Citations

Abstract A common variant on chromosomal region 15q24-25.1, marked by rs1051730, was found to be associated with lung cancer risk. Here, we attempted to confirm the second variant on 15q24-25.1 in several large sporadic lung cancer populations and determined what percentage of additional risk for lung cancer is due to the genetic effect of the second variant. SNPs rs1051730 and rs481134 were genotyped in 2,818 lung cancer cases and 2,766 controls from four populations. Joint analysis of these two variants (rs1051730 and rs481134) on 15q24-25.1 identified three major haplotypes (G_T, A_C, and G_C) and provided stronger evidence for association of 15q24-25.1 with lung cancer (P = 9.72 × 10−9). These two variants represent three levels of risk associated with lung cancer. The most common haplotype G_T is neutral; the haplotype A_C is associated with increased risk for lung cancer with 5.0% higher frequency in cases than in controls [P = 1.68 × 10−7; odds ratio (OR), 1.24; 95% confidence interval (95% CI), 1.14–1.35]; whereas the haplotype G_C is associated with reduced risk for lung cancer with 4.4% lower frequency in cases than in controls (P = 7.39 × 10−7; OR, 0.80; 95% CI, 0.73–0.87). We further showed that these two genetic variants on 15q24-25.1 independently influence lung cancer risk (rs1051730: P = 4.42 × 10−11; OR, 1.60; 95% CI, 1.46–1.74; rs481134: P = 7.01 × 10−4; OR, 0.81; 95% CI, 0.72–0.92). The second variant on 15q24-25.1, marked by rs481134, explains an additional 13.2% of population attributable risk for lung cancer. Cancer Res; 70(8); 3128–35. ©2010 AACR.

Abstract Cigarette smoking is the major cause for lung cancer, but genetic factors also affect susceptibility. We studied families that included multiple relatives affected by lung cancer. Results from linkage analysis showed strong evidence that a region of chromosome 6q affects lung cancer risk. To characterize the effects that this region of chromosome 6q region has on lung cancer risk, we identified a haplotype that segregated with lung cancer. We then performed Cox regression analysis to estimate the differential effects that smoking behaviors have on lung cancer risk according to whether each individual carried a risk-associated haplotype or could not be classified and was assigned unknown haplotypic status. We divided smoking exposures into never smokers, light smokers (<20 pack-years), moderate smokers (20 to <40 pack-years), and heavy smokers (≥40 pack-years). Comparing results according to smoking behavior stratified by carrier status, compared with never smokers, there was weakly increasing risk for increasing smoking behaviors, with the hazards ratios being 3.44, 4.91, and 5.18, respectively, for light, moderate, or heavy smokers, whereas among the individuals from families without the risk haplotype, the risks associated with smoking increased strongly with exposure, the hazards ratios being, respectively, 4.25, 9.17, and 11.89 for light, moderate, and heavy smokers. The never smoking carriers had a 4.71-fold higher risk than the never smoking individuals without known risk haplotypes. These results identify a region of chromosome 6q that increases risk for lung cancer and that confers particularly higher risks to never and light smokers. Cancer Res; 70(6); 2359–67

Local release of TGF-β during times of high bone turnover leads to elevated levels within the bone microenvironment, and we have shown that TGF-β suppresses osteoclast apoptosis. Therefore, understanding the influences of TGF-β on bone resorbing osteoclasts is critical to the design of therapies to reduce excess bone loss. Here we investigated the mechanisms by which TGF-β sustains suppression of osteoclast apoptosis. We found TGF-β rapidly increased leukemia inhibitory factor (LIF) expression and secretion by phosphorylated mothers against decapentaplegic-dependent and -independent signaling pathways. TGF-β also induced suppressor of cytokine signaling 3 (SOCS3) expression, which was required for TGF-β or LIF to promote osteoclast survival by. Blocking LIF or SOCS3 blocked TGF-β promotion of osteoclast survival, confirming that LIF and SOCS3 expression are necessary for TGF-β-mediated suppression of osteoclast apoptosis. Investigation of the mechanisms by which LIF promotes osteoclast survival revealed that LIF-induced expression of Bcl-XL and repressed Bcl-2 interacting domain expression by activating MAPK kinase, AKT, and nuclear factor-κB pathways. Suppression of Janus kinase/signal transducer and activator of transcription signaling further increased Bcl-XL expression and enhanced osteoclast survival, supporting that this pathway is not involved in prosurvival effects of TGF-β and LIF. These data show that TGF-β coordinately induces LIF and SOCS3 to promote prosurvival signaling. This alters the ratio of prosurvival Bcl2 family member Bcl-XL to proapoptotic family member Bcl-2 interacting domain, leading to prolonged osteoclast survival.

