HSP110 T17简化并改进了结直肠癌患者的微卫星不稳定性检测。

HSP110 T17 simplifies and improves the microsatellite instability testing in patients with colorectal cancer.

作者信息

Buhard Olivier, Lagrange Anaïs, Guilloux Agathe, Colas Chrystelle, Chouchène Mouna, Wanherdrick Kristell, Coulet Florence, Guillerm Erell, Dorard Coralie, Marisa Laetitia, Bokhari Adem, Greene Malorie, El-Murr Nizar, Bodo Sahra, Muleris Martine, Sourouille Isabelle, Svrcek Magali, Cervera Pascale, Blanché Hélène, Lefevre Jérémie H, Parc Yann, Lepage Come, Chapusot Caroline, Bouvier Anne-Marie, Gaub Marie-Pierre, Selves Janick, Garrett Kerryn, Iacopetta Barry, Soong Richie, Hamelin Richard, Garrido Carmen, Lascols Olivier, André Thierry, Fléjou Jean-François, Collura Ada, Duval Alex

机构信息

INSERM, UMRS 938-Centre de Recherche Saint-Antoine, Equipe 'Instabilité des Microsatellites et Cancers', Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France Université Pierre et Marie Curie, Paris, France Centre de Mathématiques Appliquées, Ecole Polytechnique and CNRS UMR 7641, 91128 Palaiseau, France.

出版信息

J Med Genet. 2016 Jun;53(6):377-84. doi: 10.1136/jmedgenet-2015-103518. Epub 2016 Feb 1.

DOI:10.1136/jmedgenet-2015-103518

PMID:26831756

Abstract

BACKGROUND

Every colorectal cancer (CRC) patient should be tested for microsatellite instability (MSI, a marker for defective DNA mismatch repair) as a first screen for Lynch syndrome (LS). In this study, we investigated whether it may be possible to improve the detection of MSI in CRC. We examined whether the HT17 DNA repeat (critical for correct splicing of the chaperone HSP110) might constitute a superior marker for diagnosis of the MSI phenotype in patients with CRC compared with the standard panel of markers (pentaplex).

METHODS

The HT17 polymorphism was analysed in germline DNA from 1037 multi-ethnic individuals. We assessed its sensitivity and specificity for detecting MSI in a multicentre, population-based cohort of 685 patients with CRC and an additional series of 70 patients with CRC considered to be at-risk of LS. All cases were screened earlier for MSI using pentaplex markers. Cases showing discordant HT17/pentaplex results were further examined for the expression of mismatch repair proteins.

RESULTS

HT17 status was analysed independently and blinded to previous results from pentaplex genotyping. HT17 showed no germline allelic variation outside a very narrow range. Compared with the pentaplex panel, HT17 showed better sensitivity (0.984 (95% CI 0.968 to 0.995) vs 0.951 (95% CI 0.925 to 0.972)) and similar specificity (0.997 (95% CI 0.989 to 1.000) for both) for the detection of MSI. Furthermore, HT17 alone correctly classified samples judged to be uncertain with the pentaplex panel and showed excellent ability to detect MSI in patients with LS.

CONCLUSIONS

HT17 simplifies and improves the current standard molecular methods for detecting MSI in CRC.

摘要

背景

每位结直肠癌（CRC）患者都应进行微卫星不稳定性（MSI，DNA错配修复缺陷的标志物）检测，作为林奇综合征（LS）的首次筛查。在本研究中，我们调查了是否有可能改善CRC中MSI的检测。我们研究了HT17 DNA重复序列（伴侣蛋白HSP110正确剪接的关键序列）与标准标志物组（五重检测法）相比，是否可能构成CRC患者MSI表型诊断的更优标志物。

方法

对1037名多民族个体的生殖系DNA进行HT17多态性分析。我们在一个基于人群的多中心队列中评估了其检测MSI的敏感性和特异性，该队列包括685例CRC患者以及另外70例被认为有LS风险的CRC患者。所有病例均先用五重检测法进行MSI筛查。对HT17/五重检测法结果不一致的病例，进一步检测错配修复蛋白的表达。

结果

HT17状态是独立分析的，且对五重基因分型的先前结果保密。HT17在非常窄的范围内没有生殖系等位基因变异。与五重检测法相比，HT17在检测MSI方面表现出更高的敏感性（0.984（95%CI 0.968至0.995）对0.951（95%CI 0.925至0.972））和相似的特异性（两者均为0.997（95%CI 0.989至1.000））。此外，仅HT17就能正确分类被五重检测法判定为不确定的样本，并且在检测LS患者的MSI方面表现出卓越的能力。