Scale helps to measure the utility of genetic counseling in tackling fear of cancer

ScienceDaily (June 8, 2011) — When a person has a family history of cancer, their worry about developing the disease may lead to them refusing to have preventive tests. Advice from genetic counselling units reduces their anxiety but, until now, nobody knew how much. Now, a scientific team has validated the 'Escala de Preocupación por el Cáncer -- EPC' (equivalent of the Cancer Worry Scale), the first of its kind in the Spanish language, in order to evaluate it.

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"Excessive concern about cancer can result in two kinds of behaviour. Some people undergo excessive and unnecessary diagnostic tests, while others do not want to take any, out of fear that they will discover they have cancer," says Esther Cabrera, lead author of the study and director of the School of Health Sciences at the Mataró-Maresme Technocampus (Barcelona).

Genetic counselling, in the case of patients with a family history of the disease, is the right kind of tool for reducing these worries. However, until now there has been no tool in the Spanish language for evaluating the effectiveness of this initiative, nor any instrument to evaluate the fear of suffering from cancer.

"I could say that genetic counselling works well, but I couldn't measure this," says Ignacio Blanco, another author of the study and director of the Genetic Counselling Unit at the Catalan Institute of Oncology (ICO) in Barcelona. Now he has access to the 'Escala de Preocupación por el Cáncer' (EPC), an equivalent of the Cancer Worry Scale that shows him "that the degree of patients' concern does not increase following this counselling -- quite the contrary," he adds.

The study, published in Medicina Clínica, shows that the EPC is a valid and reliable scale for evaluating concern about cancer in healthy people. It is a translation and a cultural adaptation of the English-language Cancer Worry Scale: six questions that measure concern on a scale ranging from 6 (the least) to 24 (the highest level).

From psychology to general medicine

The research study was carried out on 212 healthy women without any family history of breast cancer who attended the ICO Genetic Counselling Unit. Before the experts studied their family trees, the patients answered the test questions. Several days after the genetic counselling, the researchers once again distributed the scales to analyse the effectiveness of this tool.

One of the advantages of this tool is that it can be used in any of the branches of medicine that a patient seeks help from -- psychology, oncology or even general medicine. "The scale can be used in primary healthcare as a filtering instrument among the healthy population to identify individuals with high levels of concern about cancer," the researchers say.

The simplicity of the questions (for example, "How worried are you about the possibility of developing cancer one day?") and the answers ("Not at all worried/A bit worried/ Quite worried/Very worried") make it possible to easily objectify "something that is difficult to measure," explains Esther Cabrera.

The tool has shown itself to be effective in alerting healthcare professionals to certain healthy patients who are unwilling to undergo preventive testing. "On many occasions, their fears are related to their decision about whether or not to take preventive measures that would help them avoid cancer or diagnose it a very early stage," Cabrera points out.

The researchers add that the tool will be useful for comparing and understanding the factors that affect the degree to which different groups of people worry. This would also make it possible to customise educational initiatives to improve people's quality of life.

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Genetic link between emphysema, lung cancer uncovered

ScienceDaily (June 9, 2011) — A gene linked to emphysema also can be a factor for developing lung cancer unrelated to cigarette smoking, UT Southwestern Medical Center research indicates. Smoking was the only known risk factor previously associated with both diseases.

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In the study, mice bred to have the human gene pleiomorphic adenoma gene-like 2 (PLAGL2) all developed emphysema, and by gender also developed lung cancer at rates as high as one in every six rodents. Although the new study showed PLAGL2 as a contributing factor in emphysema and lung cancer development, the diseases form in opposite ways. Emphysema arises from cell death or injury, while lung cancer involves uncontrolled cell growth.

"We think this gene induces emphysema by causing stem cells in the lung to die," said Dr. Jonathan Weissler, vice chairman of the department of medicine and chief of medicine at UT Southwestern University Hospital and senior author of the study, available online and due to be published in the journal Lung Cancer in October. "The cells that don't die through apoptosis would be more likely to have uncontrolled growth" and become cancerous, suggesting a genetic link between the diseases.

The gene is a known driver of several types of cancer. The degree to which PLAGL2 turns on, or is expressed, plays a role in cancer development. Previous research has demonstrated that female lung cancer patients with higher levels of gene expression had much poorer survival rates.

Increased PLAGL2 expression also aggravates emphysema. In 2009, Dr. Weissler and UT Southwestern colleagues found that high expression of this gene led to enlarged airways (alveoli) in mice. Female mice in particular were more prone to develop emphysema.

