National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
September 6, 2011 • Volume 8 / Number 17

Cancer Research Highlights

Negative Colonoscopy Associated with Low Colorectal Cancer Risk

People who have no sign of cancer after a colonoscopy have a much lower risk of developing colorectal cancer over the next two decades than people who never had the procedure, according to a large case-control study conducted in Germany. Overall, people who had a negative colonoscopy were nearly 80 percent less likely to develop colorectal cancer than those who had never had a colonoscopy. The study was published online August 29 in the Journal of Clinical Oncology.

“Clearly, colonoscopy is not a preventive measure by itself. The strongly reduced risk among patients who underwent colonoscopy without polypectomy is therefore not a result of colonoscopy, but rather reflects the inherently low risk of patients free of endoscopically visible precancerous lesions,” wrote the study’s lead author, Dr. Hermann Brenner of the German Cancer Research Center in Heidelberg and his colleagues.

In the United States, guidelines for colorectal cancer screening with colonoscopy generally recommend screening every 10 years beginning at age 50. More vigilant screening, however, is typically recommended for those with a family history of colorectal polyps or cancer.

The study included nearly 3,600 participants. Case patients were 30 years of age or older who had been diagnosed with colorectal cancer based on symptoms or incidental findings from other procedures but not as a result of screening and were treated at 22 hospitals in southeastern Germany. Control subjects were selected from population registries. Information on previous colorectal endoscopies was obtained from interviews and medical record reviews.

Control subjects were nearly four times more likely than case patients to have had a previous negative colonoscopy. Overall, previous negative colonoscopy was associated with a 79 percent reduction in the risk of colorectal cancer. A single negative colonoscopy was associated with a 72 percent lower risk of developing colorectal cancer over the next 10 to 19 years, and a 60 percent lower risk at 20 years or longer. The lower risks were similar for men and women, former and never smokers, participants who had first-degree relatives previously diagnosed with colorectal cancer, and participants with a single previous colonoscopy.

All participants in the study were recruited between 2003 and 2007. Because colonoscopy was not routinely offered as a primary screening test for colorectal cancer in Germany until late 2002, many of the participants in the study who had undergone a colonoscopy did so because of positive findings from a fecal occult blood test that was prompted by symptoms or other indications, the authors explained.

This fact could limit the extent to which the results apply to a primary screening setting, the study authors noted. They suggested, however, that the long-term risk of colorectal cancer after a negative colonoscopy might be even lower in an unselected screening population. Indeed, although they note that the results should be confirmed in additional studies, the authors also point out that their study “supports suggestions that the majority of average-risk patients with a negative colonoscopy might not need another screening colonoscopy for at least 20 years, if at all.”

Further reading: “Sigmoidoscopy Markedly Reduces Colorectal Cancer Incidence, Mortality

Smokers at Greater Risk of Bladder Cancer than Previously Estimated

Current cigarette smokers have a higher risk of bladder cancer than previously reported, and the proportion of bladder cancers due to smoking in women is now comparable to that in men, according to a study by researchers in NCI’s Division of Cancer Epidemiology and Genetics (DCEG). Their findings were published August 17 in JAMA.

This latest study included data from more than 450,000 participants in the NIH-AARP Diet and Health Study, a questionnaire-based study that began in 1995, with follow-up through the end of 2006.

“Current smokers in our study had a fourfold excess risk of developing bladder cancer, compared to a threefold excess risk observed in previous studies,” said study co-author Dr. Neal Freedman. “The stronger association between smoking and bladder cancer is possibly due to changes in cigarette composition or smoking habits over the years.”

In the current study, former smokers were twice as likely to develop bladder cancer than those who never smoked. As with many other smoking-related cancers, the risk of bladder cancer fell after people quit smoking.

Previous studies had indicated that only 20 to 30 percent of bladder cancer cases in women were caused by smoking, but the new data indicate that smoking is responsible for about half of bladder cancer cases among women, a proportion similar to that found in men in this and previous studies. 

