Chromosome Painting, Gene Mapping of Tasmanian Devil Facial Tumor Disease
Deakin, Bender et al., PLoS Genetics
A team led by investigators at the Australian National University reports its use of "chromosome painting and gene mapping to deconstruct the DFTD [Tasmanian devil facial tumor disease] karyotype and determine the chromosome and gene rearrangements involved in carcinogenesis." Through its analysis, the team produced detailed maps of both the devil and tumor karyotypes, which the researchers say will aid future genomic investigations into the transmissible cancer.
J&J Chief (Partially) Steps Down
Johnson & Johnson's William Weldon is to resign his role as the company's chief executive, reports The New York Times. Weldon will remain chairman. "The news of Mr. Weldon's retirement comes as Johnson & Johnson has struggled to emerge from a swarm of product recalls, manufacturing lapses, and government inquiries that tarnished the name of a company that was once one of the nation's most trusted household brands," the Times says, adding that Weldon took the brunt of the blame. He will be succeeded by Alex Gorsky, who currently leads the company's medical device and diagnostics business.
This Week in the Journal of Clinical Pathology
In the Journal of Clinical Pathology, researchers in Taiwan report on their study of expression levels of a remodeling and spacing factor complex subunit in nasopharyngeal carcinomas, and their prognostic value. The researchers retroactively looked at 108 nasopharyngeal carcinoma patients and correlated their RSF-1 expression with clinical outcomes. "Rsf-1 overexpression is common and is associated with adverse prognosticators and therapeutic response, which confers tumor aggressiveness through chromatin remodeling, and represents a potential prognostic biomarker in NPC," the authors note.
Researchers led by Selvam Thavaraj at King's College London Dental Institute in the UK examined whether human papillomavirus is present in dysplastic and malignant oral verrucous lesions. Using a combination of DNA in situ hybridization, consensus PCR, and HPV genotype analysis by multiplex PCR followed by p16 immunohistochemistry assessment, the researchers found evidence to suggest that while HPV DNA may be found in a subset of lesions, it does not drive oncogenesis. "Further work is required to ascertain whether the virus is transient or persistent, to determine its biological significance and to elucidate non-HPV causative factors," Thavaraj and his colleagues add.
Researchers led by Robert Odze at Brigham and Women's Hospital in Boston report on their clinical and pathological analysis of Crohn's disease in Modern Pathology. The researchers compared patients with colonic Crohn's disease and those with colonic and ileal Crohn's disease. "Patients with isolated colonic Crohn's disease at initial presentation show distinct clinical and pathological features compared with the colon of patients who present with both ileal and colonic involvement," the authors write, adding that "further studies should be conducted to determine whether the histology of the colon in patients with colonic Crohn's disease is related to the development of malignancy, molecular phenotype, and specific outcome, on a prospective basis."
University of Minnesota Medical School's Youngki Kim and his colleagues describe their study of laminin isoform expression in diabetic neuropathy and other renal diseases in an advance, online Modern Pathology article. They found that α5, β2 and γ1 chains — which are part of the glomerular basement membrane — are over-expressed in diabetic nephropathy kidneys. "The alterations in basement membrane composition in various renal diseases seem to not only reflect the balance between synthesis and degradation of normal basement membrane constituents, but also the aberrant new expression of basement membrane molecules," Kim and his colleagues say. "Thus, tissue remodeling may incorporate both an increase of normal constituents and emergence of abnormal constituents during disease exemplified by diabetes."
Various health regulators and government bodies are reviewing gene patents, and Bloomberg says "the changing landscape" may affect companies like Quest Diagnostics, Roche, and Pfzer, as well as how personalized medicine may be implemented. In addition, the US Food and Drug Administration is considering new oversight of lab-developed tests, including genetic tests. David Mongillo, who was formerly with the American Clinical Laboratory Association, tells Bloomberg that FDA regulations would slow the field down, and hurt patients. FDA's Jeffrey Shuren disagrees, saying that bad lab tests are what hurt patients.
