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Cited by 247

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Somatic LKB1 Mutations Promote Cervical Cancer Progression

Wingo, Shana N., Gallardo, Teresa D., Akbay, Esra A., Liang, Mei-Chi, Contreras, Cristina M., Boren, Todd, Shimamura, Takeshi, Miller, David S., Sharpless, Norman E., Bardeesy, Nabeel, Kwiatkowski, David J., Schorge, John O., Wong, Kwok-Kin, Castrillon, Diego H.·2009·PLoS ONE
DOI 10.1371/journal.pone.0005137PMC PMC2660434
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Figure 1 Somatic mutations and deletions of LKB1 in cervical tumors. (A) Representative chromatograms of primary tumors. (B) C4I cell line. Lower panels, control DNA samples from each patient (for C4I, human peripheral leukocyte DNA). Wild-type sequences are shown below. Chromatograms represent forward strand except case #41 where reverse complement is shown to more clearly illustrate the deletion. Mutations are heterozygous except where indicated. (C) LKB1 deletions in primary cervical tumors by MLPA. Bars = relative signal intensity per probe. Sixteen probes (black) correspond to LKB1 locus on chromosome 19. Probe identifiers shown below. Probes 0.9M5′ and 0.6M5′ are ∼900 and 600 kb 5′ of locus (telomeric), while 10M3′ is ∼10000 kb 3′ (centromeric); remaining 13 probes correspond to LKB1 noncoding/coding exons. White bars correspond to randomly selected probes from other chromosomes.
Figure 1 Somatic mutations and deletions of LKB1 in cervical tumors. (A) Representative chromatograms of primary tumors. (B) C4I cell line. Lower panels, control DNA samples from each patient (for C4I, human peripheral leukocyte DNA). Wild-type sequences are shown below. Chromatograms represent forward strand except case #41 where reverse complement is shown to more clearly illustrate the deletion. Mutations are heterozygous except where indicated. (C) LKB1 deletions in primary cervical tumors by MLPA. Bars = relative signal intensity per probe. Sixteen probes (black) correspond to LKB1 locus on chromosome 19. Probe identifiers shown below. Probes 0.9M5′ and 0.6M5′ are ∼900 and 600 kb 5′ of locus (telomeric), while 10M3′ is ∼10000 kb 3′ (centromeric); remaining 13 probes correspond to LKB1 noncoding/coding exons. White bars correspond to randomly selected probes from other chromosomes.CC BY · PubMed Central
Figure 2 LKB1 mutations occur in each of the principal histologic subtypes of cervical cancer. (A) Histology of representative cases with LKB1 mutations (SCC = squamous cell carcinoma; Adeno = adenocarcinoma; AdenoSq = adenosquamous carcinoma; MDA = minimal deviation adenocarcinoma). Scale bar = 20 microns. (B) Relative distribution of the three principal histologic subtypes among LKB1-mutant (red) vs. LKB1-wild type (black) cases (totals = 100%) shows that the histologic spectrum is virtually identical in LKB1 null vs. wild-type tumors.
Figure 2 LKB1 mutations occur in each of the principal histologic subtypes of cervical cancer. (A) Histology of representative cases with LKB1 mutations (SCC = squamous cell carcinoma; Adeno = adenocarcinoma; AdenoSq = adenosquamous carcinoma; MDA = minimal deviation adenocarcinoma). Scale bar = 20 microns. (B) Relative distribution of the three principal histologic subtypes among LKB1-mutant (red) vs. LKB1-wild type (black) cases (totals = 100%) shows that the histologic spectrum is virtually identical in LKB1 null vs. wild-type tumors.CC BY · PubMed Central
Figure 3 Homozygous LKB1 deletions occur in majority of cervical cancer cell lines. (A) MLPA; see Figure 1 for probe details. HeLa, MS751, SiHa, and HT3 (and HeLa subclone HeLaS3) contain distinctive homozygous deletions. C4I harbors a monoallelic deletion, as evidenced by contiguous probes with half-intensity signals. (B) Southern analysis of control DNA, above cell lines, C33 (no deletion by MLPA) and HPV16/E6E7-immortalized endocervical cells from a normal patient (Endo = End1/E6E7; ATCC #CRL-2615). (C) Western analysis. LKB1 protein is undetectable in lines harboring homozygous deletions and decreased by ∼50% in C4I, consistent with monoallelic loss.
