Genetic alteration of the β-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion

Shigemitsu, Kikuo; Sekido, Yoshitaka; Usami, Noriyasu; Mori, Satoshi; Sato, Mitsuo; Horio, Yoshitsugu; Hasegawa, Yoshinori; Bader, Scott; Gazdar, Adi F.; Minna, John D.; Hida, Toyoaki; Yoshioka, Hide; Imaizumi, Munehisa; Ueda, Yuichi; Takahashi, Masahide; Shimokata, Kaoru

doi:10.1038/sj.onc.1204557

Cited by 97 publications

(88 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…23 Likewise, 1 (1%) adenocarcinoma among 90 primary lung carcinomas has been reported to have a mutation. 24 From these findings, mutation of ␤-catenin seems quite rare in NSCLCs.…”

Section: Discussionmentioning

confidence: 98%

Increased expression of β‐catenin predicts better prognosis in nonsmall cell lung carcinomas

Hommura

Furuuchi

Yamazaki

et al. 2002

Cancer

View full text Add to dashboard Cite

BACKGROUNDβ‐Catenin has been shown to function as a Wnt signaling molecule to stimulate cyclin D1 expression and cell growth in several kinds of tumors.METHODSThe authors immunohistochemically examined specimens of 217 surgically resected primary nonsmall cell lung carcinomas (NSCLCs) for β‐catenin expression and classified them semiquantitatively into three categories, including those with high, moderate, and low scores of expression.RESULTSHigh, moderate, and low scores of expression were found in 37 (17.1%), 145 (66.8%), and 35 (16.1%) tumors, respectively. β‐Catenin expression was not correlated with cyclin D1 expression, but was positively correlated with the Ki‐67 cell growth fraction (P = 0.04). The direct sequencing analysis for the β‐catenin gene mutation of 13 specimens of 217 tumors for the current study revealed no mutations. The relation between survival and β‐catenin expression was evaluated in 148 potentially curatively resected tumors with pathologic Stages I–IIIA. A trend toward better survival was found in patients with tumors having higher scores. In multivariate analysis, high β‐catenin expression was a significant and independent favorable prognostic factor (hazards ratio, 0.31; P = 0.007) as was pathologic stage. Analyzed by cell type, in nonsquamous cell carcinomas, patients with tumors having high scores survived a significantly longer time than those with tumors having moderate or low scores (5‐year survival rates, 84%, 55%, and 32%, respectively; P = 0.02), and high β‐catenin expression tended to be a favorable prognostic factor (hazards ratio, 0.32; P = 0.052).CONCLUSIONSThese results indicate that, in NSCLCs, increased expression of β‐catenin can predict favorable prognosis of patients with resected tumors, suggesting that accumulation of β‐catenin has no or little oncogenic effect via activation of the Wnt pathway, unlike in colon carcinomas or hepatomas. Cancer 2002;94:752–8. © 2002 American Cancer Society.DOI 10.1002/cncr.10213

show abstract

“…23 Likewise, 1 (1%) adenocarcinoma among 90 primary lung carcinomas has been reported to have a mutation. 24 From these findings, mutation of ␤-catenin seems quite rare in NSCLCs.…”

Section: Discussionmentioning

confidence: 98%

Increased expression of β‐catenin predicts better prognosis in nonsmall cell lung carcinomas

Hommura

Furuuchi

Yamazaki

et al. 2002

Cancer

View full text Add to dashboard Cite

show abstract

“…To date, to the best of our knowledge, 15 solid tumor cases or cell lines carrying homozygous deletions have been sequenced and reported (Canning and Dryja, 1989;Tadokoro et al, 1992;Murata et al, 1994;Pomykala et al, 1994;Kohno et al, 1996;Inoue et al, 1997;Sekido et al, 1998;Nishioka et al, 2000;Shigemitsu et al, 2001;Tamura et al, 2002). As a result, short direct repeats were found at the breakpoints in seven cases, while repetitive sequences such as long interspersed nuclear elements (LINEs) and Alu sequences appeared to be involved in five cases.…”

