转移性激素敏感性前列腺癌(mHSPC)的全外显子相关性:来自 E3805 CHAARTED 的结果。

IF 2.1 3区 工程技术 Q3 CHEMISTRY, MULTIDISCIPLINARY
Anis A. Hamid, Matias Vergara, Jihye Park, Tyler M. Chinsky, S. AlDubayan, E. Grist, Gerhardt Attard, E. V. Van Allen, Christopher Sweeney
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引用次数: 0

摘要

5088 背景:人们对mHSPC基因组变异的情况和临床影响尚不完全了解。我们已经证明,有害的种系 BRCA2 基因变异(allts)与雄激素剥夺疗法(ADT)治疗阉割耐药前列腺癌(TTCRPC)的时间缩短有关,但与 ADT+ 多西他赛(ADT+D)治疗阉割耐药前列腺癌(TTCRPC)的时间缩短无关(ASCO 2023)。mHSPC患者(pts)组织的体细胞变异特征尚不明确,可能会影响治疗效果。方法:我们对 ADT 与 ADT+D 的 CHAARTED 试验(NCT00309985)中初步诊断时获得的 HSPC 标本和患者全血中的种系 DNA 进行了全外显子测序。鉴定了体细胞单核苷酸变异(SNV)和等位基因特异性拷贝数异体(CNA),包括肿瘤突变负荷(TMB)和拷贝数负荷(CNB)的估计。对两组患者的预后效果进行了评估。所选抑癌基因的缺失定义为单拷贝或双拷贝缺失。TTCRPC和总生存期(OS)采用卡普兰-梅耶法估算。危险比(HRs)和 95% 置信区间(95% CIs)由 Cox 模型估算。结果经过质量控制,共分析了68例肿瘤正常病例。大多数病例为同步(51.5%)和高体积(58.8%)疾病。最常见的体细胞SNV是TP53(33.8%)、PTEN(7.4%)、PIK3CA(5.9%)和SPOP(5.9%)。AR扩增并不常见(4.4%),但MYC增益(60.3%)以及NKX3-1、TP53、PTEN和BRCA2的单倍缺失却很常见。全基因组加倍发生率为 14.7%。TMB和CNB的中位数分别为4.7 mut/Mb和9.1%。同步(p=0.01)和高容量(p=0.046)疾病的 CNB 升高。在总体队列(HR 2.06,95%CI 1.13-3.75,p=0.015)和 ADT+D 组(HR 2.98,95%CI 1.17-7.58,p=0.016)中,CNB 高于中位数与 TTCRPC 缩短相关。调整血容量和表现后,总体队列中的效应有所降低(HR 1.72,P=0.091)。在 ADT 治疗组中,PTEN 和 TP53 alts 的复合效应显现出来,野生型 (WT)、1 基因突变、2 基因突变的中位 TTCRPC 分别为 19.6 个月、8.5 个月和 6.3 个月。WT与1基因缺失/2基因缺失的中位OS分别为47.1个月和26.8个月(HR 2.05,95% CI 0.90-4.68,P=0.087)。ADT+D的TTCRP和OS在PTEN/ TP53状态下没有观察到类似的差异。结论mHSPC基因组图谱的特点是在已知富集于mCRPC的推定驱动因子中频繁出现异体(表)。我们观察到的基因组不稳定性和AR扩增/突变率较低,与非转移性HSPC相似。与STAMPEDE试验一致,CNB越大,进展风险越高。综合肿瘤抑制基因异型与 mHSPC 的预后有关,这可能因治疗强度而异。[表:见正文]
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Whole exome correlates in metastatic hormone sensitive prostate cancer (mHSPC): Results from E3805 CHAARTED.
5088 Background: The landscape and clinical impact of genomic variants in mHSPC are incompletely understood. We have shown that deleterious germline BRCA2 alterations (alts) associate with shorter time to castration resistant prostate cancer (TTCRPC) on androgen deprivation therapy (ADT), but not on ADT plus docetaxel (ADT+D) (ASCO 2023). Somatic variation from tissue of patients (pts) with mHSPC is not well characterized and may influence therapeutic outcomes. Methods: We performed whole exome sequencing of HSPC specimens obtained at initial diagnosis and germline DNA from whole blood from pts in the CHAARTED trial (NCT00309985) of ADT vs ADT+D. Somatic single nucleotide variants (SNV) and allele-specific copy number alts (CNAs) were identified, including estimation of tumor mutational burden (TMB) and copy number burden (CNB). Prognostic effects were evaluated in both arms. Loss of selected tumor suppressor genes was defined by monoallelic or biallelic loss. TTCRPC and overall survival (OS) were estimated by Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated by Cox models. Results: After quality control, 68 tumor-normal cases were analyzed. The majority of pts had synchronous (51.5%) and high volume (58.8%) disease. Most frequent somatic SNVs were TP53 (33.8%), PTEN (7.4%), PIK3CA (5.9%) and SPOP (5.9%). AR amplification was uncommon (4.4%), however frequent MYC gain (60.3%) was seen as well as monoallelic deletion of NKX3-1, TP53, PTEN and BRCA2. Whole genome doubling occurred in 14.7%. Median TMB and CNB were 4.7 mut/Mb and 9.1%, respectively. CNB was elevated in synchronous (p=0.01) and high volume (p=0.046) disease. CNB greater than median was associated with shorter TTCRPC in the overall cohort (HR 2.06, 95%CI 1.13-3.75, p=0.015) and ADT+D arm (HR 2.98, 95%CI 1.17-7.58, p=0.016). The effect in the overall cohort was reduced after adjustment for volume and presentation (HR 1.72, p=0.091). A compounding effect of PTEN and TP53 alts was seen in the ADT arm where median TTCRPC for wild-type (WT), 1-gene hit, 2-gene hit was 19.6 mos, 8.5 mos, 6.3 mos, respectively. The median OS of WT vs 1-hit/2-hit loss was 47.1 mos vs 26.8 mos (HR 2.05, 95% CI 0.90-4.68, p=0.087). Similar differences in TTCRP and OS by PTEN/ TP53 status were not observed with ADT+D. Conclusions: The genomic landscape of mHSPC is characterized by frequent alts in putative drivers known to be enriched in mCRPC (Table). We observed a low rate of genomic instability and AR amplification/mutation similar to non-metastatic HSPC. Concordant with the STAMPEDE trial, greater CNB confers a higher risk of progression. Combined tumor suppressor gene alts associate with prognosis in mHSPC, which may differ by therapy intensification. [Table: see text]
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来源期刊
Journal of Chemical & Engineering Data
Journal of Chemical & Engineering Data 工程技术-工程:化工
CiteScore
5.20
自引率
19.20%
发文量
324
审稿时长
2.2 months
期刊介绍: The Journal of Chemical & Engineering Data is a monthly journal devoted to the publication of data obtained from both experiment and computation, which are viewed as complementary. It is the only American Chemical Society journal primarily concerned with articles containing data on the phase behavior and the physical, thermodynamic, and transport properties of well-defined materials, including complex mixtures of known compositions. While environmental and biological samples are of interest, their compositions must be known and reproducible. As a result, adsorption on natural product materials does not generally fit within the scope of Journal of Chemical & Engineering Data.
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