The increase in the proportion of smoking-induced bladder cancer cases among women may be because smoking rates in men and women are now similar. The majority of the earlier studies were conducted at times or in places where smoking was much less common among women than men. 

“Our findings provide additional evidence of the importance of preventing smoking initiation and promoting cessation for both men and women,” said senior author Dr. Christian Abnet.

Hereditary Mutations in BAP1 Gene Raise Risk of Mesothelioma

In two independent studies, researchers have shown that people with hereditary mutations in a gene known as BAP1 are predisposed to develop malignant mesothelioma and melanoma of the eye (uveal or intraocular melanoma), and a distinctive type of benign skin tumor. The findings, published online August 28 in Nature Genetics, suggest that inherited BAP1 mutations may also be linked to some other forms of cancer, including melanoma of the skin.

In one study, supported by NCI, a team of investigators led by Dr. Joseph Testa of the Fox Chase Cancer Center and Dr. Michele Carbone of the University of Hawaii Cancer Center focused on two U.S. families with a high incidence of mesothelioma. The study is the first to show that inherited gene mutations can influence a person’s risk of mesothelioma—one of the least curable forms of cancer. Mesothelioma is typically associated with exposure to asbestos or to a similar mineral fiber, erionite.

The second study, led by Drs. Thomas Wiesner of the Medical University of Graz, Austria, and Memorial Sloan-Kettering Cancer Center (MSKCC); Boris Bastian of MSKCC; and Michael Speicher, also of the Medical University of Graz, focused on two families, one from Germany and one from Austria, in which members developed numerous small, benign skin growths starting at an early age. These raised growths occurred in pigment-producing cells called melanocytes but were skin-colored, unlike typical moles.

In both studies, researchers zeroed in on the BAP1 gene after finding genetic changes in or near the region of human chromosome 3 where BAP1 is located. The BAP1 gene encodes a protein known as BRCA1-associated protein-1, which is found in the cell nucleus and is thought to suppress tumors. The BAP1 protein has been implicated in a range of cellular processes, including regulation of cell growth and division and response to DNA damage.

In the two families with mesothelioma, Drs. Testa, Carbone, and their colleagues found BAP1 mutations in two individuals with uveal melanoma, one of whom subsequently developed mesothelioma. The research team also found hereditary alterations in BAP1 in 2 of 26 patients with sporadic mesothelioma. Both individuals had previously been diagnosed with uveal melanoma, although none of the other 24 patients had. Some of the patients with sporadic mesothelioma were found to have noninherited BAP1 alterations in their tumors.

Their findings, Drs. Testa and Carbone wrote, “suggest that individuals with uveal melanoma who carry [hereditary] BAP1 mutations are at high risk of developing mesothelioma and should be closely monitored."

In each family that Dr. Wiesner and his colleagues studied, one individual with benign skin tumors also had melanoma of the eye. In addition, three members of one family were diagnosed with skin melanoma. These investigators also found noninherited BAP1 mutations in randomly selected tumors from an independent group of patients with melanoma of the eye and skin.

In two other recent studies (here and here), noninherited mutations in BAP1 were found in tumor tissue of sporadic cases of mesothelioma and melanoma of the eye.

Use of Radioactive Iodine to Treat Thyroid Cancer on the Rise

The proportion of patients in the United States with well-differentiated thyroid cancer (papillary, follicular, or Hurthle cell tumors) who received radioactive iodine after surgery rose from 40 percent to 56 percent between 1990 and 2008, and this increase was seen across all tumor sizes. Dr. Megan R. Haymart of the University of Michigan and her colleagues reported their findings August 17 in JAMA.  

This increase came despite the low risk of recurrence for these patients after total thyroidectomy alone and conflicting evidence about whether radioactive iodine treatment benefits patients with low-risk disease. This increase in treatment may be exposing patients to unnecessary harms, as well as incurring greater costs.

