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BRCA変異とMSI-Hを同時に持つ場合

BRCA MSI がんゲノム

先週、JCOPOに興味深い報告が載っていた。複数のドライバー変異が同時に検出されていずれを治療標的にすべきか迷う局面がしばしばあるけれど、BRCA変異とMSI-Hが同時に検出された場合はBRCA変異は治療標的としてはあまり有望ではないと言う話。

PARP Inhibitor Insensitivity to BRCA1/2 Monoallelic Mutations in Microsatellite Instability-High Cancers | JCO Precision Oncology
PURPOSE To examine the overlap of homologous recombination deficiency (HRD) and microsatellite instability high (MSI-H) status, and to dissect driver versus bystander status of BRCA1/2 mutations (BRCAm) in this context. METHODS A pan-cancer comprehensive genomic profiling cohort (n = 213,199) was examined for overlap between BRCAm and MSI-H status. BRCA1/2 variant zygosity was examined and correlated with MSI-H status, tumor mutational burden, and genome-wide loss of heterozygosity (gLOH). Clinical histories of two patients with prostate cancer with co-occurring BRCAm and MSI-H are described. RESULTS HRD and MSI-H phenotypes were generally mutually exclusive events (P < .001). BRCAm that co-occurred together with high tumor mutational burden or MSI-H were predominantly monoallelic bystander alterations. In breast, ovarian, and pancreatic cancers, very few BRCAm occurred in the context of MSI-H; however, in prostate cancer, 12.8% of BRCA1 and 3.4% of BRCA2 alterations co-occurred with MSI-H. In these BRCA-associated cancers, co-occurring BRCAm were generally monoallelic and were not associated with elevated gLOH. Two patients with prostate cancer with co-occurring BRCAm and MSI-H showed resistance to poly (ADP-ribose) polymerase inhibition but sensitivity to subsequent anti–programmed cell death protein 1 therapy. CONCLUSION MSI-H status and HRD are generally mutually exclusive phenomena across cancer types, but may rarely co-occur, especially in prostate cancer. Although MSI-H samples had a higher BRCAm prevalence relative to microsatellite-stable tumors, these BRCA1/2 mutations were generally monoallelic and were not associated with elevated gLOH. Our findings suggest that most BRCAm coexisting with microsatellite instability are likely bystander events that may not result in sensitivity to poly (ADP-ribose) polymerase inhibitors.
https://ascopubs.org/doi/full/10.1200/PO.21.00531

MSI-HとBRCA変異の両方を持つ場合は大抵BRCAはLOHを伴わない片アレルのバイスタンダー変異であり、PARP阻害剤は無効であるという話。膵癌や卵巣癌ではまれだが前立腺癌ではBRCA1の12%、BRCA2の3.4%はMSI-Hと併存する。病態的には相互排他で、MSI-Hのみが治療標的となる。/JCO https://t.co/ZRRK1b0QpX

— レ点🧬 (@m0370) June 30, 2022

MSI-HとBRCA変異の両方を持つ場合は大抵BRCAはLOHを伴わない片アレルのバイスタンダー変異であり、PARP阻害剤は無効であるという話。膵癌や卵巣癌ではまれだが前立腺癌ではBRCA1の12%、BRCA2の3.4%はMSI-Hと併存する。病態的には相互排他で、MSI-Hのみが治療標的となる。

この報告では実際にPARP阻害剤の耐性まで見たのは前立腺癌の2症例っぽいので、検証の確実度でいえば前立腺がんの症例報告レベルにあたる。ただし、前立腺癌以外でも感覚的にもこの通りになりそうな気はするけれど。


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更新日:2022-07-04 閲覧数:465 views.