TP53 and OSBPL10 alterations in diffuse large B-cell lymphoma: prognostic markers identified via exome analysis of cases with extreme prognosis
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Akito Dobashi1, Yuki Togashi1,2, Norio Tanaka3, Masahiro Yokoyama4, Naoko Tsuyama2, Satoko Baba1, Seiichi Mori3, Kiyohiko Hatake4, Toshiharu Yamaguchi3, Tetsuo Noda3 and Kengo Takeuchi1,2
1Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, Koto, Tokyo, Japan
2Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Koto, Tokyo, Japan
3The Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Koto, Tokyo, Japan
4Department of Hematology and Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Koto, Tokyo, Japan
Kengo Takeuchi, email: [email protected]
Keywords: TP53; OSBPL10; diffuse large B-cell lymphoma; next-generation sequencing; prognostic marker
Received: December 29, 2017 Accepted: February 27, 2018 Published: April 13, 2018
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype characterized by both biological and clinical heterogeneity. In refractory cases, complete response/complete response unconfirmed rates in salvage therapy remain low. We performed whole-exome sequencing of DLBCL in a discovery cohort comprising 26 good and nine poor prognosis cases. After candidate genes were identified, prognoses were examined in 85 individuals in the DLBCL validation cohort. In the discovery cohort, five patients in the poor prognosis group harbored both a TP53 mutation and 17p deletion. Sixteen mutations were identified in OSBPL10 in nine patients in the good prognosis group, but none in the poor prognosis group. In the validation cohort, TP53 mutations and TP53 deletions were confirmed to be poor prognostic factors for overall survival (OS) (P = 0.016) and progression-free survival (PFS) (P = 0.023) only when both aberrations co-existed. OSBPL10 mutations were validated as prognostic markers for excellent OS (P = 0.037) and PFS (P = 0.041). Significant differences in OS and PFS were observed when patients were stratified into three groups—OSBPL10 mutation (best prognosis), the coexistence of both TP53 mutation and TP53 deletion (poorest prognosis), and others. In this study, the presence of both TP53 mutation and 17p/TP53 deletion, but not the individual variants, was associated with poor prognosis in DLBCL patients after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or similar regimens. We also identified OSBPL10 mutation as a marker for patients with excellent prognosis in the R-CHOP era.
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