Epigenetics Changes in Cancer Cells

Highlights of the American Association for Cancer Research Special Conference on Chromatin, Chromosomes, and Cancer Epigenetics; November 10-14, 2004; Waikoloa, Hawaii

Kris Novak, PhD

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In This Article

Measuring Methylation Patterns

Aside from concerns about the side effects of drugs designed to alter epigenetic mechanisms, methylation patterns have emerged as useful biomarkers of cancer risk and prognosis. Steven Belinsky,[8] of the Lovelace Respiratory Research Institute, Albuquerque, New Mexico, discussed highly sensitive assays that have been developed to measure gene-promoter methylation in biological fluids. His group has shown that aberrant methylation of the p16Ink4 and MGMT promoters could be detected in DNA from the sputum of patients with squamous cell carcinoma up to 3 years before clinical diagnosis.[9] In addition, the prevalence of methylation in sputum samples from current and former, cancer-free smokers was significantly less than in patients with squamous cell carcinoma. These findings suggest that methylation patterns detected in sputum samples may be useful in identifying individuals at a greater risk of developing lung cancer.

A nested, case-controlled study of 3000 current and former smokers with chronic obstructive pulmonary disease and smoking histories of over 30 pack-years was initiated to assess whether a panel of genes inactivated by methylation can be used to determine individual lung cancer risk. So far, 78 cases of lung cancer have been selected and matched with cancer-free controls for the methylation patterns of 15 genes in sputum samples.

In samples collected in the year before the development of lung cancer, methylation of the p16Ink4, RASSF1A, or PAX5-beta genes was associated with a 5.4-fold increase in the relative risk for lung cancer. The sensitivity of this assay was 77% and the specificity 61%. Concomitant methylation of these 3 genes, however, was associated with a 15-fold increase in the relative risk for lung cancer. So, looking for alterations in methylation patterns of groups of genes in sputum samples may be an effective, noninvasive approach for identifying smokers at risk of developing lung cancer.

As other researchers have reported the presence of free, circulating DNA in the plasma or serum fractions of some patients with lung cancer, Belinsky[8,9] is participating in studies designed to evaluate methylation patterns of genes isolated from blood samples. In a cohort of women with different levels of risk for lung cancer, the prevalence of methylation of the p16Ink4, MGMT, and RASSF1A genes is being compared with DNA from blood samples of never-smokers (n, 74), current/former smokers (n, 122), and individuals previously resected for stage 1 lung cancer (n, 56).

Methylation of 1 or more genes in plasma samples was detected in 13% of never-smokers, 22% of smokers, and 36% of former lung cancer patients. The relative risk for plasma DNA methylation increased to 1.8 in smokers and 3.8 in former lung cancer patients. So, methylation patterns of specific genes or groups of genes may be useful in the early detection of lung cancer.

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