Abstract Background: Genetic factors play important roles in lung cancer susceptibility. In this study, we replicated the association of 5p15.33 and 6p21.33 with familial lung cancer. Taking into account the previously identified genetic susceptibility variants on 6q23-25/RGS17 and 15q24-25.1, we further determined the cumulative association of these four genetic regions and the population attributable risk percent of familial lung cancer they account for. Methods: One hundred ninety-four case patients and 219 cancer-free control subjects from the Genetic Epidemiology of Lung Cancer Consortium were used for the association analysis. Each familial case was chosen from one high-risk lung cancer family that has three or more affected members. Single nucleotide polymorphisms (SNP) on chromosomal regions 5p15.33, 6p21.33, 6q23-25/RGS17, and 15q24-25.1 were assessed for their associations with familial lung cancer. The cumulative association of the four chromosomal regions with familial lung cancer was evaluated with the use of a linear logistic model. Population attributable risk percent was calculated for each SNP using risk ratio. Results: SNP rs31489 showed the strongest evidence of familial lung cancer association on 5p15.33 (P = 2 × 10−4; odds ratio, 0.57; 95% confidence interval, 0.42-0.77), whereas rs3117582 showed a weak association on 6p21.33 (P = 0.09; odds ratio, 1.47; 95% confidence interval, 0.94-2.31). Analysis of a combination of SNPs from the four regions provided a stronger cumulative association with familial lung cancer (P = 6.70 × 10−6) than any individual SNPs. The risk of lung cancer was increased to 3- to 11-fold among those subjects who had at least one copy of risk allele at each region compared with subjects without any of the risk factors. These four genetic regions contribute to a total of 34.6% of familial lung cancer in smokers. Conclusions: The SNPs in four chromosomal regions have a cumulative and significant association with familial lung cancer and account for about one-third of the population attributable risk for familial lung cancer. Cancer Epidemiol Biomarkers Prev; 19(2); 517–24

Background Hepatitis B virus (HBV) genotype B and C seem not to affect the therapeutic response to lamivudine (3TC). Whether a given genotype has an earlier emergence of 3TC resistance remains unclear. We thus conducted this study to elucidate the association of HBV genotype with the emergence of 3TC-resistant strains in Taiwanese patients. Methods Forty chronic hepatitis B patients who developed resistance after 3TC therapy were retrospectively enrolled. HBV genotype, serum alanine aminotransferase (ALT) and HBV DNA levels were determined at baseline. The presence of 3TC-resistant mutations was confirmed by direct sequencing whenever biochemical breakthrough developed. Results The distribution of HBV genotype B and C in 40 patients receiving 3TC therapy were 60% and 40%, respectively. The mean interval to detect 3TC- resistant strain was 19.6 ±1.7 months. By using multivariate analysis, HBV genotype B and higher pre-treatment HBV DNA level were independently associated with earlier detection of 3TC-resistant strains. In addition, genotype B was significantly associated with development of 3TC resistance within the first 12 months of 3TC therapy compared with genotype C (odds ratio 8.27; P=0.004). Conclusions Compared with HBV genotype C, genotype B appears to have an earlier biochemical resistance to 3TC than genotype C. Therefore, more frequent monitoring of viral load or genotypical resistance might be needed for patients with HBV genotype B infection receiving 3TC therapy, especially during the first year.

Abstract Recent genome-wide association studies have linked the chromosome 15q24-25.1 locus to nicotine addiction and lung cancer susceptibility. To refine the 15q24-25.1 locus, we performed a haplotype-based association analysis of 194 familial lung cases and 219 cancer-free controls from the Genetic Epidemiology of Lung Cancer Consortium (GELCC) collection, and used proliferation and apoptosis analyses to determine which gene(s) in the 15q24-25.1 locus mediates effects on lung cancer cell growth in vitro. We identified two distinct subregions, hapL (P = 3.20 × 10−6) and hapN (P = 1.51 × 10−6), which were significantly associated with familial lung cancer. hapL encompasses IREB2, LOC123688, and PSMA4, and hapN encompasses the three nicotinic acetylcholine receptor subunit genes CHRNA5, CHRNA3, and CHRNB4. Examination of the genes around hapL revealed that PSMA4 plays a role in promoting cancer cell proliferation. PSMA4 mRNA levels were increased in lung tumors compared with normal lung tissues. Down-regulation of PSMA4 expression decreased proteasome activity and induced apoptosis. Proteasome dysfunction leads to many diseases including cancer, and drugs that inhibit proteasome activity show promise as a form of cancer treatment. Genes around hapN were also investigated, but did not show any direct effect on lung cancer cell proliferation. We concluded that PSMA4 is a strong candidate mediator of lung cancer cell growth, and may directly affect lung cancer susceptibility through its modulation of cell proliferation and apoptosis. [Cancer Res 2009;69(19):7844–50]

