Citations

Lynch syndrome was described over a century ago but information on the medical consequences and optimal management of this disorder continue to amass and evolve. This brief overview highlights the gene-specific and site-specific cancer penetrance and management options for those with Lynch syndrome.

Abstract Genome-wide association studies (GWAS) of 10 different cancers have identified pleiotropic cancer predisposition loci across a region of chromosome 5p15.33 that includes the TERT and CLPTM1L genes. Of these, susceptibility alleles for pancreatic cancer have mapped to the CLPTM1L gene, thus prompting an investigation of the function of CLPTM1L in the pancreas. Immunofluorescence analysis indicated that CLPTM1L localized to the endoplasmic reticulum where it is likely embedded in the membrane, in accord with multiple predicted transmembrane domains. Overexpression of CLPTM1L enhanced growth of pancreatic cancer cells in vitro (1.3–1.5–fold; PDAY7 < 0.003) and in vivo (3.46-fold; PDAY68 = 0.039), suggesting a role in tumor growth; this effect was abrogated by deletion of two hydrophilic domains. Affinity purification followed by mass spectrometry identified an interaction between CLPTM1L and non-muscle myosin II (NMM-II), a protein involved in maintaining cell shape, migration, and cytokinesis. The two proteins colocalized in the cytoplasm and, after treatment with a DNA-damaging agent, at the centrosomes. Overexpression of CLPTM1L and depletion of NMM-II induced aneuploidy, indicating that CLPTM1L may interfere with normal NMM-II function in regulating cytokinesis. Immunohistochemical analysis revealed enhanced staining of CLPTM1L in human pancreatic ductal adenocarcinoma (n = 378) as compared with normal pancreatic tissue samples (n = 17; P = 1.7 × 10−4). Our results suggest that CLPTM1L functions as a growth-promoting gene in the pancreas and that overexpression may lead to an abrogation of normal cytokinesis, indicating that it should be considered as a plausible candidate gene that could explain the effect of pancreatic cancer susceptibility alleles on chr5p15.33. Cancer Res; 74(10); 2785–95. ©2014 AACR.

Abstract Cigarette smoking (CS), hormone therapy (HT), and folate intake (FI) are each thought to influence colorectal cancer risk, but the underlying molecular mechanisms remain incompletely defined. The TP53 (p53) protein, encoded by the TP53 tumor-suppressor gene that is commonly mutated in colorectal cancer, can be readily assessed to differentiate biologically distinct colorectal cancer subtypes. In this prospective cohort study, we examined CS-, HT-, and FI-associated colorectal cancer risks by TP53 protein expression level among Iowa Women's Health Study (IWHS) participants. The IWHS recruited 41,836 randomly selected Iowa women, ages 55 to 69 years, with a valid driver's license at study entry in 1986. Self-reported exposure variables were assessed at baseline. Incident colorectal cancer cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected and evaluated for TP53 protein expression by immunohistochemistry. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI) for associations between CS, HT, or FI and TP53-defined colorectal cancer subtypes. Informative environmental exposure and protein expression data were available for 492 incident colorectal cancer cases: 222 (45.1%) TP53 negative, 72 (14.6%) TP53 low, and 198 (40.2%) TP53 high. Longer duration (>5 years) of HT was inversely associated with TP53 high colorectal cancers (RR, 0.50; 95% CI, 0.27–0.94). No other statistically significant associations were observed. These data support possible heterogeneous effects from HT on TP53-related pathways of colorectal carcinogenesis in older women. Cancer Epidemiol Biomarkers Prev; 23(2); 350–5. ©2013 AACR.

ABSTRACTBackgroundVariants within the leucine‐rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine‐rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late‐onset sporadic disorders like Parkinson's disease.MethodsThe Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine‐rich repeat kinase 2 gene across 23 different sites in 15 countries.ResultsHerein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K‐R1398H‐K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups.ConclusionsEstablishing individual patient‐based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. © 2013 International Parkinson and Movement Disorder Society

BACKGROUND Friedreich ataxia (FRDA) is caused by reduced frataxin (FXN) concentrations. A clinical diagnosis is typically confirmed by DNA-based assays for GAA-repeat expansions or mutations in the FXN (frataxin) gene; however, these assays are not applicable to therapeutic monitoring and population screening. To facilitate the diagnosis and monitoring of FRDA patients, we developed an immunoassay for measuring FXN. METHODS Antibody pairs were used to capture FXN and an internal control protein, ceruloplasmin (CP), in 15 μL of whole blood (WB) or one 3-mm punch of a dried blood spot (DBS). Samples were assayed on a Luminex LX200 analyzer and validated according to standard criteria. RESULTS The mean recovery of FXN from WB and DBS samples was 99%. Intraassay and interassay imprecision (CV) values were 4.9%–13% and 9.8%–16%, respectively. The FXN limit of detection was 0.07 ng/mL, and the reportable range of concentrations was 2–200 ng/mL. Reference adult and pediatric FXN concentrations ranged from 15 to 82 ng/mL (median, 33 ng/mL) for DBS and WB. The FXN concentration range was 12–22 ng/mL (median, 15 ng/mL) for FRDA carriers and 1–26 ng/mL (median 5 ng/mL) for FRDA patients. Measurement of the FXN/CP ratio increased the ability to distinguish between patients, carriers, and the reference population. CONCLUSIONS This assay is applicable to the diagnosis and therapeutic monitoring of FRDA. This assay can measure FXN and the control protein CP in both WB and DBS specimens with minimal sample requirements, creating the potential for high-throughput population screening of FRDA.