Figure 3 Homozygous LKB1 deletions occur in majority of cervical cancer cell lines. (A) MLPA; see Figure 1 for probe details. HeLa, MS751, SiHa, and HT3 (and HeLa subclone HeLaS3) contain distinctive homozygous deletions. C4I harbors a monoallelic deletion, as evidenced by contiguous probes with half-intensity signals. (B) Southern analysis of control DNA, above cell lines, C33 (no deletion by MLPA) and HPV16/E6E7-immortalized endocervical cells from a normal patient (Endo = End1/E6E7; ATCC #CRL-2615). (C) Western analysis. LKB1 protein is undetectable in lines harboring homozygous deletions and decreased by ∼50% in C4I, consistent with monoallelic loss.CC BY · PubMed Central
Figure 4 LKB1 deletion breakpoints in cervical cancer cell lines. (A) LKB1 locus (chromosome 19p13.3). (B) 140 kb region (Ensembl50; 1050000–1190000) spanning LKB1 and immediately flanking loci; intervals = 10 kb. (C) Deletion breakpoints for cell lines harboring homozygous deletions. In MS751, deleted sequences are discontinuous as shown, consistent with a more complex rearrangement. Arrows = PCR primers for HeLa specific PCR (400 bp). (D) HeLa specific PCR (400 bp) confirms presence of deletion in HeLaS3. (E) HeLa intragenic LKB1 deletion occurred in vivo. Archival blocks were cored for DNA preparation. Lanes are as follows: (−) control = no template control; tumor = metastatic adrenal deposit; non-tumor = normal adrenal (same tissue block); (+) control = HeLa cell line DNA.
Figure 4 LKB1 deletion breakpoints in cervical cancer cell lines. (A) LKB1 locus (chromosome 19p13.3). (B) 140 kb region (Ensembl50; 1050000–1190000) spanning LKB1 and immediately flanking loci; intervals = 10 kb. (C) Deletion breakpoints for cell lines harboring homozygous deletions. In MS751, deleted sequences are discontinuous as shown, consistent with a more complex rearrangement. Arrows = PCR primers for HeLa specific PCR (400 bp). (D) HeLa specific PCR (400 bp) confirms presence of deletion in HeLaS3. (E) HeLa intragenic LKB1 deletion occurred in vivo. Archival blocks were cored for DNA preparation. Lanes are as follows: (−) control = no template control; tumor = metastatic adrenal deposit; non-tumor = normal adrenal (same tissue block); (+) control = HeLa cell line DNA.CC BY · PubMed Central
Figure 5 Progression-free survival of patients with LKB1-wild type vs. LKB1-mutant tumors. Kaplan-Meier curves show the percentage of patients with disease progression over time. The curves compare patients whose tumors were heterozygous or homozygous for mutations/deletions (LKB1) vs. patients with no mutations/deletions (wt). Patients with >1 follow-up visit were included in the analysis. P value per log-rank test.
Figure 5 Progression-free survival of patients with LKB1-wild type vs. LKB1-mutant tumors. Kaplan-Meier curves show the percentage of patients with disease progression over time. The curves compare patients whose tumors were heterozygous or homozygous for mutations/deletions (LKB1) vs. patients with no mutations/deletions (wt). Patients with >1 follow-up visit were included in the analysis. P value per log-rank test.CC BY · PubMed Central

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Citations

Cites

Research works printed but not linked: 29

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Metadata

Authors
Wingo, S. N., Gallardo, T. D., Akbay, E. A., Liang, M.-C., Contreras, C. M., Boren, T., Shimamura, T., Miller, D. S., Sharpless, N. E., Bardeesy, N., Kwiatkowski, D. J., Schorge, J. O., Wong, K.-K., & Castrillon, D. H.
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2009-04-02
Volume
4
Issue
4
Pages
e5137
ISSN
1932-6203
DOI
10.1371/journal.pone.0005137
PMC
PMC2660434
Cited by
247
References
2
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (unspecified)

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