Scientists from the British Columbia Cancer Agency and the University of Chile in Santiago, together with support from the Chilean government, next month will begin screening lung cancer patients in northern Chile where the chance of dying from the disease is three times higher than the national average.
The team of researchers will use bacterial artificial chromosome arrays for comparative genomic hybridization developed in part at the BC Cancer Research Centre to screen patient samples for copy number alterations that may be associated with their increased risk for the disease.
According to Victor Martinez, a researcher at the BC Cancer Research Centre in Vancouver, the high incidence of lung cancer in northern Chile, where the economy has traditionally revolved around mining, has been attributed to a higher concentration of arsenic, a known carcinogen and contributor to lung cancer, in the region’s drinking water.
An August 2006 study in Environmental Health Perspectives, for example, showed that during the 1950s and 1960s, residents of the Antofagasta region in northern Chile were exposed to as much as 1,000 micrograms of arsenic per liter. Water safety standards implemented by the Chilean government in the 1970s gradually reduced the maximum allowed concentration of arsenic per liter to 50 micrograms, which is still five times the World Health Organization’s standard of 10 micrograms per liter.
Martinez told BioArray News last week that the array-based screening program will be implemented next month to follow lung cancer patients at every stage of the disease in order to develop biomarkers for risk and treatment prediction.
The screening program will be led by a consortium of organizations, including the faculty of medicine of the University of Chile, three public hospitals — including the Regional Hospital of Antofagasta in northern Chile, and one private clinic, in close collaboration with the British Columbia Cancer Agency. The program is expected to run for three years and is being funded by the Chilean Economic Development Agency.
“The association between arsenic and lung cancer has existed for maybe 10 years, and we expect to look at some specific genes that can predispose people to have cancer if they live in an arsenic-explosive zone or of they smoke,” he said. “We decided that we wanted to have a general picture of the genome, and we decided to look at copy number variation and correlate that to people who develop lung cancer when they are exposed to arsenic.”
For its part, the BC Cancer Agency will supply Chilean authorities with its internally developed BAC array platform for CGH, called the submegabase resolution tiling set, or SMRT array. The array consists of 32,433 overlapping BAC clones covering the entire human genome.
“With this technology we can detect cancer in people with no symptoms of lung cancer and we can identify the patients in a timely manner so that they can receive good treatment.”
Martinez said that as part of the new screening program, the Ministry of Health in Chile will run a public campaign to encourage people to go for traditional lung cancer examinations and to provide samples that will be run in Chile on the SMRT array platform.
“With this technology we can detect cancer in people with no symptoms of lung cancer and we can identify the patients in a timely manner so that they can receive good treatment,” said Martinez. “We will also have more data and more information about the patients so that we can characterize lung cancer cases in different stages.
“We can probably identify how these alterations are progressing during the progression of cancer and we want to establish a timeline about how these alterations are evolving in the development of tumors,” he added. “That is the scientific goal of the new project.”
Martinez said he initially began looking at CNVs in lung cancer patients because he only had access to DNA from formalin-fixed, paraffin-embedded samples from the Regional Hospital of Antofagasta. However, because the new screening project will be collecting new samples, the researchers working on the project will attempt to study the problem from other perspectives.
Specifically, the group plans to look at gene expression in the samples using an as-yet undetermined commercial platform. Martinez said he is also interested in looking at epigenetic changes in the samples to develop a “more complete picture of what is happening with arsenic and lung cancer.”
Proof of Principle
Martinez said his research at BCCRC has been supported by the Canadian government through its Canada-Chile Leadership Exchange Scholarship Program. Still, Martinez and his colleagues have yet to publish their preliminary work on the samples from Antofagasta. However, he presented some data from an initial study at the World Microarray Congress, held in Vancouver, BC, last week.
The main objective of that study was to identify specific copy-number alterations for lung squamous cancer cells from non-smokers living in an arsenic-contaminated area — in this case, northern Chile.
Martinez said that a panel of 20 paraffin-embedded lung cancer samples from smokers and non-smokers was selected from Regional Hospital of Antofagasta, while 21 samples from non-arsenic exposed patients were collected from the BC Cancer Research Centre’s archives for comparison.
Using the SMRT array to survey the samples, Martinez found that frequency of alterations in 3q, the most consistently over-represented region in squamous cancer cells related to tobacco smoking in the non-smoking arsenic-exposed group of samples, was lower than in smokers.
The non-smoking, arsenic-exposed group of samples, meantime, showed specific gains at 19p13.11-p12 involving a cluster of Kruppel-type zinc finger genes. Members of this family are involved in cell differentiation, cell proliferation, apoptosis, and neoplastic transformation, Martinez noted. Specific losses were observed in 7q36.3, a region said to contain a gene member of the protein tyrosine phosphatase family, which is believed to be a putative tumor suppressor gene.
“We wanted to see if lung tumors from Antofagasta are different from lung tumors from Vancouver,” Martinez said. Based on the data, “we think that there are alternative pathways to develop lung cancer in these two groups.”
Because the main cause of lung cancer in Antofagasta samples was exposure to arsenic, and the main cause of cancer in the Vancouver samples was smoking, Martinez hypothesized that there are probably two alternative pathways to develop lung cancer.
“If that is true there is probably some explanation why people who never smoke can develop cancer too,” he said. “That is what we are trying to determine.”