Abstract We report two patients with systemic necrotizing vasculitis (microscopic polyarteritis) and associated recurrent pulmonary capillaritis, in whom progressive irreversible airway dysfunction began approximately 10 yr after disease onset. Their course was characterized by repeated episodes of diffuse alveolar hemorrhage, glomerulonephritis, palpable purpura, and splinter hemorrhages. The lung revealed intraalveolar hemorrhage, neutrophilic infiltration and cellular fragmentation, fibrinoid necrosis of the alveolar interstitium, and parenchymal hemosiderin deposits. No medium-sized vessel involvement, granulomatous inflammation, or bronchiolar obliteration were seen. Renal biopsies revealed focal segmental necrotizing glomerulonephritis, and a cutaneous biopsy in one case showed a leukocytoclastic vasculitis. Immunofluorescent studies of lung and kidney showed minimal or no immunoreactivity. The clinical course and serologic tests did not support another systemic vasculitis, connective tissue disease, or antiglomerular basement membrane antibody disease. The acute episodes responded to antiinflammatory and immunosuppressive therapy. Symptoms, serial pulmonary function tests, and chest imaging documented the development of a progressive irreversible obstructive airway disease. No other predisposing factors were identified. These cases demonstrate the unexpected appearance of an irreversible obstructive airway disease with lung parenchymal hyperinflation after systemic necrotizing vasculitis associated with recurrent pulmonary capillaritis and diffuse alveolar hemorrhage.

Abstract Findings of surgical lung biopsy (SLB) are important in categorizing patients with idiopathic interstitial pneumonia (IIP). We investigated whether histologic variability would be evident in SLB specimens from multiple lobes in patients with IIP. SLBs from 168 patients, 109 of whom had multiple lobes biopsied, were reviewed by three pathologists. A diagnosis was assigned to each lobe. A different diagnosis was found between lobes in 26% of the patients. Patients with usual interstitial pneumonia (UIP) in all lobes were categorized as concordant for UIP (n = 51) and those with UIP in at least one lobe were categorized as discordant for UIP (n = 28). Patients with nonspecific interstitial pneumonia (NSIP) in all lobes were categorized as having fibrotic (n = 25) or cellular NSIP (n = 5). No consistent distribution of lobar histology was noted. Patients concordant for UIP were older (63 ± 9 [mean ± SD] yr; p < 0.05 as compared with all other groups) than those discordant for UIP (57 ± 12 yr) or with fibrotic NSIP (56 ± 11 yr) or cellular NSIP (50 ± 9 yr). Semiquantitative high-resolution computed tomography demonstrated a varied profusion of fibrosis (p < 0.05 for all group comparisons), with more fibrosis in concordant UIP (2.13 ± 0.62) than in discordant UIP (1.42 ± 0.73), fibrotic NSIP (0.83 ± 0.58), or cellular NSIP (0.44 ± 0.42). Survival was better for patients with NSIP than for those in both UIP groups (p < 0.001), although survival in the two UIP groups was comparable (p = 0.16). Lobar histologic variability is frequent in patients with IIP, patients with a histologic pattern of UIP in any lobe should be classified as having UIP.

Abstract It is not known if a surgical lung biopsy is necessary in all patients for the diagnosis of idiopathic pulmonary fibrosis (IPF). We conducted a blinded, prospective study at eight referring centers. Initially, cases were evaluated by clinical history and examination, transbronchial biopsy, and high-resolution lung computed tomography scans. Pulmonologists at the referring centers then assessed their certainty of the diagnosis of IPF and provided an overall diagnosis, before surgical lung biopsy. The lung biopsies were reviewed by a pathology core and 54 of 91 patients received a pathologic diagnosis of IPF. The positive predictive value of a confident (certain) clinical diagnosis of IPF by the referring centers was 80%. The positive predictive value of a confident clinical diagnosis was higher, when the cases were reviewed by a core of pulmonologists (87%) or radiologists (96%). Lung biopsy was most important for diagnosis in those patients with an uncertain diagnosis and those thought unlikely to have IPF. These studies suggest that clinical and radiologic data that result in a confident diagnosis of IPF by an experienced pulmonologist or radiologist are sufficient to obviate the need for a lung biopsy. Lung biopsy is most helpful when clinical and radiologic data result in an uncertain diagnosis or when patients are thought not to have IPF.