Yabushita Tomohiro, Shimomura Yoshimitsu, Maruoka Hayato, Katoh Daisuke, Yamashita Daisuke, Satake Hironaga, Hiramoto Nobuhiro, Yoshioka Satoshi, Yonetani Noboru, Nishikori Momoko, Morimoto Takeshi, Imai Yukihiro, Ishikawa Takayuki
Department of Hematology Kobe City Medical Center General Hospital Kobe Japan.
International Research Center for Medical Sciences Kumamoto University Kumamoto Japan.
EJHaem. 2024 Jun 18;5(4):698-708. doi: 10.1002/jha2.921. eCollection 2024 Aug.
Somatic hypermutations (SHMs) in the variable region (V) of the immunoglobulin heavy chain (IgH) gene are common in diffuse large B-cell lymphoma (DLBCL). Recently, IgH V SHMs have become known as immunogenic neoantigens, but few studies have evaluated the prognostic impact of the frequency of V SHMs in DLBCL. The BIOMED-2 protocol is the gold standard polymerase chain reaction (PCR) for clonality analysis in lymphoid malignancies, but can produce false negatives due to the presence of IgH V SHMs. To overcome this problem, three primer sets were designed for the three framework regions (FR1, FR2, and FR3). We evaluated the predictive value of this PCR pattern in patients with DLBCL. To evaluate the prognostic impact of complete detection of the clonal amplifications (VFR1-J, VFR2-J, and VFR3-J) in the BIOMED-2 protocol, we retrospectively analyzed 301 DLBCL patients who were initially treated with anthracycline-based immunochemotherapy. Complete detection of the FR1 to FR3 primer-based IgH V PCR patterns in the BIOMED-2 protocol was associated with low frequency of V SHMs ( < 0.001). Patients who were positive for all these three PCRs ( = 79) were significantly associated with shorter 5-year overall survival (OS; 54.2% vs. 73.2%; = 0.002) and progression-free survival (PFS; 34.3% vs. 59.3%; < 0.001) compared to patients with other PCR patterns ( = 202). Specifically, the successful FR3-J detection was associated with significantly worse OS ( < 0.001) and PFS ( < 0.001). PCR patterns of complete IgH rearrangement using the BIOMED-2 protocol are clinically meaningful indicators for prognostic stratification of DLBCL patients.
免疫球蛋白重链（IgH）基因可变区（V）中的体细胞超突变（SHMs）在弥漫性大B细胞淋巴瘤（DLBCL）中很常见。最近，IgH V SHMs已被视为免疫原性新抗原，但很少有研究评估DLBCL中V SHMs频率的预后影响。BIOMED-2方案是淋巴恶性肿瘤克隆性分析的金标准聚合酶链反应（PCR），但由于存在IgH V SHMs可能会产生假阴性。为克服这一问题，针对三个框架区（FR1、FR2和FR3）设计了三组引物。我们评估了这种PCR模式在DLBCL患者中的预测价值。为评估BIOMED-2方案中克隆扩增（VFR1-J、VFR2-J和VFR3-J）完全检测的预后影响，我们回顾性分析了301例最初接受蒽环类药物为基础的免疫化疗的DLBCL患者。BIOMED-2方案中基于FR1至FR3引物的IgH V PCR模式的完全检测与V SHMs的低频率相关（<0.001）。与其他PCR模式的患者（n = 202）相比，这三种PCR均为阳性的患者（n = 79）的5年总生存期（OS；54.2%对73.2%；P = 0.002）和无进展生存期（PFS；34.3%对59.3%；P < 0.001）明显更短。具体而言，成功检测到FR3-J与明显更差的OS（P < 0.001）和PFS（P < 0.001）相关。使用BIOMED-2方案进行完全IgH重排的PCR模式是DLBCL患者预后分层的临床有意义指标。
