinum 応答 biomarker
• Triple-negative breast cancer: BRCA2 mutation で platinum + PARP combination の rationale

メカニズム

BRCA2 は DSB 後の RAD51 ATPase の DNA 結合 / nucleofilament 形成を媒介、HRR で error-free repair を駆動する。BRCA2 loss → RAD51 機能不全 → DSB が NHEJ / MMEJ 経由 error-prone repair に shunt → genomic instability / HRD scar (large rearrangement, LOH, signature 3) 蓄積。PARP inhibitor は base excision repair の trapping → replication fork collapse → DSB → HR 不能なら cell death (synthetic lethality)。耐性機序: BRCA2 reversion mutation, HR restoration (RAD51 hyperactivation), PARP1 reduction, replication fork protection 異常。

臨床位置づけ

NSCLC で BRCA2 mutation 頻度は低いが、Foundation One / NCC OncoPanel 等 NGS panel で routinely 検出。HRD signature (mutational signature 3, LOH) が platinum 応答 / PARP inhibitor benefit の予測因子として研究中。Pan-cancer HRD basket trial (TAPUR, NCI-MATCH) で BRCA1/2/ATM/PALB2 等 HRR 群を共通 cohort 化。SCLC では SLFN11 / MYC 等と組合せた HRD-like phenotype が PARP inhibitor benefit を予測する可能性。

Open Questions

• NSCLC BRCA2 mutation での PARP inhibitor benefit: rare cohort prospective evidence
• HRD signature の standardization (myChoice / Foundation HRD score の predictive value)
• PARP inhibitor 耐性 の解析 (reversion mutation の clinical impact)
• PARP + IO combination: cGAS-STING activation 経由の synergy

関連エンティティ

• 関連経路: Homologous-recombination-repair-pathway / DDR-pathway / p53-pathway
• 関連遺伝子: BRCA1 / ATM / TP53 / SLFN11 / MYC
• 関連薬剤: PARP-inhibitor / Platinum-chemotherapy / PD-1-inhibitor
• 関連概念: Synthetic-lethality / Genomic-instability-cancer / Tumor-mutational-burden

関連論文

直近 30 件のみ表示中 (関連 45 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Extracellular vesicles

• Lucas et al. AnnOncol 2016 — Minimally invasive genomic and transcriptomic profiling of visceral cancers by next-generation sequencing of circulat…
• Castillo et al. AnnOncol 2018 — Surfaceome profiling enables isolation of cancer-specific exosomal cargo in liquid biopsies from pancreatic cancer

Basic-Immunotherapy

• Hugo et al. Cell 2016 — Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma
• Marzio et al. Cell 2022 — EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion
• Pires et al. NatMater 2026 — IL-12-releasing nanoparticles for effective immunotherapy of metastatic ovarian cancer

Basic-Liquid-biopsy

• Batool et al. CellRepMed 2023 — Extrinsic and intrinsic preanalytical variables affecting liquid biopsy in cancer
• Sinicrope et al. JClinOncol 2026 — Tissue-free circulating tumor DNA assay and patient outcome in a phase III trial of FOLFOX-based adjuvant chemotherap…
• Nakamura et al. NatMed 2020 — Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer SCRUM-japan GI-SCREEN and
• Herberts et al. Nature 2022 — Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer

Basic-Oncogene and genetics

• RojoDeLaVega et al. CancerCell 2018 — NRF2 and the hallmarks of cancer
• Huang et al. Cell 2018 — Pathogenic germline variants in 10,389 adult cancers
• Wang et al. NatCommun 2018 — Whole-genome sequencing reveals genomic signatures associated with the inflammatory microenvironments in chinese NSCLC
• Weinstein et al. NatGenet 2013 — The cancer genome atlas pan-cancer analysis project
• Cortes et al. NatGenet 2020 — Ciriano-Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing
• Helleday et al. NatRevGenet 2014 — Mechanisms underlying mutational signatures in human cancers
• ICGCTCGA et al. Nature 2020 — Pan-cancer analysis of whole genomes
• Funnell et al. Nature 2022 — Single-cell genomic variation induced by mutational processes in cancer
• Anusewicz et al. SciRep 2020 — Lung squamous cell carcinoma and lung adenocarcinoma differential gene expression regulation through pathways of notch,

Basic-Others

• Pongor et al. GenomeMed 2015 — A genome-wide approach to link genotype to clinical outcome by utilizing next generation sequencing and gene chip data
• Rottenberg et al. NatRevCancer 2021 — The rediscovery of platinum-based cancer therapy

Clinical-Methodology

• Sunami et al. CancerSci 2019 — Feasibility and utility of a panel testing for 114 cancer-associated genes in a clinical setting A hospital-based study

Clinical-NSCLC-Driver negative

• Sha et al. CancerDiscov 2020 — Tumor mutational burden as a predictive biomarker in solid tumors
• Ricciuti et al. JAMAOncol 2022 — Association of high tumor mutation burden in non-small cell lung cancers with increased immune infiltration and
• Schlauch et al. JCOPrecisOncol 2021 — Tumor-specific and tumor-agnostic molecular signatures associated with response to immune checkpoint inhibitors
• Casarrubios et al. JImmunotherCancer 2022 — Tumor microenvironment gene expression profiles associated to complete pathological response and disease progression in

Clinical-NSCLC-Driver-Other

• Jonna et al. ClinCancerRes 2019 — Detection of NRG1 gene fusions in solid tumors
• Wong et al. LungCancer 2021 — MET exon 14 skipping mutation positive non-small cell lung cancer response to systemic therapy

Clinical-SCLC

• Su et al. ClinCancerRes 2019 — Inferring the evolution and progression of small-cell lung cancer by single-cell sequencing of circulating tumor cells
• Sabari et al. NatRevClinOncol 2017 — Unravelling the biology of SCLC implications for therapy

Clinical-Thymic

• Mohrmann et al. Med 2025 — Genomic landscape and molecularly informed therapy in thymic carcinoma and other advanced thymic epithelial tumors