e19014

Background: Stromal Antigen 2 (STAG2), located on Xq25, is the most mutated (m) cohesin-complex gene in myeloid neoplasm (MN) patients (pts). mSTAG2 is present in around 5% of MN and has been linked to secondary AML and potential poor impact on outcome. Methods: We retrospectively screened MN pts who had next-generation sequencing (NGS) (OncoHeme) performed at Mayo Clinic between 2018-2021. mSTAG2 pts were included at the date of NGS. Charts were reviewed for clinical information after obtaining IRB approval. BlueSky Software V7.40 was used for statistical analysis. Results: Characteristics: 70 pts with mSTAG2 MN were identified, their median age was 72 years (range 25-91); with 55 pts (79%) being males. Complete blood counts showed median white blood cell count of 2.8 x10⁹/L, hemoglobin of 8.9 gm/dL and platelets of 89 x10⁹/L. The diagnosis was MDS in 38 pts (54%), AML in 20 (29%), MDS/MPN in 9 (13%), MPN in 2 (3%), and CCUS in 1 (1%). 11 cases (16%) were defined as therapy-related MN (tMN). Cytogenetics were normal in 45 pts (64%) and abnormal in 22 (31%). 10/50 non-AML pts progressed to AML (after median time of 9.8 months). Hematopoietic cell transplantation (HCT) was done in 20 pts (29%). mSTAG2: median VAF (mVAF) was 50% (range, 5%-100%). Males had higher mVAF compared to females (64% vs. 27%, p= .001), and tMN pts had higher mVAF compared to de novo (dn) MN pts (66% vs. 43%, p= .03). mVAF had no correlation with disease classification (50% in AML, 52% in MDS, 41% in MDS/MPN, 36% in MPN and 5% in CCUS, p= .5). STAG2 mutations were nonsense, frameshift, and splice site in 50%, 37%, and 13%, respectively. Co-mutations: median number of co-mutations was 3 (range, 0-6). Most common co-mutations were ASXL1 (66%), SRSF2 (37%), TET2 (36%), RUNX1 (29%), IDH2 (21%), BCOR (20%) and U2AF1 (16%) while least common were TP53, SETBP and ZRSR2 (1% each). Neither number (p= .08) nor type of co-mutation correlated with MN classification. There was no difference in the co-mutational pattern between tMN and dnMN pts. Survival: median overall survival (mOS) was 16.3 months with a median follow up time of 24.5 months. Pts who received HCT had better OS compared to non-HCT pts (mOS not reached vs. 14.9 months, p= .003). Pts with an isolated mSTAG2 had better OS than co-mutated pts (p= .04), while the type of STAG2 mutation did not affect OS (p= .3). Pts with tMN had worse OS than dnMN pts (9.9 vs. 20.4 months, p= .02). VAF ≥75% had a negative impact on OS (20.5 vs 8.1 months, p= .008). mOS did not differ based on MN diagnosis. On multivariate analysis, only HCT (HR 0.3, p= .01) and VAF ≥75% (HR 2.3, p= .02) had impact on OS. Conclusions: mSTAG2 was more common in elderly males and MDS diagnosis. mSTAG2 was uncommon as an isolated mutation, indicating a possible role in disease progression with preferred certain co-mutations (ASXL1/SRSF2/RUNX1/IDH2). mOS was poor regardless of MN diagnosis indicating a molecularly driven significance of an aggressive disease. The study needs to be validated by larger studies.

e19014

背景：位于 Xq25 上的基质抗原 2 ( STAG2 ) 是髓系肿瘤 (MN) 患者 (pts) 中突变最多的 (m) 黏着蛋白复合基因。mSTAG2存在于大约 5% 的 MN 中，并且与继发性 AML 和对结果的潜在不良影响有关。方法：我们回顾性筛选了 2018-2021 年间在 Mayo Clinic 进行了二代测序 (NGS) (OncoHeme) 的 MN 患者。m STAG2 pts 包括在 NGS 日期。在获得 IRB 批准后，对图表进行临床信息审查。BlueSky Software V7.40 用于统计分析。结果：特征： 70 pts with mSTAG2确定了 MN，他们的中位年龄为 72 岁（范围 25-91）；55 分 (79%) 为男性。全血细胞计数显示中位白细胞计数为 2.8 x10 ⁹ /L，血红蛋白为 8.9 gm/dL，血小板为 89 x10 ⁹ /L。诊断为MDS 38 例（54%），AML 20 例（29%），MDS/MPN 9 例（13%），MPN 2 例（3%），CCUS 1 例（1%）。11 例 (16%) 被定义为治疗相关 MN (tMN)。45 例 (64%) 的细胞遗传学正常，22 例 (31%) 异常。10/50 非 AML 患者进展为 AML（中位时间为 9.8 个月后）。20 名患者 (29%) 接受了造血细胞移植 (HCT)。mSTAG2：中值 VAF (mVAF) 为 50%（范围，5%-100%）。男性的 mVAF 高于女性（64% 对 27%，p=.001），tMN 患者的 mVAF 高于新发（dn）MN 患者（66% 对 43%，p=.03）。mVAF 与疾病分类无关（AML 为 50%，MDS 为 52%，MDS/MPN 为 41%，MPN 为 36%，CCUS 为 5%，p=0.5）。STAG2突变是无意义、移码和剪接位点，分别占 50%、37% 和 13%。共突变：共突变的中位数为3（范围，0-6）。最常见的共突变是ASXL1 (66%)、SRSF2 (37%)、TET2 (36%)、RUNX1 (29%)、IDH2 (21%)、BCOR (20%) 和U2AF1(16%) 而最不常见的是TP53、SETBP和ZRSR2（各 1%）。数量 (p= .08) 和共突变类型都与 MN 分类无关。tMN 和 dnMN pts 之间的共突变模式没有差异。生存期：中位总生存期 (mOS) 为 16.3 个月，中位随访时间为 24.5 个月。与非 HCT 患者相比，接受 HCT 的患者的 OS 更好（未达到 mOS 与 14.9 个月，p=0.003）。具有孤立的 m STAG2的患者比共同突变的患者具有更好的 OS (p= .04)，而STAG2的类型突变不影响 OS (p= .3)。tMN 患者的 OS 比 dnMN 患者差（9.9 个月 vs. 20.4 个月，p= .02）。VAF ≥75% 对 OS 有负面影响（20.5 个月 vs 8.1 个月，p= .008）。根据 MN 诊断，mOS 没有差异。在多变量分析中，只有 HCT (HR 0.3, p= .01) 和 VAF ≥75% (HR 2.3, p= .02) 对 OS 有影响。结论： mSTAG2在老年男性和MDS诊断中更为常见。mSTAG2作为一种孤立突变并不常见，表明在疾病进展中可能发挥作用，并具有优选的某些共突变 ( ASXL1/SRSF2/RUNX1/IDH2 )。无论 MN 诊断如何，mOS 都很差，表明侵袭性疾病的分子驱动意义。该研究需要通过更大规模的研究来验证。