Citations

Abstract MMSET, identified by its fusion to the IgH locus in t(4;14)-associated multiple myeloma, possesses domains found within chromatin regulators, including the SET domain. MMSET protein is overexpressed and highly associated with chromatin in myeloma cell lines carrying t(4;14). MMSET possesses methyltransferase activity for core histone H3 lysine 4 and histone 4 lysine 20, whereas MMSET made in cells only modified H4. Segments of MMSET fused to the Gal4 DNA binding domain repressed transcription of a chromatin-embedded Gal4 reporter gene. MMSET-mediated repression was associated with increased H4K20 methylation gene and loss of histone acetylation. Consistent with this repressive activity, MMSET could form a complex with HDAC1 and HDAC2, mSin3a, and the histone demethylase LSD1, suggesting that it is a component of corepressor complexes. Furthermore, MMSET coexpression enhances HDAC1- and HDAC2-mediated repression in transcriptional reporter assays. Finally, shRNA-mediated knockdown of MMSET compromised viability of a myeloma cell line, suggesting a biologic role for the protein in malignant cell growth. Collectively, these data suggest that, by acting directly as a modifier of chromatin as well as through binding of other chromatin-modifying enzymes, MMSET influences gene expression and potentially acts as a pathogenic agent in multiple myeloma.

Abstract Recent publications have reported that common variants on 8q24 are associated with both prostate and colorectal cancers (CRC). In addition, one of these studies (the ARCTIC study) initially observed an association with a single nucleotide polymorphism (SNP) on 9p24 that was not confirmed in some of their validation data sets. In the research described here, we conducted a case-unaffected sibling analysis using population- and clinic-based discordant sibships (N = 1,567 sibships) from the Colon Cancer Family Registry (Colon CFR) to investigate the associations between common variants at 9p24 and 8q24 and risk of CRC. We also evaluated whether these associations differed by age, family history, and tumor characteristics, including microsatellite instability and tumor site. Associations were estimated using conditional logistic regression, treating sibship as the matching factor. Analyses were adjusted for age and sex, and stratified by ascertainment source (population versus clinic). We observed an association between a SNP on 9p24 (rs719725) and risk of CRC in the population-based series (AA versus CC: odds ratios, 1.46; 95% confidence interval, 1.06–2.02; AC versus CC: odds ratios, 1.50; 95% confidence interval, 1.14–1.98; P = 0.011 on 2 df). In the population-based series, we also detected statistically significant associations between two SNPs on 8q24, rs10505477 and rs6983267, and risk of CRC (P = 0.005 and P = 0.002, respectively). There was no evidence of statistically significant heterogeneity by age at diagnosis, family history of CRC, microsatellite instability, or tumor site at either locus and no evidence of interaction between SNPs on 8q24 and 9p24. These data suggest that common variants may play important roles in the risk of CRC. [Cancer Res 2007;67(23):11128–32]

Background— Brugada syndrome is a rare, autosomal-dominant, male-predominant form of idiopathic ventricular fibrillation characterized by a right bundle-branch block and ST elevation in the right precordial leads of the surface ECG. Mutations in the cardiac Na + channel SCN5A on chromosome 3p21 cause ≈20% of the cases of Brugada syndrome; most mutations decrease inward Na + current, some by preventing trafficking of the channels to the surface membrane. We previously used positional cloning to identify a new locus on chromosome 3p24 in a large family with Brugada syndrome and excluded SCN5A as a candidate gene. Methods and Results— We used direct sequencing to identify a mutation (A280V) in a conserved amino acid of the glycerol-3-phosphate dehydrogenase 1–like ( GPD1-L ) gene. The mutation was present in all affected individuals and absent in >500 control subjects. GPD1-L RNA and protein are abundant in the heart. Compared with wild-type GPD1-L, coexpression of A280V GPD1-L with SCN5A in HEK cells reduced inward Na + currents by ≈50% ( P <0.005). Wild-type GPD1-L localized near the cell surface to a greater extent than A280V GPD1-L. Coexpression of A280V GPD1-L with SCN5A reduced SCN5A cell surface expression by 31±5% ( P =0.01). Conclusions— GPD1-L is a novel gene that may affect trafficking of the cardiac Na + channel to the cell surface. A GPD1-L mutation decreases SCN5A surface membrane expression, reduces inward Na + current, and causes Brugada syndrome.

Abstract Introduction: Colorectal adenomas and other types of polyps are commonly used as end points or risk factors in epidemiologic studies. However, it is not known how accurately patients are able to self-report the presence or absence of adenomas following colonoscopy. Methods: Participants in the Colon Cancer Family Registry provided self-reports of recent colorectal cancer (CRC) screening activity, and whether or not they had ever been told they had a polyp. Positive and negative predictive values for polyp self-report were calculated by comparing medical records with self-reports from 488 participants. Results: The positive predictive value for self-reported polyp was 80.9%, and the negative predictive value was 85.8%. The predictive values did not differ by age group or sex, but participants with a previous diagnosis of CRC had a lower negative predictive value (76.2%) than participants with no personal history of CRC (89.0%; P = 0.04). Conclusions: Predictive values for self-reports of polyps are fairly high, but researchers needing accurate polyp data should obtain medical record confirmation. Pursuing medical records on only those participants self-reporting a polyp could result in an underestimation of the polyp prevalence in a study population. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1898–901)

AbstractProperly performed clinical trials provide a foundation for evidence‐based medical practice. The surgeon plays a central role in the management of patients with malignant solid tumors, including thyroid cancer, because operative extirpation of the malignancy is the essential first step in effective therapy. This article discusses the role of the surgeon in the clinical research of thyroid cancer and also reviews the important clinical trials that have influenced the treatment of patients with thyroid cancer. Recent discoveries defining the genetic mutations underlying the various types of thyroid cancers have led to the development of targeted therapies. These chemical compounds, which are now being evaluated in clinical trials, hold great promise for the treatment of patients with locally advanced and distant metastatic disease. The surgical investigator also plays an important role in procuring tumor tissue from patients in clinical trials. The molecular analysis of these tissues is of critical importance in selecting specific therapies and predicting patient response and prognosis.