"The mice in that study developed the same type of emphysema seen in smokers despite the fact they were not exposed to cigarette smoke," said Dr. Weissler, director of the James M. Collins Center for Biomedical Research.

The new study revealed higher incidence of lung cancer in male mice. Of two PLAGL2 mice groups tested, lung cancer developed in 12.5 percent and 18.5 percent of male mice. The rate for female mice was zero and 3.7 percent.

In human cases, the association between these two diseases also is stronger in men. One study showed that about 10 percent of patients with severe emphysema -- all men -- also had lung cancer. The reasons for these gender differences are as yet unknown, although this information eventually could be used to help identify patients at risk for cancer.

"PLAGL2 expression could be used as a marker for cells that are at risk of undergoing malignant transformation," Dr. Weissler said.

Other researchers involved in the study were lead authors Dr. Yih-Sheng Yang and Dr. Meng-Chun Yang, both former assistant professors of internal medicine at UT Southwestern.

The study was supported by the National Heart, Lung and Blood Institute, the Will Rogers Institute and the Collins Center for Biomedical Research.

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Apparent genetic link to prostate cancer in African-American men determined

ScienceDaily (May 24, 2011) — Some men of African descent may have a higher genetic risk of developing prostate cancer, according to research conducted at the Keck School of Medicine of the University of Southern California (USC).

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The genome-wide association study, published in the journal Nature Genetics on May 22, determined a marker of risk for prostate cancer in men of African descent, who tend to more susceptible to prostate cancer than men of non-African descent. The research team was led by Christopher Haiman, ScD., at the USC Norris Comprehensive Cancer Center and Hospital, part of the Keck School.

"This is a novel risk locus for prostate cancer, and the first study of its kind conducted in men of African ancestry," said Haiman, associate professor in the Keck School Department of Preventive Medicine. "We have been trying to figure out why African American men have a greater risk for prostate cancer. These findings may help us better understand if there is a genetic contribution to disparities in risk for this common cancer."

The research looked at common risk alleles for prostate cancer in men of African descent to determine a possible reason for the high incidence of prostate cancer in this population. The research focused on approximately one million single nucleotide polymorphism (SNP) markers across the genome of 3,425 African-American men with prostate cancer and 3,290 African-American male controls. The research turned up a novel risk variant on chromosome 17q21. The frequency of this marker is 5 percent in men of African ancestry but is rare in other populations.

The discovery builds on findings several years ago by Haiman's team of a risk region on chromosome 8q24, which also contains clues as to why more men in this population are likely to develop prostate cancer.

The findings support the need for additional genome-wide investigations to locate risk markers that are common or rare, which may play a role in racial and ethnic disease disparities, Haiman said.

The research is part of the Multiethnic Cohort study (MEC), conducted between the Keck School and the University of Hawai'i, and funded by the National Cancer Institute.

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Vulnerability to nicotine addiction appears to have a genetic basis, study suggests

ScienceDaily (May 13, 2011) — A person's vulnerability to nicotine addiction appears to have a genetic basis, at least in part. A region in the midbrain called the habenula (from Latin: small reins) plays a key role in this process, as Dr. Inés Ibañez-Tallon and her team from the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany, have now shown. They also shed light on the mechanism that underlies addiction to nicotine.

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According to the World Health Organization WHO in Geneva, it is estimated that tobacco use kills more than five million people each year worldwide. Many of them die of lung cancer. "Two years ago, studies indicated that genetic variations in a specific gene cluster are risk factors for nicotine dependence and lung cancer," Dr. Ibañez-Tallon pointed out. She and her team, together with researchers from the Pasteur Institute in Paris, France and the Russian Academy of Sciences in Moscow, have now elucidated the mechanism underlying this dependence.

They investigated a specific receptor for the neurotransmitter acetylcholine, which is activated by nicotine in smokers and is encoded by this specific gene cluster, consisting of three subunits, that is three genes. "Although this gene cluster is present in the DNA of every cell, the receptor is only expressed in a few restricted areas of the brain. One of them is the habenula in the midbrain," Dr. Ibañez-Tallon explained.

The MDC researchers investigated this receptor and its subunits in egg cells of the African clawed frog (Xenopus laevis) and in transgenic mice. One of the three genes of the cluster is alpha5. "An important percentage of heavy smokers carry a single mutation in this gene. They are more prone to become addicted to nicotine and to develop lung cancer than individuals without this mutation," Dr. Ibañez-Tallon said.

Strong Aversion to Nicotine

A second gene in the gene cluster encoding this receptor is beta4. The MDC researchers demonstrated that transgenic mice expressing high levels of the beta4 gene have increased sensitivity to nicotine. These mice have a strong aversion to drinking water containing nicotine.

