APC mutations are infrequent but present in human lung cancer

Ohgaki, Hideaki; Kros, Johan M.; Okamoto, Yoshikazu; Gaspert, Ariana; Huang, Hongyi; Kurrer, Michael

doi:10.1016/j.canlet.2003.10.020

Cited by 75 publications

(45 citation statements)

References 28 publications

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“…In PC02T, a missense mutation (p.E1284K) in APC was identified. Located in a mutation cluster in codons 1248-1522 of the APC gene, this mutation was previously discovered in a small-cell lung cancer (33). In addition, we detected an inactivating mutation in RNF43 (p.G659fs) in case PC05T.…”

Section: Mutational Landscape In Pcmentioning

confidence: 55%

Genomic profiling reveals mutational landscape in parathyroid carcinomas

Pandya¹,

Uzilov²,

Bellizzi³

et al. 2017

JCI Insight

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Section: Mutational Landscape In Pcmentioning

confidence: 55%

Genomic profiling reveals mutational landscape in parathyroid carcinomas

Pandya¹,

Uzilov²,

Bellizzi³

et al. 2017

JCI Insight

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“…Its role in other epithelial cancers has been less clear, and in lung cancer, mutations in the Wnt/β-catenin pathway are not found at high frequency (10,11,13,14). The cell of origin for most lung cancers remains elusive, but several studies have pointed to cells residing in the BADJ region (18,53).…”

Section: Discussionmentioning

confidence: 99%

“…The role of Wnt/β-catenin signaling in lung cancer remains somewhat unclear. Mutations in β-catenin and adenomatous polyposis coli (APC), the most commonly mutated factors found in other cancers, are found only rarely in human lung tumors, and previous mouse models of Wnt/β-catenin activation in the postnatal lung have not produced a significant level of lung oncogenesis (10)(11)(12)(13)(14). Recently, it has been shown using human lung tumor cell lines that increased Wnt/β-catenin signaling can lead to increased tumor metastasis (15).…”

Section: Introductionmentioning

confidence: 99%

Wnt/β-catenin signaling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium

Pacheco-Pinedo¹,

Durham²,

Stewart³

et al. 2011

J. Clin. Invest.

143

115

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Although mutations in Kras are present in 21% of lung tumors, there is a high level of heterogeneity in phenotype and outcome among patients with lung cancer bearing similar mutations, suggesting that other pathways are important. Wnt/β-catenin signaling is a known oncogenic pathway that plays a well-defined role in colon and skin cancer; however, its role in lung cancer is unclear. We have shown here that activation of Wnt/β-catenin in the bronchiolar epithelium of the adult mouse lung does not itself promote tumor development. However, concurrent activation of Wnt/β-catenin signaling and expression of a constitutively active Kras mutant (KrasG12D) led to a dramatic increase in both overall tumor number and size compared with KrasG12D alone. Activation of Wnt/β-catenin signaling altered the KrasG12D tumor phenotype, resulting in a phenotypic switch from bronchiolar epithelium to the highly proliferative distal progenitors found in the embryonic lung. This was associated with decreased E-cadherin expression at the cell surface, which may underlie the increased metastasis of tumors with active Wnt/β-catenin signaling. Together, these data suggest that activation of Wnt/β-catenin signaling can combine with other oncogenic pathways in lung epithelium to produce a more aggressive tumor phenotype by imposing an embryonic distal progenitor phenotype and by decreasing E-cadherin expression. IntroductionLung cancer is the second most common cancer in both men and women, accounting for approximately 15% of all newly diagnosed cancers (1, 2). Despite extensive investment of research dollars into developing new treatments for lung cancer, it remains responsible for 29% of cancer deaths in the United States, which is more than breast, colon, and prostate cancer combined. The overall 5-year survival rate is only 15.8%, making lung cancer one of the most deadly and difficult to diagnose cancers in humans.Although smoking is the primary cause of most lung cancer, approximately 10%-15% of lung cancers are found in nonsmokers, suggesting additional genetic causes of this disease. Extensive research into the underlying molecular insults leading to lung epithelial oncogenesis has resulted in the finding that Kras and EGFR mutations account for a large number of pulmonary cancers (3-7). However, there is significant heterogeneity among patients with similar mutations, suggesting the contribution of additional molecular pathways in the regulation of lung oncogenesis.Wnt/β-catenin signaling is a well-described oncogenic pathway that plays important roles in several cancers, including colon cancer, where it is the most common genetic cause of oncogenesis (8, 9). The role of Wnt/β-catenin signaling in lung cancer remains somewhat unclear. Mutations in β-catenin and adenomatous polyposis coli (APC), the most commonly mutated factors found in other cancers, are found only rarely in human lung tumors, and previous mouse models of Wnt/β-catenin activation in the postnatal

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“…Although p53 is a well-established target gene for mutational inactivation in >50% of lung cancers, SMAD4 is rarely targeted for mutational inactivation in lung cancer (34)(35)(36). Furthermore, p73 and APC are prominent tumor suppressor genes localized to 1p and 5q, respectively, and associated with lung cancer; however, the roles of these target genes or others in advanced lung cancer require systematic studies (37,38).…”

Section: Discussionmentioning

confidence: 99%

Loss of Heterozygosity Patterns Provide Fingerprints for Genetic Heterogeneity in Multistep Cancer Progression of Tobacco Smoke–Induced Non–Small Cell Lung Cancer

et al. 2005

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Dilution end point loss of heterozygosity (LOH) analysis, a novel approach for the analysis of LOH, was used to evaluate allelic losses with the use of 21 highly polymorphic microsatellite markers at nine chromosomal sites most frequently affected in smoking-related non-small cell lung cancers. Allelotyping was done for bronchial epithelial cells and matching blood samples from 23 former and current smokers and six nonsmokers as well as in 33 adenocarcinomas and 25 squamous cell carcinomas (SCC) and corresponding matching blood from smokers. Major conclusions from these studies are as follows: (a) LOH at chromosomal sites 8p, 9p, 11q, and 13q (P > > 0.05, Fisher's exact test) are targeted at the early stages, whereas LOH at 1p, 5q, 17p, and 18q (P < < 0.05, Fisher's exact test) occur at the later stages of non-small cell lung cancer progression; (b) LOH at 1p, 3p, 5q, 8p, 9p, 11q, 13q, 17p, and 18q occurs in over 45% of the tobacco smokers with SCC and adenocarcinoma; (c) compared with bronchial epithelial cells from smokers, there is a significantly higher degree of LOH at 1p, 5q, and 18q in adenocarcinoma and at 1p, 3p, and 17p in SCC (P < < 0.05, Fisher's exact test). We propose that lung cancer progression induced by tobacco smoke occurs in a series of target gene inactivations/activations in defined modules of a global network. The gatekeeper module consists of multiple alternate target genes, which is inclusive of but not limited to genes localized to chromosomal loci 8p, 9p, 11q, and 13q.

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APC mutations are infrequent but present in human lung cancer

Cited by 75 publications

References 28 publications

Genomic profiling reveals mutational landscape in parathyroid carcinomas

Genomic profiling reveals mutational landscape in parathyroid carcinomas

Wnt/β-catenin signaling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium

Loss of Heterozygosity Patterns Provide Fingerprints for Genetic Heterogeneity in Multistep Cancer Progression of Tobacco Smoke–Induced Non–Small Cell Lung Cancer

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