Abstract High-risk susceptibility genes explain &lt;40% of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)–tagging approach to evaluate common variants in 13 genes involved in cell cycle control—CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D—and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark (∼1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States (∼2,000 cases and ∼3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85–0.98) for rs3731257; and OR, 0.93 (0.87–0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies. [Cancer Res 2007;67(7):3027–35]

Lipolysis of adipose tissue triglycerides releases glycerol. Twenty-four volunteers, of whom 6 were obese and 13 were women, received a primed-constant infusion of 2H5-glycerol for 120 min during postabsorptive steady-state conditions. Arterial, abdominal venous, and interstitial (microdialysis) samples were taken, and a four-compartment model was applied to assess subcutaneous abdominal adipose tissue glycerol kinetics. Adipose tissue blood flow was measured using 133Xe washout. Venous glycerol concentrations (median 230 μmol/l [interquartile range 210–268]) were consistently greater than those of arterial blood (69.1 μmol/l [56.5–85.5]), while glycerol isotopic enrichments (tracer-to-tracee ratio) were greater in arterial blood (8.34% [7.44–10.1]) than venous blood (2.34% [1.71–2.69], P &lt; 0.01). Microdialysate glycerol enrichment was 1.44% (1.11–1.79), indicating incomplete permeability of glycerol between capillary blood and interstitium. Calculated interstitial glycerol concentrations were between 270 μmol/l (256–350) and 332 μmol/l (281–371) (examining different boundary conditions). The calculated capillary diffusion capacity (ps) was between 2.21 ml · 100 g tissue−1 · min−1 (1.31–3.13) and 3.09 ml · 100 g tissue−1 · min−1 (1.52–4.90) and correlated inversely with adiposity (Rs ≤ −0.45, P &lt; 0.05). Our results support previous estimates of interstitial glycerol concentration within adipose tissue and reveal capillary diffusion capacity is reduced in obesity.

AbstractBackgroundSince the human genome has been sequenced many mysteries of cell biology have been unravelled, thereby clarifying the pathogenesis of several diseases, particularly cancer. In members of kindreds with certain hereditary diseases, it is now possible early in life to predict with great certainty whether or not a family member has inherited the mutated allele causing the disease. In hereditary malignancies this has been particularly important, because in affected family members there is the possibility of removing the organ destined to develop cancer before malignancy develops or while it is in situ. At first consideration, it would appear that “prophylactic surgery” would have a place in many hereditary malignancies; however, the procedure has applicability only if certain criteria are met: (1) the genetic mutation causing the hereditary malignancy must have a very high penetrance and be expressed regardless of environmental factors; (2) there must be a highly reliable test to identify patients who have inherited the mutated gene; (3) the organ must be removed with minimal morbidity and virtually no mortality; (4) there must be a suitable replacement for the function of the removed organ; and (5) there must be a reliable method of determining over time that the patient has been cured by “prophylactic surgery.”ConclusionsIn this monograph we review several hereditary malignancies and consider those where prophylactic surgery might be useful. As we learn, there are various barriers to performing the procedure in many common hereditary cancer syndromes. The archetype disease syndromes, which meet each of the five criteria mentioned above and where prophylactic surgery is most useful, are the type 2 multiple endocrine neoplasia (MEN) syndromes: MEN2A, MEN2B, and the related familial medullary thyroid carcinoma. An additional benefit of the Human Genome Project, has been the development of pharmacologic and biologic compounds that block the metabolic pathway(s) activated by specific genetic mutations. Many of these compounds have shown efficacy in patients with locally advanced or metastatic cancers, and there is the likelihood that they will prove beneficial in preventing the outgrowth of malignant cells in patients destined to develop a hereditary cancer.

Purpose The role of high-degree microsatellite instability (MSI-H) as a marker to predict benefit from adjuvant chemotherapy remains unclear. Patients and Methods To help define its impact, we conducted an analysis of National Surgical Adjuvant Breast and Bowel Project (NSABP) patients who were randomly assigned to a surgery-alone group (untreated cohort) and patients assigned to an adjuvant fluorouracil (FU) -treated group (treated cohort). MSI-H and other potential markers were assessed (TGF-BRII, p53, thymidylate synthase, and Ki67). Results In all, 98 (18.1%) of 542 patients exhibited MSI-H, and there was a strong inverse relationship between MSI-H and mutant p53 status (P < .001). The prognostic analyses showed increased recurrence-free survival (RFS) for MSI-H patients versus MSS/MSI-L patients (P = .10), but showed no difference in overall survival (OS; P = .67). There was a potential interaction between MSI-H and mutant p53 in terms of improved RFS (P = .03). In the predictive marker analysis, we observed no interaction between MSI status and treatment for either RFS (P = .68) or OS (P = .62). Hazard ratios (HR) for RFS for MSI-H versus MSS/MSI-L patients were 0.77 (95% CI, 0.40 to 1.48) in the untreated-patients group and 0.60 (95% CI, 0.30 to 1.19) in the treated-patients group. HRs for OS were 0.82 (95% CI, 0.44 to 1.51) and 1.02 (95% CI, 0.56 to 1.85) for the respective groups. There was a trend toward improved RFS in patients with MSI-H and mutant p53. Conclusion These results do not support the use of MSI-H as a predictive marker of chemotherapy benefit.