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PNAS:对恶性淋巴瘤测序或可帮助开发新型的靶向疗法

来源:生物谷 2013-10-23 00:07

2013年10月23日 讯 /生物谷BIOON/ --套细胞淋巴瘤是一种起源于血细胞和淋巴结,恶性而且难以治疗的癌症,为了鉴别该肿瘤发生的分子特性以及开发出相应的疗法,近日,来自巴塞罗那大学等处的研究者通过研究对30多个淋巴瘤患者的机体肿瘤进行了测序,该项研究成果刊登于国际杂志PNAS上。

文章中,研究者Silvia Bea表示,这项研究为我们揭示了这种复杂肿瘤的发病原因以及起源,而且该研究中我们也鉴别出了治疗该肿瘤的新型靶点。

研究者在患者癌症发病初期以及治疗后的数年内癌症复发时,对患者机体的肿瘤细胞进行测序分析,这就有可能来评估和疾病恶化相关的基因组的改变情况。随后研究者在疾病快速恶化的一组病人机体中鉴别出了NOTCH1和NOTCH2基因突变;这些突变或许成为新型疗法的治疗靶点,因为研究者可以通过药物来阻断这些基因的活性,而这些基因又参与了套细胞淋巴瘤的形成过程。

研究者同时也在一组病人中发现了一些少量的基因突变,当然研究者表示,对这些淋巴瘤患者进行测序一定会帮助其开发相应的针对每个病人的个体化疗法,这项研究由国际癌症研究协会等机构提供资助,相关研究将使得研究者不断使用基因组学的研究来引用于临床试验中,从而改善疾病的诊断情况以及癌症病人的治疗。(生物谷Bioon.com)

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Sílvia Beàa,1, Rafael Valdés-Masb, Alba Navarroa, Itziar Salaverriaa, David Martín-Garciaa, Pedro Jaresa, Eva Ginéa, Magda Pinyola, Cristina Royoa, Ferran Nadeua, Laura Condea, Manel Juana, Guillem Clota, Pedro Vizánc, Luciano Di Crocec, Diana A. Puenteb, Mónica López-Guerraa, Alexandra Morosa, Gael Rouea, Marta Aymericha, Neus Villamora, Lluís Colomoa, Antonio Martíneza, Alexandra Valeraa, José I. Martín-Suberoa, Virginia Amadora, Luis Hernándeza, Maria Rozmana, Anna Enjuanesa, Pilar Forcadad, Ana Muntañolad, Elena M. Hartmanne, María J. Calasanzf, Andreas Rosenwalde, German Ottg, Jesús M. Hernández-Rivash, Wolfram Klapperi, Reiner Siebertj, Adrian Wiestnerk, Wyndham H. Wilsonl, Dolors Colomera, Armando López-Guillermoa, Carlos López-Otínb,2, Xose S. Puenteb,1,2, and Elías Campoa,1,2

Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.

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