Purpose In February 2000, the criteria for measuring tumor shrinkage as an indicator of antitumor activity were redefined by the Response Evaluation Criteria in Solid Tumors (RECIST). This resulted in simplifying bidimensional to unidimensional measurement of lesions. Under RECIST, all lesions, up to 10, must be measured. Scanning and measuring multiple lesions is costly, time-consuming, and a disincentive to participation in clinical trials. We investigated whether fewer than 10 lesions can be measured without compromising the accuracy of assessing a regimen's activity. Patients and Methods Thirty-two North Central Cancer Treatment Group trials including 2,374 patients were analyzed. Twelve studies were conducted before RECIST; 20 were conducted post-RECIST. Agreement between objective status by cycle, confirmed response, overall response rate, and time to progression (TTP) was evaluated based on all 10 versus the largest one through five lesions. Results The median number of lesions reported on RECIST trials did not differ from pre-RECIST trials (median = 2.0). One lesion at baseline was reported in 49% of patients, two lesions in 28% of patients, three lesions in 12% of patients, four lesions in 6% of patients, and five lesions in 5% of patients in post-RECIST trials. Utilizing the largest two lesions produced excellent concordance with that using all lesions for all end points. In no trial did the overall response rate differ by more than 3% when two versus all lesions were considered. Evaluating more than two lesions did not significantly improve agreement. Conclusion Based on these trials, the assessment of more than two lesions did not alter the conclusions regarding a treatment's efficacy as judged by response rate or TTP.

Abstract Purpose: We have previously mapped a major susceptibility locus influencing familial lung cancer risk to chromosome 6q23-25. However, the causal gene at this locus remains undetermined. In this study, we further refined this locus to identify a single candidate gene, by fine mapping using microsatellite markers and association studies using high-density single nucleotide polymorphisms (SNP). Experimental Design: Six multigenerational families with five or more affected members were chosen for fine-mapping the 6q linkage region using microsatellite markers. For association mapping, we genotyped 24 6q-linked cases and 72 unrelated noncancer controls from the Genetic Epidemiology of Lung Cancer Consortium resources using the Affymetrix 500K chipset. Significant associations were validated in two independent familial lung cancer populations: 226 familial lung cases and 313 controls from the Genetic Epidemiology of Lung Cancer Consortium, and 154 familial cases and 325 controls from Mayo Clinic. Each familial case was chosen from one high-risk lung cancer family that has three or more affected members. Results: A region-wide scan across 6q23-25 found significant association between lung cancer susceptibility and three single nucleotide polymorphisms in the first intron of the RGS17 gene. This association was further confirmed in two independent familial lung cancer populations. By quantitative real-time PCR analysis of matched tumor and normal human tissues, we found that RGS17 transcript accumulation is highly and consistently increased in sporadic lung cancers. Human lung tumor cell proliferation and tumorigenesis in nude mice are inhibited upon knockdown of RGS17 levels. Conclusion: RGS17 is a major candidate for the familial lung cancer susceptibility locus on chromosome 6q23-25.

Under most conditions, resorbed bone is nearly precisely replaced in location and amount by new bone. Thus, it has long been recognized that bone loss through osteoclast-mediated bone resorption and bone replacement through osteoblast-mediated bone formation are tightly coupled processes. Abundant data conclusively demonstrate that osteoblasts direct osteoclast differentiation. Key questions remain, however, as to how osteoblasts are recruited to the resorption site and how the amount of bone produced is so precisely controlled. We hypothesized that osteoclasts play a crucial role in the promotion of bone formation. We found that osteoclast conditioned medium stimulates human mesenchymal stem (hMS) cell migration and differentiation toward the osteoblast lineage as measured by mineralized nodule formation in vitro. We identified candidate osteoclast-derived coupling factors using the Affymetrix microarray. We observed significant induction of sphingosine kinase 1 (SPHK1), which catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (S1P), in mature multinucleated osteoclasts as compared with preosteoclasts. S1P induces osteoblast precursor recruitment and promotes mature cell survival. Wnt10b and BMP6 also were significantly increased in mature osteoclasts, whereas sclerostin levels decreased during differentiation. Stimulation of hMS cell nodule formation by osteoclast conditioned media was attenuated by the Wnt antagonist Dkk1, a BMP6-neutralizing antibody, and by a S1P antagonist. BMP6 antibodies and the S1P antagonist, but not Dkk1, reduced osteoclast conditioned media-induced hMS chemokinesis. In summary, our findings indicate that osteoclasts may recruit osteoprogenitors to the site of bone remodeling through SIP and BMP6 and stimulate bone formation through increased activation of Wnt/BMP pathways.