Irregular molecules in the lining of the mouth, the saliva, the fallopian tube, or the bladder can identify early stage cancer, according to research presented this week at the annual meeting of the American Association for Cancer Research.
Scientists attempting to apply basic knowledge to medical practice are developing tests that diagnose, predict, or monitor cancer risks without invasive tissue sampling.
[Oral Epithelium as a Surrogate Tissue for Assessing Smoking-Induced Molecular Alterations in the Lungs: Abstract 1599]
Doctors may be able to determine the extent of a smoker’s lung damage by looking in his or her mouth, according to new research from the University of Texas M D Anderson Cancer Center.
Because smoking exposes the lungs and oral cavity to tobacco carcinogens, the scientists hypothesized that cells lining the mouth undergo molecular alterations similar to those in other parts of the airway and could be used as surrogate tissue to assess molecular damage to the lungs, says senior study author Li Mao, MD, a professor of thoracic/head and neck medical oncology and of systems biology at M DAnderson.
Mao and colleagues, analyzing lung and mouth tissue samples from 125 chronic smokers enrolled in a cancer prevention trial, found similar molecular changes in both types of tissue.
“Our study provides the first systematic evidence that readily accessible tissue from the mouth can be used to monitor molecular events in inaccessible tissue like the lungs, offering a convenient biomonitoring method to provide insight into the molecular events that take place in lungs of chronic smokers,” Mao said. “An oral brush is easy to obtain and noninvasive; it allows us to test for lung damage without having to do a bronchoscopy.”
Using a lab technique called methylation-specific polymerase chain reaction, which enables the production of millions of copies of a specific DNA sequence in a short period of time, the researchers analyzed promoter methylation (a DNA modification that shuts down gene expression) of the tumor suppressor genes p16 and FHIT in 1,774 samples of oral and bronchial tissue taken from study participants. They found methylation patterns observed in the oral tissues correlated with those observed for bronchial tissues.
At the study’s start, researchers observed promoter methylation in 23% of bronchial tissues and 19% of oral tissues for p16; 17% of bronchial tissues and 15% of oral tissues for FHIT; and 35% of bronchial tissues and 31% of oral tissues for any combination of the two genes. Among the 39 participants with oral tissue methylation in both genes, the average bronchial methylation index was 0.52 (meaning 52% of tissues sampled had molecular changes), compared to 0.27 for the 86 cases without oral tissue methylation.
Similar correlations were observed in tissue samples obtained 3 months later.
Mao says it is possible that oral tissue may contain other molecular signatures that predict the presence of primary lung cancer and other aerodigestive malignancies attributable to cigarette smoking. The tissue could serve as a tool to monitor therapeutic outcomes in cancer patients.
[Noninvasive genetic detection of head and neck squamous cell carcinoma: Abstract 1795]
Analyzing the DNA in one’s saliva may detect early signs of head and neck squamous cell carcinoma (HNSCC), according to researchers from the Henry Ford Hospital in Detroit.
Most cases of HNSCC are diagnosed in advanced stages when prognosis is poor, says lead researcher Seema Sethi, MD, of the Department of Otolaryngology-Head and Neck Surgery at Henry Ford Hospital in Detroit. "However, the development of the disease in high-risk populations, such as smokers, takes many years,” she said. “This ‘window’ period offers a unique opportunity to screen for HNSCC. This exploratory study indicates potential gene-based HNSCC detection.”
Sethi and her colleagues took saliva samples from 27 patients with HNSCC and 10 healthy control participants, and extracted DNA from the samples. Using a multiplex ligation-dependent probe amplification assay, the researchers examined 82 genes with known associations to HNSCC. The data were analyzed to determine whether genetic alterations distinguished subjects with HNSCC from healthy controls. Eleven genes showed a high individual predictive ability for HNSCC.
The researchers then examined PMAIP1, a tumor suppression gene on chromosome 18, and PTPN1, an oncogene on chromosome 20. An increase in PMAIP1 alone or with an increase in PTPN1 identified all subjects with HNSCC with 100% sensitivity, the true positive rate, and 100% specificity, the true negative rate. Further validation results showed a sensitivity of 96% and a specificity of 90%.
The other nine genes that showed some predictive ability were: ERBB2, ABCC4, UTY, DNMT1, CDKN2B, CDKN2D, NFKB1, TP53, and DCC.
More than 40,000 Americans are affected by HNSCC and approximately 12,000 die of it annually, according to the researchers. "Early detection of HNSCC will reduce the mortality, devastating morbidities and associated health care costs," Sethi said.
The results of the study are preliminary, Sethi stresses, but she expects that the analysis could detect HNSCC at its earliest stage. As for why these genes in particular were associated with HNSCC detection, Sethi said, "The genes are located at chromosomal segments that have been reported as commonly altered in HNSCC and therefore may be relevant to HSNCC."