This Week in Clinical Chemistry
Researchers led by Christian Mueller from University Hospital Basel in Switzerland report in Clinical Chemistry on growth differentiation factor-15's potential as a diagnostic and risk-stratification marker for acute myocardial infarction as GDF-15 is a stress-responsive marker. In their prospective, mulitcenter study, the researchers measured GDF-15, high-sensitivity cardiac troponin T, and B-type natriuretic peptide levels in 646 patients with acute chest pain. "GDF-15 predicts all-cause mortality in unselected patients with acute chest pain independently of and more accurately than hs-cTnT and BNP," the researchers report. "However, GDF-15 does not seem to help in the early diagnosis of AMI."
Cornell University's Michael King and his colleagues describe their device to capture circulating tumor cells in an online early Clinical Chemistry article. "We designed a microscale flow device with a functionalized surface of E-selectin and antibody molecules against epithelial markers. The device was additionally enhanced with a halloysite nanotube coating," the researchers say. In their test, the device captured about half of the circulating tumor cells with purities greater than 50 percent. "[This] demonstrates the functionality of this device in a clinical setting and opens the door for personalized cancer therapies," the researchers add.
This Week in the Journal of Molecular Diagnostics
In the Journal of Molecular Diagnostics, researchers led by Jeanne Jordon at George Washington University in DC compare different sample extraction techniques for PCR analysis of pathogens in blood. They used silica spin columns, phenol-chloroform, and an automated magnetic capture of polymer-complexed DNA to purify nucleic acids to prepare samples for TaqMan assays to detect Staphylococcus aureus. The researchers note that samples prepared using silica columns needed to be diluted to reduced the effect of sodium polyanetholsulfonate, which inhibits PCR, while the other methods needed little dilution. Further, phenol-chloroform and the magnetic capture approach could detect S. aureus two hours sooner than the silica approach could. "These findings highlight the importance of considering the mechanism when selecting a DNA extraction methodology," the researchers say.
In addition, Johns Hopkins University's James Eshleman and his colleagues report on their new software program called Pyromarker that simulates pyrosequencing results. "Simulated pyrograms can aid in the analysis of complex pyrosequencing results in which various hypothesized mutations can be tested, and the resultant pyrograms can be matched with the actual program," Eshelman and his colleagues write. They tested their program using KRAS and BRAF mutations, and find that it handles the identification of complex mutations efficiently.
Part of the payroll tax cut agreement between the US House of Representatives and the Senate affects clinical labs. According to Bloomberg Businessweek, the current plan includes a 2 percent cut in Medicare payments to clinical labs in 2013. Additionally, Goldman Sachs'Isaac Ro says in a research note on the pending legislation that "we believe that these potential unexpected cuts highlight ongoing pricing risk to the US clinical lab industry in an environment centered on austerity and reducing healthcare costs."
This Week in Experimental and Molecular Pathology
Researchers led by Chirayu Auewarakul from Siriraj Hospital in Bangkok, Thailand, report in Experimental and Molecular Pathology on BCR-ABL kinase domain mutations in Southeast Asian patients with chronic myeloid leukemia. Mutations in the BCR-ABL kinase domain are associated with resistance to tyrosine kinase inhibitors used to treat CML. Using high-performance liquid chromatography and direct sequencing, the researchers studies the mutation status of 80 treatment-naïve CML patients and 91 patients receiving first-generation or second-generation TKI therapy. From this, they found 13 known and 8 novel mutations. "T315I resistant mutation was completely undetectable in this naïve Southeast Asian cohort; its incidence, however, increases with drug exposure," the authors write.
