小柯机器人

英国剑桥大学Serena Nik-Zainal和Johan Staaf等研究人员合作对三阴性乳腺癌进行全基因组测序。2019年9月30日《自然—医学》杂志在线发表了这项成果。

全基因组测序（WGS）为癌症基因组解释带来了全面的见解。为了探索WGS的临床价值，研究人员对254例三阴性乳腺癌（TNBC）进行了测序，通过基于人群的瑞典癌基因分析网络-乳腺癌（SCAN-B）项目（2010年至2015年）收集了相关治疗和结果数据。

应用基于HRDetect突变特征的算法对肿瘤进行分类，预测有59％具有同源重组修复缺陷（HRDetect-高）：67％由BRCA1/BRCA2的生殖细胞/体细胞突变、BRCA1启动子超甲基化、RAD51C超甲基化组成或PALB2的双等位基因丢失。生殖细胞SINE-VNTR-Alu逆转座子揭示了BRCA1丢失的新机制。HRDetect提供独立的预后信息，无论是否已发现遗传/表观因素，与HRDetect-低相比，HRDetect-高的患者在有创无病生存的辅助化疗中有更好的预后（危险比（HR）= 0.42；95％置信区间（CI）= 0.2-0.87）和远端无复发间隔（HR = ect0.31，CI = 0.13-0.76）。

HRDetect-中，其中一些具有潜在可针对性的生物学异常，结果最差。HRDetect-低的癌症也有不足的结果：大约4.7％的错配修复缺陷型（另一个可靶向的缺陷，不是通常寻找的），并且它们富集了（但不限于）PIK3CA / AKT1途径异常。对于现在可区分的HRDetect-中和HRDetect-低类别，需要考虑新的治疗方案。

这项基于人群的研究表明TNBC的WGS能够更好地为试验分级提供信息并提高临床决策。

附：英文原文

Title: Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study

Author: Johan Staaf, Dominik Glodzik, Ana Bosch, Johan Vallon-Christersson, Christel Reuterswrd, Jari Hkkinen, Andrea Degasperi, Tauanne Dias Amarante, Lao H. Saal, Cecilia Hegardt, Hilary Stobart, Anna Ehinger, Christer Larsson, Lisa Rydn, Niklas Loman, Martin Malmberg, Anders Kvist, Hans Ehrencrona, Helen R. Davies, ke Borg, Serena Nik-Zainal

Issue&Volume: 2019-09-30

Abstract: Whole-genome sequencing (WGS) brings comprehensive insights to cancer genome interpretation. To explore the clinical value of WGS, we sequenced 254 triple-negative breast cancers (TNBCs) for which associated treatment and outcome data were collected between 2010 and 2015 via the population-based Sweden Cancerome Analysis NetworkBreast (SCAN-B) project (ClinicalTrials.gov ID:NCT02306096). Applying the HRDetect mutational-signature-based algorithm to classify tumors, 59% were predicted to have homologous-recombination-repair deficiency (HRDetect-high): 67% explained by germline/somatic mutations of BRCA1/BRCA2, BRCA1 promoter hypermethylation, RAD51C hypermethylation or biallelic loss of PALB2. A novel mechanism of BRCA1 abrogation was discovered via germline SINE-VNTR-Alu retrotransposition. HRDetect provided independent prognostic information, with HRDetect-high patients having better outcome on adjuvant chemotherapy for invasive disease-free survival (hazard ratio (HR)=0.42; 95% confidence interval (CI)=0.20.87) and distant relapse-free interval (HR=0.31, CI=0.130.76) compared to HRDetect-low, regardless of whether a genetic/epigenetic cause was identified. HRDetect-intermediate, some possessing potentially targetable biological abnormalities, had the poorest outcomes. HRDetect-low cancers also had inadequate outcomes: ~4.7% were mismatch-repair-deficient (another targetable defect, not typically sought) and they were enriched for (but not restricted to) PIK3CA/AKT1 pathway abnormalities. New treatment options need to be considered for now-discernible HRDetect-intermediate and HRDetect-low categories. This population-based study advocates for WGS of TNBC to better inform trial stratification and improve clinical decision-making. 

DOI: 10.1038/s41591-019-0582-4

Source: https://www.nature.com/articles/s41591-019-0582-4

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
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投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex