hairy cell leukemiaにおけるBRAF (V600E)全例変異のその後

昨年６月のhairy cell leukemiaにおけるBRAF (V600E)全例変異報告は衝撃的であった。この遺伝子のその後について３報noteしよう。


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2011年6月19日日曜日

Hairly cell leukemiaで驚くべき遺伝子変異！：NEJM

今週号のNew England Journal of Medicineには驚いたのだ。Hairly cell leukemiaではBRAF変異が100％認められるという報告だ。希な病気だから興味が湧かないそこの貴方。BRAF変異なんて「なにそれ」といわれる方々よ。こんなこと(100%の遺伝子変異頻度）は、この世界に30年近くいる小生にも初めての経験なのだ。簡単にまとめてみよう。
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（１）まず一報目はイタリアグループからの続報でありBloodに11月に報告されたもの62例全例で陽性とある。

Blood November 9, 2011 blood-2011-08-368209

The BRAF V600E mutation in hairy cell leukemia and other mature B-cell neoplasms

Luca Arcaini1,*, Silvia Zibellini1, Emanuela Boveri2, Roberta Riboni2, Sara Rattotti1, Marzia Varettoni1, Maria Luisa Guerrera1, Marco Lucioni2, Annamaria Tenore1, Michele Merli3, Silvia Rizzi1, Lucia Morello1, Chiara Cavalloni1, Matteo C. Da Vià1, Marco Paulli2, and Mario Cazzola1

Department of Hematology Oncology,Department of Human Pathology, Fondazione IRCCS Policlinico San Matteo & University of Pavia, Pavia, Italy;Division of Hematology, Department of Internal Medicine, Ospedale di Circolo, Fondazione Macchi, Varese, Italy

• Abstract: The somatically acquired V600E mutation of the BRAF gene has been recently described as a molecular marker of hairy cell leukemia (HCL). We developed an allele-specific PCR for this mutation, and studied 62 patients with HCL, one with HCL variant, 91 with splenic marginal zone lymphoma, 29 with Waldenström macroglobulinemia, and 57 with B-cell chronic lymphoproliferative disorders. The BRAF V600E mutation was detected in all HCL cases (62cases), and in only two of the remaining 178 patients. These two subjects had a B-cell chronic lymphoproliferative disorders that did not fulfill the diagnostic criteria for HCL. Despite the PCR positivity, the mutation could not be detected by Sanger sequencing in these two cases, suggesting that it was associated with a small subclone. We conclude that the BRAF V600E mutation is present in all HCL patients and that, in combination with clinical and morphological features, represents a reliable molecular marker for this condition.

（２）その後いくつか続報があるが、最新ではNIHからの続報がBloodに４月に報告されたもの：42例(79%)で陽性とある。こまかなサブタイプに触れているが、これはこの病気のclinical entityとも関わることであり、大目にみよう。全例ではないという報告がBloodに出たことは残念であるが、それでも79%は高い。治療の可能性があるからね。そしてその治療について最近NEJMにドイツのグループから報告が出た。

Blood April 5, 2012 vol. 119 no. 14 3330-3332
Both variant and IGHV4-34–expressing hairy cell leukemia lack the BRAF V600E mutation

Liqiang Xi1,*, Evgeny Arons2,*, Winnifred Navarro1, Katherine R. Calvo3, Maryalice Stetler-Stevenson1, Mark Raffeld1,†, and Robert J. Kreitman2,†

Laboratory of Pathology and 2Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD; and 3Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD

Abstract

• Recently, the BRAF V600E mutation was reported in all cases of hairy cell leukemia (HCL) but not in other peripheral B-cell neoplasms. We wished to confirm these results and assess BRAF status in well-characterized cases of HCL associated with poor prognosis, including the immunophenotypically defined HCL variant (HCLv) and HCL expressing the IGHV4-34 immunoglobulin rearrangement. Fifty-three classic HCL (HCLc) and 16 HCLv cases were analyzed for BRAF, including 5 HCLc and 8 HCLv expressing IGHV4-34. BRAF was mutated in 42 (79%) HCLc, but wild-type in 11 (21%) HCLc and 16 (100%) HCLv. All 13 IGHV4-34+ HCLs were wild-type. IGHV gene usage in the 11 HCLc BRAF wild-type cases included 5 IGHV4-34, 5 other, and 1 unknown. Our results suggest that HCLv and IGHV4-34+ HCLs have a different pathogenesis than HCLc and that a significant minority of other HCLc are also wild-type for BRAF V600.

（３）最近NELMにBRAF 抑制薬(vemurafenib) をHairy-Cell Leukemiaに使ったらよく効いたというドイツからの一例報告

N Engl J Med 2012; 366:2038-2040May 24, 2012
Correspondence
BRAF Inhibition in Refractory Hairy-Cell Leukemia