[The fallopian tube epithelium as the field of origin for ovarian serous carcinoma: Abstract 4917]
Researchers report the fallopian tube fimbria rather than ovarian surface cells may be the site of origin for more than 50% of sporadic and hereditary serous carcinoma, the most aggressive form of ovarian cancer. The new knowledge may enable earlier detection, better treatment, and potential prevention of the most lethal gynecologic malignancy in Western countries.
“With the correct cell-of-origin in hand, we can now look for differences between the benign cells and the tumor that arises from them and develop early detection biomarkers. We can identify aberrations in signaling pathway and genetic alterations in serous cancers compared with the fallopian tube secretory epithelial cells (FTSECs), and propose new targeted therapies to tackle these pathways,” said lead researcher Keren Levanon, MD, PhD. Levanon is a postdoctoral research fellow in the lab of Ronny I. Drapkin, MD, PhD, at the Dana-Farber Cancer Institute in Boston.
The inner lining of the fallopian tube is composed of ciliated and secretory cells.
Ciliated cells, which are characterized by distinctive hair-like structures, transport unfertilized egg and sperm cells toward each other and transport a fertilized egg toward the uterus. “We never find this type of cell in high-grade tumors of the ovary,” Levanon said.
Secretory cells, as their name suggests, secrete molecules essential to the maintenance of the egg and sperm and facilitate fertilization.
“This type of cell is uniquely represented in the precursor lesions leading to early and eventually invasive serous cancer,” Levanon said. Only a handful of biomarkers that distinguish secretory from ciliated cells have been reported: Bcl-2, HMFG2 and Pax-8.
Using a new model system to study these cells, Levanon finds that FTSECs appear to respond faster to DNA damage, adding that DNA repair mechanisms are more effective in FTSECs than in neighboring ciliated cells. The research team is investigating the potential implications of these differences in response rates and whether ovulation elicits a similar response.
“The identification of the FTSEC as a cell-of-origin has a number of translational implications,” Levanon said. “We are now at a unique position to start understanding the normal biology of the fallopian tube and how it is affected by hormonal and inflammatory insults throughout life. The understanding of risk factors at a molecular level may, in the future, evolve into recommendations for primary prevention.”
Levanon said the team’s findings would likely change how pathologists examine fallopian tubes after surgical removal, with a new emphasis on the fimbria to measure the incidence of precursors and early cancers among women who carry BRCA mutations. Future studies may explore connections between specific genetic or environmental modifiers and the incidence of precursor lesions in the fimbria.
[Serological autoantibody profiling in bladder cancer using protein arrays: Abstract 5158]
A novel application of high-throughput protein arrays for serum autoantibody profiling offers a new, comprehensive, non-invasive diagnostic tool for bladder cancer, and suggests a potential therapeutic target for the disease, according to researchers from the Spanish National Cancer Research Center.
Using protein arrays with more than 12,000 proteins, Marta Sánchez-Carbayo, PhD, and colleagues at the Center in Madrid, Spain, examined serum samples from 18 patients with bladder cancer and six control participants. The control group included patients with other neoplasias, benign urological diseases, and healthy individuals.
The researchers identified a panel of 171 autoantibodies in patients with bladder cancer that were differentially expressed from the control group. These bladder cancer tumor-specific antigens (TAAs) included proteins linked to cell proliferation, signal transduction, apoptosis (programmed cell death), DNA-binding, and transcription factors.
“The study has identified many bladder cancer TAAs in the serum, representing a mirror of the bladder tumors,” Sánchez-Carbayo said. “Thus, autoantibody profiling represents a high-throughput approach for biomarker discovery and characterizing bladder cancer progression.”
Immunohistochemical analyses confirmed the increased protein expression of identified TAAs in bladder tumors, according to Sánchez-Carbayo. In addition, they highlighted the significance of protein expression patterns for bladder cancer diagnostics, tumor staging, and prognosis.
Researchers determined that clusterin protein expression patterns were strongly linked to tumor size, T1 substaging, or progression into muscle invasive disease.
“The novel application of high-throughput protein arrays for serum autoantibody profiling is also providing critical information to identify potential immunological therapeutic targets,” Sánchez-Carbayo said.
She said the results are promising but a lot of work remains. In the next step, researchers will try to determine if autoantibody profiling can subclassify noninvasive and muscle-invasive bladder tumors and predict clinical response to current immunotherapy and chemotherapy. Research will also continue on developing novel therapies that target the immune system or the tumor, Sánchez-Carbayo says.
The mission of the American Association for Cancer Research is to prevent and cure cancer. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis, and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants.