Somatic LKB1 mutations promote cervical cancer progression

Shana N. Wingo, Teresa D. Gallardo, Esra A. Akbay, Mei Chi Liang, Cristina M. Contreras, Todd Boren, Takeshi Shimamura, David S. Miller, Norman E. Sharpless, Nabeel Bardeesy, David J. Kwiatkowski, John O. Schorge, Kwok Kin Wong, Diego H. Castrillon

Research output: Contribution to journalArticlepeer-review

189 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere5137
JournalPloS one
Volume4
Issue number4
DOIs
StatePublished - Apr 2 2009

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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