Somatic LKB1 mutations promote cervical cancer progression.
Somatic LKB1 mutations promote cervical cancer progression.
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DOI：
10.1371/journal.pone.0005137
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Castrillon DH
中科院分区：
文献类型：
--
作者：
Wingo SN;Gallardo TD;Akbay EA;Liang MC;Contreras CM;Boren T;Shimamura T;Miller DS;Sharpless NE;Bardeesy N;Kwiatkowski DJ;Schorge JO;Wong KK;Castrillon DH
人乳头瘤病毒（HPV）是宫颈癌的病原。然而，感染HPV并不足以引起宫颈癌，因为大多数感染的妇女会出现短暂的上皮发育不良，并自发消退。浸润性癌症的进展可归因于多种宿主因素，如免疫或激素状态，因为在宫颈癌中未发现复发性遗传改变。因此，关于宫颈癌进展的生物学基础的紧迫问题仍未解决，阻碍了新疗法和预后测试的发展。在这里，我们表明至少20%的宫颈癌在LKB1肿瘤抑制因子中存在体获得性突变。大约一半的突变肿瘤包含单核苷酸取代或外显子测序可识别的微缺失，而另一半包含更大的单等位基因或双等位基因缺失，可通过多重连接探针扩增（MLPA）检测到。在大多数宫颈癌细胞系中发现双等位基因突变；HeLa是第一个人类细胞系，具有在体内发生的25 kb纯合子缺失。原发性肿瘤中LKB1失活与疾病进展加速相关。lkb1缺陷型肿瘤患者的中位生存期仅为13个月，而lkb1野生型肿瘤患者的中位生存期为100个月（P = 0.015， log rank检验；风险比= 0.25,95% CI = 0.083 ~ 0.77）。因此，LKB1是一种主要的宫颈肿瘤抑制因子，表明获得性基因改变驱动hpv诱导的发育不良向侵袭性、致死性癌症发展。此外，LKB1水平可用于临床预测疾病复发。
Human Papilloma Virus (HPV) is the etiologic agent for cervical cancer. Yet, infection with HPV is not sufficient to cause cervical cancer, because most infected women develop transient epithelial dysplasias that spontaneously regress. Progression to invasive cancer has been attributed to diverse host factors such as immune or hormonal status, as no recurrent genetic alterations have been identified in cervical cancers. Thus, the pressing question as to the biological basis of cervical cancer progression has remained unresolved, hampering the development of novel therapies and prognostic tests. Here we show that at least 20% of cervical cancers harbor somatically-acquired mutations in the LKB1 tumor suppressor. Approximately one-half of tumors with mutations harbored single nucleotide substitutions or microdeletions identifiable by exon sequencing, while the other half harbored larger monoallelic or biallelic deletions detectable by multiplex ligation probe amplification (MLPA). Biallelic mutations were identified in most cervical cancer cell lines; HeLa, the first human cell line, harbors a homozygous 25 kb deletion that occurred in vivo. LKB1 inactivation in primary tumors was associated with accelerated disease progression. Median survival was only 13 months for patients with LKB1-deficient tumors, but >100 months for patients with LKB1-wild type tumors (P = 0.015, log rank test; hazard ratio = 0.25, 95% CI = 0.083 to 0.77). LKB1 is thus a major cervical tumor suppressor, demonstrating that acquired genetic alterations drive progression of HPV-induced dysplasias to invasive, lethal cancers. Furthermore, LKB1 status can be exploited clinically to predict disease recurrence.
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影响因子：
64.8
作者：
Ji, Hongbin;Ramsey, Matthew R.;Wong, Kwok-Kin
通讯作者：
Wong, Kwok-Kin
影响因子：
3.9
作者：
Boudeau, J.;Kieloch, A.;Resta, N.
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影响因子：
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Contreras, Cristina M.;Gurumurthy, Sushma;Castrillon, Diego H.
通讯作者：
Castrillon, Diego H.
影响因子：
11.4
作者：
BOSHART, M;GISSMANN, L;HAUSEN, HZ
通讯作者：
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影响因子：
8
作者：
Matsumoto, S.;Iwakawa, R.;Yokota, J.
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Yokota, J.