Also in Experimental and Molecular Pathology, Kee Yang Chung from the Yonsei University College of Medicine in Seoul and his colleagues studied the expression pattern of matrix metalloproteinases in cutaneous oncogenesis. In particular, they used immunohistochemical staining and quantitative RT-PCR to examine the expression patterns of MMP-2,-9, MT1-MMP, and TIMP-2 proteins in squamous cell carcinoma, Bowen's disease, and normal samples. "Our results revealed significantly increased MT1-MMP and MMP-2 expression and decreased TIMP-2 expression in cutaneous SCC, and the expression correlated with the invasiveness of SCC cell lines," the authors write. "Therefore, the expression of these factors in cutaneous tumors may serve as an indicator of tumor aggressiveness and invasion."
This Week in the Journal of Clinical Pathology
Andresa Borges Soares from the São Leopoldo Mandic Institute and Research Center in Brazil and colleagues report in the Journal of Clinical Pathology that a number of growth factors are involved in the recurrence of pleomorphic adenoma, a common, benign salivary gland tumor. Using immunohistochemistry and qPCR, the researchers determined the expression levels of the growth factors PDGF-A, PDGF-B, PDGF-Rα, FGF-2, Flg and BEK in pleomorphic adenoma, recurrent pleomorphic adenoma, and recurrent pleomorphic adenoma with malignant transformation. They found that there were significant differences in growth factor expression in the different tumor types. "This research suggests that PDGF-A, PDGF-B, PDGF-Rα, FGF-2, BEK and Flg can be related to the recurrence of PA," Soares and colleagues say. "In addition, this study shows that TRPA cells overexpress all growth factors, which has been reported in association with the malignant transformation."
Researchers in Nantes, France, look at KRAS heterogeneity in some metastatic colorectal carcinomas in the Journal of Clinical Pathology. In addition to determining the KRAS status of the 18 patients' metastases, the researchers also examined the primary tumors, the synchronous and metachronous metastases, and a recurrence. KRAS status was determined using PCR and direct sequencing. "In addition to heterogeneity between primary tumour and metastases, other levels of KRAS status heterogeneity exist between (1) different metastases in a given patient, and also (2) within a given metastasis," the researchers report. They add that "In the clinical practice, the knowledge of patients with KRAS mutated primary tumour and wild-type metastases is of great importance for treatment planning, since these patients could benefit from monoclonal anti-EGFR antibody. Furthermore, these results imply that the KRAS mutation analysis of residual metastatic lesions should be considered in patient management."
Finally, researchers from the Università di Udine in Italy report in the Journal of Clinical Pathology that Dicer and Drosha expression is varied in triple-negative breast cancers. Using both immunocytochemistry and RT-qPCR, the researchers examined the Dicer and Droshap expression levels in 31 formalin-fixed, paraffin-embedded breast cancer samples, six controls, and four breast cancer cell lines. Despite variation, "as a group, triple-negative breast cancers overexpress Drosha mRNA," the researchers say, adding that "as a group, instead, Dicer mRNA levels were not significantly different between triple-negative breast cancer and normal breast tissues."
Pathway Genomics Joins the American Clinical Laboratory Association
Pathway Genomics is now a member of the American Clinical Laboratory Association, according to a company news release. Pathway Genomics specializes in genetic tests, especially for drug response, pregnancy planning, and disease risk assessment for conditions like Alzeimer's disease, Type 2 diabetes, and lupus, among others. "Pathway Genomics is another example of our nation's laboratories that are at the forefront of genetic testing and personalized medicine," says Alan Mertz, the ACLA president, in a statement.
In Modern Pathology, researchers from Shimane University School of Medicine, in Izumo, Japan, examine whether ARID1A mutations, which are common in ovarian clear cell carcinoma, are of prognostic value. From their study of 77 formalin-fixed, paraffin embedded ovarian cancer samples — 60 clear cell carcinomas and 17 high-grade serous adenocarcinomas — the researchers found that ARID1A expression is more frequently lost in ovarian clear cell carcinomas than serous adenocarcinomas. Further, the "loss of ARID1A in ovarian clear cell carcinomas predicted a shorter progression-free interval," the researchers say, as those tumors did not respond as well to chemotherapy.