However, when the researchers expressed the mutated variant of the alpha5 gene via a lentivirus in the habenular brain region of these mice, after only two weeks the mice showed a preference for nicotine. Dr. Ibañez-Tallon and her colleagues conclude that only a balanced activity of these two genes can rein in nicotine use.

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Researchers home in on genetic signature of esophageal cancer

ScienceDaily (May 20, 2011) — University of Rochester Medical Center researchers have pinpointed two genes that are amplified in the worst cases of esophageal cancer, providing data to support a new investigational treatment that targets those same genes.

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The study, led by Tony Godfrey, Ph.D., a research associate professor of Surgery at the James P. Wilmot Cancer Center at URMC, was published by the journal Clinical Cancer Research. It explores the chromosomal abnormalities that influence poor survival rates of esophageal adenocarcinoma (EAC), the more common type of esophageal cancer which occurs at the junction of the stomach and esophagus.

Considered uncommon 20 years ago, the incidence of EAC has grown faster than any tumor type in the United States, Godfrey said. Health authorities believe high rates of obesity and gastroesophageal reflux disease (GERD) contribute to the rising numbers. And despite more awareness, early detection, and newer combinations of cancer therapies, overall survival of esophageal adenocarcinoma ranges from 70 percent to 80 percent for early-stage patients to only 5 percent to 20 percent for stage 3 or 4 patients. Since most cases are discovered when the cancer has already spread, EAC is often a devastating disease.

Until lately, the identification of gene targets for EAC had been limited by too few tissue samples and the inability of technology to provide a finely detailed map of gene mutations.

However, Godfrey's lab was able to collect tumors samples from 116 EAC patients, and then use modern molecular analysis tools -- microarray technology -- to investigate the DNA in the tissue. The goal was to study known chromosomal regions associated with EAC and look for subsets of genes involved in malignancy that might also be markers of poor survival.

A better understanding of genetic markers is important because many modern cancer drugs, known as "targeted therapies," are designed to chemically inhibit or block the effect of oncogenes.

Prior studies on EAC had shown an extra copy of a DNA sequence in the 7q21 chromosome region. However, Godfrey and colleagues believe they are the first to map the region with fine enough resolution to identify six genes within the core of the amplified region, and to compare them to patient outcomes.

They further honed in on two genes, CDK6 and CDK4, and through laboratory experiments proved that both genes are critical for the growth of esophageal cancer cells.

Amin Ismal, Ph.D., the postdoctoral scientist in Godfrey's lab who led the research, explained that the two molecules appear to do exactly the same thing, however CDK4 is located elsewhere, in the 12q13 chromosome region, and although it is less frequently amplified compared to CDK6, its high expression in EAC may be attributed to other genetic alterations.

Researchers explored the activity of CDK4 and CDK6 both independently and in combination. They paid special attention to CDK6, which also has been associated with poor survival in T-cell lymphoma and two common brain cancers, gliomas and medulloblastomas. CDK6 is a known regulator of the cell cycle, and thus researchers theorized that if they could shut down the CDK6 activity, the proliferation of cancer should also cease.

These experiments, Ismail said, led to the discovery that CDK6 is not acting completely alone, and that the combined over-expression of CDK6/4 was a more accurate marker of poor survival than the amplification of either gene alone.

Meanwhile, researchers knew that an experimental drug (known as PD-0332991) targeting CDK6/4 had been developed by Pfizer and Onyx, and was already being used in early clinical trials, showing promise against a range of cancers.

Therefore, the Wilmot research team tested PD-0332991 in the laboratory on esophageal cancer cells and discovered that, indeed, the drug halted CDK6/4 by inhibiting the entire cell-cycle process involved in malignancy.

"Our data provide direct evidence that CDK6 and CDK4 are strong predictors of poor survival, and that targeting those molecules is a viable treatment option," Godfrey said. "Although we still have more work to do, we are excited about the excellent progress in the effort to find better treatments for esophageal cancer."

The approach used by Godfrey and his team follows a classic example of another success story in cancer research. Decades ago scientists discovered that the protein HER-2 (human epidermal growth factor receptor 2) is frequently amplified in some breast cancers, causing them to become more aggressive. They reasoned that a drug was needed to effectively interfere with the HER-2 gene. That drug, known as Herceptin, was developed and then approved by the U.S. Food and Drug Administration in 1998 and is widely used today to boost the life expectancy of thousands of women. Interestingly, some patients with EAC also take Herceptin, due to recent studies showing that HER-2 also is over-expressed in a subset of esophageal tumors.

The National Institutes of Health funded the URMC study.

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