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Gene-promoter hypermethylation as a biomarker in lung cancer

Nature Reviews Cancer volume 4, pages 707–717 (2004)Cite this article

Key Points

  • Lung cancer accounts for 30% of all deaths from cancer. Detection often occurs at an advanced stage and conventional chemotherapy is of limited effectiveness.

  • There is no validated screening approach for early detection of lung cancer. Spiral computed tomography and fluorescence bronchoscopy are being examined, but both might lack diagnostic sensitivity and specificity.

  • Epigenetic-mediated gene silencing in the form of aberrant promoter hypermethylation constitutes an alternative to coding-region mutation for loss of gene function.

  • Loss of gene transcription by promoter methylation is a crucial event in lung cancer initiation and progression. Genes involved in all aspects of normal cellular function are silenced by methylation.

  • The development of the methylation-specific PCR assay enabled the rapid identification of genes that are methylated in cancer. The high sensitivity and specificity of this assay also makes it feasible to detect gene methylation in biological fluids where heterogeneity exists between normal and premalignant/cancer cells.

  • The detection of gene-specific promoter methylation in sputum in people who developed squamous-cell lung cancer provided the first proof of concept that methylation changes could potentially be used as a molecular marker system in screening for early lung cancer.

Abstract

Silencing of genes by aberrant promoter hypermethylation is now recognized as a crucial component in cancer initiation and progression. Highly sensitive assays have been developed to assess gene-promoter methylation in biological fluids. The detection of methylated genes in sputum could lead to the development of a screening test to non-invasively identify early cancer in high-risk people.

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Figure 1: Histological and epigenetic progression in the development of squamous-cell carcinoma of the lung.
Figure 2: Methylation as a biomarker for early detection of lung cancer.

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Acknowledgements

The author apologizes to colleagues whose work was not cited in this review due to space constraints. The author's work is supported by grants from National Institute of Health the Department of Energy and the Department of Defense.

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  1. Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, 87108, New Mexico, USA

    Steven A. Belinsky

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Steven Belinsky is a consultant to Oncomethylome. Under a licensing agreement between Lovelace Respiratory Research Institute and Oncomethylome, nested methylation-specific PCR was licensed to Oncomethylome, and the author is entitled to a share of the royalties received by the institute from sales of the licensed technology. The institute, in accordance with its conflict-of-interest policies, is managing the terms of this arrangement.

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DATABASES

Cancer.gov

breast cancer

colon cancer

head and neck cancer

non-small-cell lung cancer

pancreatic cancer

prostate cancer

small-cell lung cancer

Entrez Gene

CD19

CDK4

CDK6

CDKN2A

CHFR

cyclin D1

DAPK

E-cadherin

H-cadherin

KRAS

LAMA3

LAMB3

LAMC2

MGMT

PAX5

RASSF1A

RB

TP53

FURTHER INFORMATION

American College of Radiologists Imaging Network

DNA Methylation Society

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Specialized Programs of Research Excellence

Glossary

SPIRAL COMPUTED TOMOGRAPHY

An X-ray imaging procedure where several detectors are arrayed in parallel, enabling an image of the entire thoracic cavity to be acquired in less than 20 seconds. This approach avoids inaccuracies caused by motions such as breathing and has a high resolution that allows detection of lesions less than 1 cm in size.

PARENCHYMA

The gas-exchange area of the lungs, which includes the alveolar septae and space.

PACK YEARS

The number of packs (20 cigarettes per pack) of cigarettes smoked each day times the number of years. For example, a person who smokes 2 packs of cigarettes a day for 20 years has a 40-pack-year history of smoking.

BRONCHOSCOPY

A procedure in which a fibre-optic scope is inserted into the lungs to allow internal visualization of the bronchial tree for detection of premalignant and malignant lesions.

DYSPLASIA

Dysplasia refers to a disorderly but non-neoplastic proliferation that involves a loss in the uniformity of the individual cells as well as a loss in their architectural orientation. Dysplastic cells show variation in size and shape, and often possess prominently stained nuclei that are abnormally large for the size of the cell.

CARCINOMA IN SITU

When dysplastic changes are marked and involve the entire thickness of the epithelium, the lesion is considered a pre-invasive neoplasm and is referred to as a carcinoma in situ. However, carcinoma in situ lesions have not invaded the basement membrane. Once the lesion invades the basement membrane it becomes a malignant neoplasm.

MICROSATELLITES

Short DNA sequences of di- or trinucleotide repeats of variable lengths distributed widely throughout the genome.

PROMOTER HYPERMETHYLATION

The addition of a methyl group to the cytosine ring at the 5th carbon position to form methyl cytosine throughout the CpG island of a gene promoter. The cytosines that become methylated are 5′ to guanosine.

CPG ISLAND

This is a contiguous stretch of DNA of at least 200 bp that often extends from the gene promoter into exon 1. The ratio of G:C content has been defined as at least 50% and the ratio of observed CpG frequency over the expected exceeds 0.6.

HYPERPLASIA

The proliferation of cells normally contained within a tissue is referred to as hyperplasia. Alveolar hyperplasia commonly involves the proliferation of the type II cell within the lung alveoli.

METAPLASIA

Metaplasia involves the proliferation of a cell type that is not commonly found in a tissue space. For example, squamous metaplasia occurs in the airways of smokers and represents the replacement of columnar epithelial cells with squamous cells.

FIELD CANCERIZATION

The development of premalignant clones of cells throughout the aerodigestive tract because of repeated exposure of the tissue to carcinogens in tobacco products. This leads to an increased risk for developing numerous independent foci of malignant lesions.

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Belinsky, S. Gene-promoter hypermethylation as a biomarker in lung cancer. Nat Rev Cancer 4, 707–717 (2004). https://doi.org/10.1038/nrc1432

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