Rafael Fonseca from the Mayo Clinic in Scottsdale, Ariz., and his colleagues report on their genomic analysis of marginal zone lymphomas and lymphoplasmacytic lymphomas, two cancers that can be difficult to distinguish from other non-Hodgkin's lymphomas. "Although the entities share a common set of genomic abnormalities they are also characterized by the presence of genes and cellular pathways differentially affected," the authors write. "Elucidation of the genetic alterations contributing to the pathogenesis of the analyzed non-Hodgkin lymphoma subtypes may guide design of specific therapeutic approaches."
Researchers from the University of Michigan Medical School report in the online early edition of Modern Pathology that breast metaplastic carcinomas express epithelial-to-mesenchymal-transition markers. In particular, they looked at the expression of ZEB1 and E-cadherin, and the presence or absence of tumor-initiating cells in 27 primary metaplastic carcinomas of the breast. "Our study shows that metaplastic carcinomas of the breast have histological evidence and express biological markers of an epithelial to mesenchymal transition characterized by progressive overexpression of ZEB1 and downregulation of E-cadherin," the researchers report, adding that "as the process of epithelial to mesenchymal transition and the presence of breast cancer stem cells have been reported to enhance breast cancer metastasis, our data support the hypothesis that blockade of the epithelial to mesenchymal transition and/or tumor stem cells may improve the outcome of patients with metaplastic breast carcinomas."
Earnings Up, But Not to Expectations
The Laboratory Corporation of America marked a three percent increase in earnings for the fourth quarter of 2011, reports the Associated Press. LabCorp's net income for Q4 was $135.4 million, or $1.34 per share, as compared to $131.8 million, or $1.26 per share, for 2010. "The adjusted earnings topped Wall Street estimates, but the revenue figure was slightly below Wall Street expectations and its forecast for 2012 revenue was short of estimates," the AP notes. The Sample's sister publication GenomeWeb Daily News has more here.
This Week in Clinical Chemistry
Researchers from Exact Sciences report in Clinical Chemistry on their quantitative allele-specific real-time target and signal amplification, or QuARTS, method. This approach includes "polymerase-based target amplification with an invasive cleavage-based signal amplification. The fluorescence signal is detected in a fashion similar to real-time PCR," the authors say. In their paper, the researchers describe using the approach to measure levels of methylated DNA extracted from colorectal cancer samples. "At a diagnostic specificity cutoff of 95 percent, methylated BMP3, NDRG4, VIM, and TFPI2 detected 84 percent, 92 percent, 86 percent, and 92 percent of colorectal cancers, and 68 percent, 76 percent, 76 percent, and 88 percent of adenomas, respectively," the authors write.
In a Clinical Chemistry article published online in advance, University of Virginia researchers led by James Landers describe their multiplex, PCR-based assay for determining warfarin-sensitivity genotypes. "The assay was developed with conventional PCR equipment and demonstrated for microfluidics infrared-mediated PCR. Genotypes were determined by [microchip gel electrophoresis] on the basis of the pattern of PCR products," the researchers say. Our sister publication PCR Insider has more on this work.
Finally, George Yousef from St. Michael's Hospital in Toronto writes in a new opinion piece that one of the challenges in implementing personalized medicine is the ability to extract helpful information from massive datasets. Yousef considers a strategy put forth by Michigan's Arul Chinnaiyan and his lab that combines whole-genome sequencing, whole-exome sequencing, and transcriptome sequencing of tumor and normal DNA to identify clinically relevant mutations. "Although the results are promising, the Michigan study highlights several existing challenges that need to be addressed, including certification of the technique, ethics approval, and the patient's informed consent," Yousef adds. "Cost remains a substantial challenge for scaling up the experiment; however, the cost is expected to decrease after the technique becomes approved for clinical practice."