Section: Discussionmentioning

confidence: 99%

Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at distal 17p13.3 in human lung cancer

et al. 2003

View full text Add to dashboard Cite

17p13.3 is one of the chromosomal regions most frequently affected by allelic loss in a variety of human neoplasms including lung cancer. A number of loss of heterozygosity (LOH) analyses have suggested the existence of a tumor suppressor gene at 17p13.3, distal to the p53 locus at 17p13.1. In the present study, we characterized a homozygous deletion at 17p13.3 in a small cell lung cancer cell line by constructing a bacterial artificial chromosome (BAC) contig and a restriction map surrounding the region, as well as by utilizing publicly available draft sequences. We defined the breakpoint, assigned and analysed two known genes, 14-3-3e and CRK, and a novel gene LOST1 within or at the end of the homozygous deletion of about 170 kb in size. Marked reduction of LOST1 expression was detected in 69% (11/ 16) of lung cancer specimens by quantitative real-time RT-PCR, while significant DNA hypermethylation was observed at the 5 0 end of the LOST1 gene in four of six lung cancer cell lines with negligible LOST1 expression. We also show here that a polymorphic marker D17S1174, which resides within the homozygous deletion, was apparently located in the middle of the minimum LOH region, providing further supportive evidence for the presence of a tumor suppressor gene(s) in this region.

show abstract

“…Exon 3 of b-catenin, a mutation hotspot region containing the GSK3 phosphorylation sites (Shigemitsu et al, 2001), was amplified from genomic DNA for 35 cycles using the primers listed in Supplementary Table 1. Sequencing was performed in an ABI Prism 377 DNA Sequencer (PE Applied Biosystems, Foster City, CA, USA).…”

Section: Mutation Analysis Of B-cateninmentioning

confidence: 99%

Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type β-catenin nuclear accumulation in lung tumorigenesis

et al. 2008

View full text Add to dashboard Cite

b-catenin accumulation is often found in lung tumors, but only a few patients have mutations in b-catenin gene. In addition, activated p53 downregulates b-catenin. Therefore, we postulated that alteration of the degradation complex AXIN2 (axis inhibition protein 2) and betaTrCP (b-transducin repeat-containing protein) and p53 regulation could result in b-catenin protein accumulation in lung cancer. Using the immunohistochemical and sequencing analyses, we found that patients with b-catenin accumulation without mutation were associated with patients with p53 overexpression and low AXIN2 expression (P ¼ 0.023B0.041). Alteration of AXIN2 was associated with poor survival in early stage patients (P ¼ 0.016). Low expression of AXIN2 and betaTrCP was significantly associated with promoter hypermethylation and histone deacetylation. Ectopic expression and knockdown of p53, AXIN2 and betaTrCP genes in A549 (p53 wild-type) and H1299 (p53 null) lung cancer cell lines showed cooperation between p53 and AXIN2/betaTrCP in the reduction of b-catenin expression. Our clinical and cell model findings provide new evidence that epigenetic silencing of AXIN2/betaTrCP in the degradation complex and deregulation of p53-mediated control lead to wild-type b-catenin nuclear accumulation in non-small cell lung cancer tumorigenesis. In addition, a high level of p53 downregulates the b-catenin expression, but this effect is attenuated by non-functional AXIN2 or betaTrCP in lung cancer.

show abstract

Genetic alteration of the β-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion

Cited by 97 publications

References 32 publications

Increased expression of β‐catenin predicts better prognosis in nonsmall cell lung carcinomas

Increased expression of β‐catenin predicts better prognosis in nonsmall cell lung carcinomas

Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at distal 17p13.3 in human lung cancer

Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type β-catenin nuclear accumulation in lung tumorigenesis

Contact Info

Product

Resources

About