PO.TB09.02 · 肿瘤生物学
卵巢癌幸存者中克隆性造血的动态：与卡铂和PARP抑制剂暴露的相关性
Dynamics of clonal hematopoiesis in ovarian cancer survivors: Correlation with carboplatin and PARP inhibitor exposure
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
卵巢癌(OC)幸存者可能发生治疗相关性髓系肿瘤(TMN)，且PARP抑制剂(PARPi)暴露会增加风险。我们在CHANCES(癌症幸存者中的克隆性造血)研究中，对OC幸存者血液中可能先于TMN出现的克隆性造血(CH)及其与治疗暴露的关系进行了表征。我们使用BROCA-MY(我们定制的二代测序(NGS)panel，含72个与OC、骨髓衰竭、白血病及CH相关的基因)对血细胞DNA进行测序，并在≥1%变异等位基因频率(VAF)下识别致病性变异(CHV)。我们对170例接受卡铂化疗的OC患者(OC化疗组)、24例在PARPi试验中且在随后诊断为TMN之前采集样本的OC患者(pre-TMN组)以及180例对照受试者(包括57例未接受化疗的OC患者和123例年龄匹配的无癌女性)的血液进行了测序。CHV在所有样本组中均常见，但在OC化疗组(88/170，52%)中显著高于对照组(68/180，38%，p=0.01)。在OC化疗病例中，PARPi暴露与CHV检出显著相关：39例(34.2%)有0个CHV，20例(17.5%)有1个CHV，55例(48.2%)有≥2个CHV；而无PARPi暴露者：51例(51%)有0个CHV，29例(29%)有1个CHV，20例(20%)有≥2个CHV(P<0.0001，趋势卡方检验)。OC化疗病例中TP53(7.6%对1.7%，p=0.009)、CHEK2(11.2%对0.6%，p<0.0001)和PPM1D(21.8%对0.6%，p<0.0001)的CHV显著多于对照组，而DNMT3A(21.8%对20.6%)和TET2(10%对7.2%)的CHV检出频率相似。接受>1个铂类方案的OC化疗和pre-TMN病例，其TP53突变型CH的频率更高(19/96，19.8%)，而接受≤1个铂类方案者为(4/81，4.9%，p=0.003)。我们为有完整血细胞计数结果的样本计算了CH风险评分(CHRS)；CHRS对CH进展为显性恶性肿瘤的风险进行分层。伴CH的OC化疗病例更可能被归类为高风险(7/23，30.4%，CHRS≥1.0预示10年内进展为髓系肿瘤的风险>50%)，而伴CH的对照组为(2/43，4.7%，p=0.007)。在CHANCES研究中从41名参与者采集的系列样本中，83/88(94.4%)个CHV在所有样本中均可检测到。CH在OC化疗病例和对照组中均常见，但突变数量和涉及基因因暴露而异，化疗选择性富集CHEK2、PPM1D和TP53中的CHV。已知与衰老相关的DNMT3A和TET2的CHV未受化疗暴露影响，而TP53突变型CH与铂类暴露直接相关，与TMN发生风险增加相一致。我们将继续通过CHANCES研究采集系列样本，以表征癌症幸存者的CH动态和TMN风险，目标是生成TMN特异性风险计算器并制定癌症幸存者CH监测建议。
查看英文原文 English abstract
Ovarian cancer (OC) survivors may develop therapy-related myeloid neoplasia (TMN), and risk is increased by PARP inhibitor (PARPi) exposure. We characterized clonal hematopoiesis (CH), which may pre-date TMN, in blood from OC survivors, and its relationship to therapeutic exposures in the CHANCES ( C lonal H ematopoiesis in c ANCE r S urvivors) study. We sequenced blood cell DNA using BROCA-MY, our custom next-generation sequencing (NGS) panel with 72 genes associated with OC, bone marrow failure, and leukemia and CH and identified pathogenic variants (CHVs) at ≥1% variant allele frequency (VAF).We sequenced blood from 170 OC patients treated with carboplatin-based chemotherapy (OC chemo), 24 OC patients on a PARPi trial collected prior to subsequent diagnosis of TMN (pre-TMN), and 180 control subjects including OC patients without chemotherapy exposure (N=57) and age-matched cancer-free females (N=123). CHVs were common across all sample groups but were significantly more frequent in OC chemo (88/170, 52%) than controls (68/180, 38%, p=0.01). Within OC chemo cases, PARPi exposure was significantly associated with CHV detection: 39 (34.2%) had 0 CHV, 20 (17.5%) had 1 CHV and 55 (48.2%) had ≥2 CHVs, versus no PARPi exposure: 51 (51%) had 0 CHV, 29 (29%) had 1 CHV, and 20 (20%) had ≥2 CHVs (P<0.0001, chi-squared test for trend). CHVs were significantly more common in OC chemo cases than controls for TP53 (7.6% vs 1.7%, p=0.009), CHEK2 (11.2% vs 0.6%, p<0.0001) and PPM1D (21.8% vs 0.6%, p<0.0001) while CHVs in DNMT3A (21.8% vs 20.6%) and TET2 (10% vs 7.2%) were identified at similar frequency. OC chemo and pre-TMN cases receiving more >1 platinum regimen had greater frequency of TP53 -mutated CH (19/96, 19.8%), compared to ≤1 platinum regimens (4/81, 4.9%, p=0.003) We calculated the CH risk score (CHRS) for samples with available complete blood count results; the CHRS stratifies the risk of progression from CH to overt malignancy. OC chemo cases with CH were more likely to be categorized as high risk (7/23, 30.4%, CHRS≥1.0 predicting a >50% 10-year risk of progression to myeloid neoplasia) versus controls with CH (2/43, 4.7%, p=0.007). In serial samples collected from 41 participants in the CHANCES study, 83/88 (94.4%) CHVs were detectable in all samples. CH is frequent in both OC chemo cases and controls, but the number of mutations and involved genes vary by exposures, with chemotherapy selecting CHV in CHEK2, PPM1D, and TP53 . DNMT3A and TET2 CHVs, known to be associated with aging, were not impacted by chemotherapy exposure, while TP53 -mutated CH was directly associated with platinum exposure, consistent with an increased risk for TMN development. We continue to collect serial samples via the CHANCES study to characterize CH dynamics and TMN risks in cancer survivors with the goal to generate a risk calculator specific for TMN and establish recommendations for surveillance of CH in cancer survivors.
利益披露 Disclosure
E. M. Swisher,
ideaya bioscience Independent Contractor, Stock, Stock Option.
M. R. Radke, None..
N. Khasnavis, None..
J. Lopez Ochoa, None..
M. Rubin-Saika, None..
E. Manhardt, None..
E. Oshima, None..
A. Bachmann, None..
R. Gamboa, None..
D. Wu, None..
S. Keel, None..
S. Doulatov, None.