The researchers used data from 189,219 thyroid cancer patients in the National Cancer Database, which is maintained by the American College of Surgeons Commission on Cancer and the American Cancer Society and captures about 85 percent of patients with thyroid cancer in the United States.

Patients who were younger and healthier were more likely to receive radioactive iodine, but African American patients and those without health insurance were less likely to receive radioactive iodine. In an analysis of radioactive iodine use by stage of disease in patients treated in 2004 to 2008, patients with the earliest-stage tumors (stage I) were less likely than those with stage IV disease to receive radioactive iodine. However, there was no difference in use between patients with stage II or stage IV disease or between patients with stage III or stage IV disease.

Hospitals varied widely in their use of radioactive iodine for patients with all stages of the disease, as well. Using data from 2004 to 2008, the authors also found that patients treated at a hospital with a higher case volume of thyroid cancer patients were more likely to be treated with radioactive iodine. “For every 1 additional case a hospital treats, the odds of radioactive iodine use increase by 0.6 percent,” explained the authors.

Characteristics of the patients and their tumors accounted for just 21 percent of the variation among hospitals, and unknown hospital factors accounted for 29 percent of the variation, suggesting that “disease severity is not the sole determinant of radioactive iodine use,” they noted.

The data set used provides “incomplete knowledge about how and why care was delivered in hospitals showing variation,” wrote Dr. Edward H. Livingston of the University of Texas Southwestern Medical Center and Dr. Robert A. McNutt of the Rush University School of Medicine in an accompanying editorial. “Without an assessment of hard, irrefutable measures of clinical decision making that include individual preferences for treatment, decisions about the appropriateness of clinical treatments and variations of care cannot be made.”

According to data from NCI’s Surveillance, Epidemiology, and End Results program, the incidence of well-differentiated thyroid cancer has more than doubled in the last 30 years. “This study highlights the need to develop better prognostic models for these patients, since it’s unlikely that a randomized trial [of radioactive iodine] will ever be done,” due to the very large number of patients and long follow-up that would be required, commented Dr. Ann W. Gramza, a physician with NCI’s Thyroid Clinical Research Program at the NIH Clinical Center.

Colorectal Cancer Genomes Sequenced

Researchers have used whole-genome sequencing to survey the genetic alterations in colorectal tumors and matched normal cells from nine patients with the disease. Among other findings, the researchers identified a fused gene in a small percentage of tumors. As with all such genome projects, the results, published online September 4 in Nature Genetics, are preliminary, and further studies will be needed to capture the extent of genomic changes in this disease.

Dr. Matthew Meyerson of the Dana-Farber Cancer Institute and his colleagues found a range of genomic rearrangements, including exchanges of DNA between and within chromosomes (known as translocations). The researchers identified 11 translocations that could give rise to fusion genes, which are created when DNA from different parts of the genome merges. Specific fusion genes, and the fusion proteins they encode, have been reported in common cancers such as lung and prostate, but little is known about their possible role in colorectal cancer.

One of the 11 gene fusions was of particular interest. The fusion involves the genes VTI1A and TCF7L2, which encodes a transcription factor that regulates the activity of genes that are essential for the proliferation and development of intestinal epithelial cells. In addition, previous research has linked the expression of TCF7L2 to survival in colorectal cancer. Among a set of 97 colorectal tumors the researchers tested, three had this fusion. 

To test the functional importance of the VTI1A-TCF7L2 fusion gene, the researchers identified a colorectal cancer cell line that included the fusion. Experiments with these cells suggested that the fusion gene plays a “critical role” in their growth, the researchers found. But they noted that further research is needed to understand what role, if any, the gene may play in the disease.

The discovery of the VTI1A-TCF7L2 fusion gene shows that “functionally important fusion events occur in this disease and suggest that further structural characteri­zation will likely identify additional new recurrent rearrangements,” Dr. Meyerson and his colleagues concluded.  

They noted that large sequencing projects will be needed to catalog the genomic changes in the disease; one such project is The Cancer Genome Atlas.

Further reading: "More DNA Rearrangements Found in Prostate Cancers"