Citations

Abstract Catechol O-methyltransferase (COMT)-catalyzed methylation of catecholestrogens has been proposed to play a protective role in estrogen-induced genotoxic carcinogenesis. We have taken a comprehensive approach to test the hypothesis that genetic variation in COMT might influence breast cancer risk. Fifteen COMT single nucleotide polymorphisms (SNPs) selected on the basis of in-depth resequencing of the COMT gene were genotyped in 1,482 DNA samples from a Mayo Clinic breast cancer case control study. Two common SNPs in the distal promoter for membrane-bound (MB) COMT, rs2020917 and rs737865, were associated with breast cancer risk reduction in premenopausal women in the Mayo Clinic study, with allele-specific odds ratios (OR) of 0.70 [95% confidence interval (CI), 0.52–0.95] and 0.68 (95% CI, 0.51–0.92), respectively. These two SNPs were then subjected to functional genomic analysis and were genotyped in an additional 3,683 DNA samples from two independent case control studies (GENICA and GESBC). Functional genomic experiments showed that these SNPs could up-regulate transcription and that they altered DNA-protein binding patterns. Furthermore, substrate kinetic and exon array analyses suggested a role for MB-COMT in catecholestrogen inactivation. The GENICA results were similar to the Mayo case control observations, with ORs of 0.85 (95% CI, 0.72–1.00) and 0.85 (95% CI, 0.72–1.01) for the two SNPs. No significant effect was observed in the GESBC study. These studies showed that two SNPs in the COMT distal promoter were associated with breast cancer risk reduction in two of three case control studies, compatible with the results of functional genomic experiments, suggesting a role for MB-COMT in breast cancer risk. [Cancer Res 2008;68(14):5997–6005]

Object The cervical foraminotomy was pioneered in the 1940s to address radicular symptoms via a posterior approach, but the long-term outcome has not been adequately studied. Methods The authors retrospectively analyzed data obtained from 303 patients (188 male and 115 female, mean age 49.2 years) who had consecutively undergone a single-level posterior foraminotomy for cervical radiculopathy between 1972 and 1992. The median follow-up duration was 7.1 years. The major end point studied was the development of symptomatic adjacent- or same-segment disease. Incidence rates per 1000 person-years were calculated, and the natural history of the disease was predicted using Kaplan–Meier survivorship analysis. In 15 (4.9%) of 303 patients, symptomatic adjacent-segment disease developed, yielding a rate of 6.4/1000 person-years at risk. This included nine (2.9%) of 303 patients requiring reoperation, yielding a rate of 3.8/1000 person-years. Kaplan–Meier survivorship analysis suggested a relatively stable annual 0.7% rate for developing adjacent-segment disease, with a 10-year rate of 6.7%. Ten patients developed same-segment disease, yielding a risk rate of 3.9/1000 person-years. Kaplan–Meier survivorship analysis demonstrated a 5- and 10-year risk rate of developing same-segment disease of 3.2 and 5.0%, respectively. Conclusions Although additional study is needed, analysis of the present data suggests that posterior foraminotomy is associated with a low rate of same- and adjacent-segment disease.

AbstractLeukemia-cell expression of ZAP-70, CD38, or unmutated immunoglobulin heavy chain variable region genes (U-IGHV) each is associated with aggressive disease in patients with chronic lymphocytic leukemia (CLL). To assess the relative strength of each marker, we defined thresholds for designating a case as positive for CD38 or ZAP-70 in a test cohort of 307 patients and used these data-defined criteria to stratify patients in an independent cohort of 705 patients. Multivariable analysis revealed that ZAP-70 was the strongest risk factor. Knowledge of the IGHV mutation status or CD38 did not improve our ability to predict the time to first treatment except for ZAP-70–negative cases, which could be segregated into 2 groups of intermediate-risk or low-risk disease based on whether they expressed unmutated or mutated IGHV. ZAP-70 maintained its high relative prognostic value for the subset of patients with early-stage, asymptomatic disease, including patients evaluated within 1 year of diagnosis. Although it is premature to recommend therapy based on these risk factors, patients with ZAP-70–positive CLL cells should be monitored closely for disease progression as they have a median time from diagnosis to requiring initial therapy by standard criteria of approximately 3 years.

Study Design and SettingA two‐center prospective case series analysis.PatientsOne hundred fourteen patients with previously treated laryngeal or pharyngeal squamous cell carcinoma who underwent salvage transoral laser microsurgery (TLM).InterventionsTLM in 114 patients, neck dissection in 22 (19%) patients, adjuvant radiotherapy in 12 (11%) patients.ResultsNinety‐one (80%) patients had recurrent primary tumors whereas 23 (20%) patients had second primary tumors occur within a previously irradiated field. The minimum follow‐up was 1 year (median, 3 years). The distribution of tumor location was oropharynx 52 (46%), glottic and subglottic larynx 44 (39%), supraglottic larynx 11 (10%), and pyriform/hypopharynx 7 (6%). Overall, three‐year local and locoregional control estimates were 70 percent and 67 percent, respectively; and three‐year survival and disease‐free survival estimates were 62 percent and 64 percent, respectively. The average duration of hospitalization was 2.3 days. Four (3.5%) patients had significant postoperative bleeding. Two (<2%) patients had treatment‐related deaths.ConclusionsTransoral laser microsurgery offers select patients an attractive alternative salvage surgical therapy to the recurrent and second primary tumor site.

Abstract Base excision repair and nucleotide excision repair are vital responses to multiple types of DNA damage, including damage from tobacco exposure. Single-nucleotide polymorphisms (SNP) in these pathways may affect DNA repair capacity and therefore influence risk for cancer development. We performed a clinic-based, case-control study comprising 481 consecutive patients with confirmed pancreatic adenocarcinoma and 625 healthy controls. Allele and genotype frequencies for 16 SNPs in DNA repair genes ERCC1, XPD/ERCC2, XPC, XPF/ERCC4, OGG1, and XRCC1 were compared after adjusting for age, sex, and smoking history. Subgroup analysis by sex and smoking history was performed. Carriers of one or two XPF/ERCC4 minor alleles at R415Q had decreased risk of pancreatic adenocarcinoma compared with those who had two major alleles [odds ratio (OR), 0.59; 95% confidence interval (95% CI), 0.40–0.85]. Heavy smokers (&gt;40 pack-years) had increased risk for cancer if they were carriers of at least one minor allele for XPD/ERCC2 at D312N (OR, 2.78; 95% CI, 1.28–6.04) or D711D (OR, 2.19; 95% CI, 1.01–4.73). No other significant differences in risk were identified. Minor alleles in DNA repair genes XPF/ERCC4 and XPD/ERCC2 were associated with altered risk for pancreatic cancer. [Cancer Res 2008;68(12):4928–35]