Biomarker Commons

Subject review: pancreatic ductal adenocarcinoma in the setting of mutations in the cystic fibrosis transmembrane conductance regulator gene: case report and review of the literature.

J Gastrointest Surg. 2011 Dec;15(12):2284-90

Authors: Rittenhouse DW, Talbott VA, Anklesaria Z, Brody JR, Witkiewicz AK, Yeo CJ

Abstract
BACKGROUND: Cystic fibrosis (CF) is the most commonly inherited lethal autosomal recessive genetic disease amongst Caucasians. CF results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Patients with homozygous or compound heterozygous CFTR mutations have a risk of pancreatitis, but typically do not live long enough to develop pancreatic ductal adenocarcinoma (PDA), a disease that has an average age at diagnosis of 65 years. Little is known about the risk of the development of PDA in people who are heterozygous for mutations in the CFTR gene.
PATIENTS AND METHODS: We report a case of a patient with PDA who underwent resection, who is a carrier for the W1282X nonsense mutation in the CFTR gene. The patient is of Ashkenazi Jewish ethnicity and has a family history of CF, but no family history of PDA. We reviewed the English language literature for the prevalence of PDA in CF patients (and CFTR mutations in the setting of PDA) and their significance in terms of screening, and the use of this mutation as a biomarker for an increased risk of the development of PDA.
CONCLUSION: We conclude that patients with CFTR mutations, who also have other risks for the development of PDA such as a family history of the disease, should undergo screening and be educated about their risks.

PMID: 21809164 [PubMed - indexed for MEDLINE]

The chitinase-like protein YKL-40 modulates cystic fibrosis lung disease.

PLoS One. 2011;6(9):e24399

Authors: Hector A, Kormann MS, Mack I, Latzin P, Casaulta C, Kieninger E, Zhou Z, Yildirim AÖ, Bohla A, Rieber N, Kappler M, Koller B, Eber E, Eickmeier O, Zielen S, Eickelberg O, Griese M, Mall MA, Hartl D

Abstract
The chitinase-like protein YKL-40 was found to be increased in patients with severe asthma and chronic obstructive pulmonary disease (COPD), two disease conditions featuring neutrophilic infiltrates. Based on these studies and a previous report indicating that neutrophils secrete YKL-40, we hypothesized that YKL-40 plays a key role in cystic fibrosis (CF) lung disease, a prototypic neutrophilic disease. The aim of this study was (i) to analyze YKL-40 levels in human and murine CF lung disease and (ii) to investigate whether YKL-40 single-nucleotide polymorphisms (SNPs) modulate CF lung disease severity. YKL-40 protein levels were quantified in serum and sputum supernatants from CF patients and control individuals. Levels of the murine homologue BRP-39 were analyzed in airway fluids from CF-like βENaC-Tg mice. YKL-40SNPs were analyzed in CF patients. YKL-40 levels were increased in sputum supernatants and in serum from CF patients compared to healthy control individuals. Within CF patients, YKL-40 levels were higher in sputum than in serum. BRP-39 levels were increased in airways fluids from βENaC-Tg mice compared to wild-type littermates. In both CF patients and βENaC-Tg mice, YKL-40/BRP-39 airway levels correlated with the severity of pulmonary obstruction. Two YKL-40 SNPs (rs871799 and rs880633) were found to modulate age-adjusted lung function in CF patients. YKL-40/BRP-39 levelsare increased in human and murine CF airway fluids, correlate with pulmonary function and modulate CF lung disease severity genetically. These findings suggest YKL-40 as a potential biomarker in CF lung disease.

PMID: 21949714 [PubMed - indexed for MEDLINE]

In vivo fluorescence imaging of bacteriogenic cyanide in the lungs of live mice infected with cystic fibrosis pathogens.

PLoS One. 2011;6(7):e21387

Authors: Nam SW, Chen X, Lim J, Kim SH, Kim ST, Cho YH, Yoon J, Park S

Abstract
BACKGROUND: Pseudomonas aeruginosa (PA) and Burkholderia cepacia complex (Bcc), commonly found in the lungs of cystic fibrosis (CF) patients, often produce cyanide (CN), which inhibits cellular respiration. CN in sputa is a potential biomarker for lung infection by CF pathogens. However, its actual concentration in the infected lungs is unknown.
METHODS AND FINDINGS: This work reports observation of CN in the lungs of mice infected with cyanogenic PA or Bcc strains using a CN fluorescent chemosensor (4',5'-fluorescein dicarboxaldehyde) with a whole animal imaging system. When the CN chemosensor was injected into the lungs of mice intratracheally infected with either PA or B. cepacia strains embedded in agar beads, CN was detected in the millimolar range (1.8 to 4 mM) in the infected lungs. CN concentration in PA-infected lungs rapidly increased within 24 hours but gradually decreased over the following days, while CN concentration in B. cepacia-infected lungs slowly increased, reaching a maximum at 5 days. CN concentrations correlated with the bacterial loads in the lungs. In vivo efficacy of antimicrobial treatments was tested in live mice by monitoring bacteriogenic CN in the lungs.
CONCLUSIONS: The in vivo imaging method was also found suitable for minimally invasive testing the efficacy of antibiotic compounds as well as for aiding the understanding of bacterial cyanogenesis in CF lungs.

PMID: 21750709 [PubMed - indexed for MEDLINE]