Potential location of a bladder tumor suppressor gene on chromosome 9q at 9q13 to 9q22.1

Allelic losses involving chromosome 9q occur in a significant percentage of bladder tumors. Experimental evidence suggests that a putative tumor suppressor gene located on this chromosome may play a role in the development of bladder cancer. The precise location of this potential tumor suppressor gene is not clear. Previous studies have targeted a large region between 9p12-13 and 9q22 or 9p12 and 9q34.1 as the likely site. To further delineate the location of this gene, we examined 49 tumors by loss of heterozygosity (LOH) analysis, using seven microsatellite polymorhpic loci spanning from 9p21 to 9q34 of the chromosome. LOH was found in at least one of the loci in 20 (41%) of the tumors examined, and the majority (12 of 17; 71%) of the losses on 9q involved large segments or the entire chromosome arm. Although many of the tumors with large losses on 9q also involved 9p21, several tumors with small losses did not involve the 9p marker. Conversely, there were tumors with 9p21 losses that did not involve the q-arm. These data agree with recent findings that distinct tumor suppressor genes associated with bladder cancer are located on separate arms of chromosome 9. Among tumors with single locus LOHs, the most common deletion was located in 9q 13-21.2, which was detected by probe D9S15. This also is the smallest area of critical loss when LOH patterns of tumors with partial or interstitial losses were examined. Results of the study therefore suggest that a potential tumor suppressor gene may reside within or near the region of 9q13-22.1.     

Myeloid Neoplasms with inv(3)(q21q26.2) or t(3;3)(q21;q26.2)

Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) [inv3/t(3;3)] is a distinct entity under the subgroup of AMLs with recurrent genetic abnormalities in the 2008 World Health Organization classification. Myelodysplastic syndrome (MDS) with inv3/t(3;3) has a high risk of progression to AML. AML and MDS with inv3/t(3;3) have a similarly aggressive clinical course with short overall survival (OS) and are commonly refractory to therapy. In this article, clinical and pathologic features and prognosis in AML and MDS with inv3/t(3;3) are reviewed, and other myeloid neoplasms with similar dysplastic features to be differentiated from AML and MDS with inv3/t(3;3) are discussed.     

Clinical significance of chromosome 8p, 10q,and 16q deletions in prostate cancer

BACKGROUND: We lack simple and reliable diagnostic tools to predict pathological staging as well as further progression of prostate cancer in individual cases. METHODS: We studied deletions on 8p (8p22 and 8p23-pter), 10q (10q24-qter), and 16q (16q24) by fluorescence in situ hybridization in 53 specimens from patients with prostate cancer, and compared the status of these deletions with various clinical parameters. Forty-five cases were further evaluated regarding disease progression with a median follow-up period of 62 months. RESULTS: The overall frequencies of deletions for 8p, 10q, and 16q were 74, 55, and 55%, respectively. The frequency of 8p and 16q deletions increased significantly in parallel with tumor grade (P < 0.01 and < 0.05, respectively), while that of 10q deletions did not. Patients whose tumors showed 8p22 deletions had a significantly higher frequency in pT3 or metastatic tumors than in pT2 tumors. Patients whose tumors showed both 8p22 and 16q24 deletions had a significantly higher frequency of nodal metastases than non-metastases. A Cox hazard proportional model revealed 8p22 deletion to be the strongest parameter predictive of disease progression (hazard ratio = 6.624; P = 0.0001). CONCLUSION: Estimation of 8p22 and 16q24 deletions may serve as a genetic diagnosis for predicting pathological staging as well as disease progression in prostate cancer.     

8q24 and 17q Prostate cancer susceptibility loci in a multiethnic Asian cohort

ObjectivesRecently, several genome-wide association studies have demonstrated a cumulative association of 5 polymorphic variants in chromosomes 8q24 and 17q with prostate cancer (CaP) risk in Caucasians, particularly those harboring aggressive clinicopathologic characteristics. The purpose of this study was to evaluate the influence of these variants on CaP susceptibility in Singaporean Asian men.Materials and methodsWe performed a case-control study in 289 Chinese CaP patients and 412 healthy subjects (144 Chinese, 134 Malays, and 134 Indians), and examined the association of the 5 single nucleotide polymorphisms (SNPs) with CaP.ResultsIn the healthy subjects, rs16901979 A-allele frequency was highest amongst Chinese (0.32) compared with Malays (0.13; P < 0.0001) or Indians (0.09; P < 0.0001); rs6983267 G-allele was highest in Indians (0.51) compared with Chinese (0.42; P = 0.041) or Malays (0.43; P = 0.077); whereas rs1859962 G-allele frequency was highest amongst Indians (0.56) compared with Chinese (0.40; P = 0.0002) or Malays (0.38; P < 0.0001). Individuals with the rs4430796 TT genotype were at increased CaP risk in the Chinese via a recessive model (odds ratios (OR) = 1.56, 95% CI = 1.04–2.33). Significant associations were observed for rs4430796 TT with Gleason scores of ≥7 (OR = 1.76, 95% CI = 1.14–2.73) and prostate-specific antigen (PSA) levels of ≥10 ng/ml at diagnosis (OR = 1.63, 95% CI = 1.01–2.63), as well as for rs6983267 GG with stage 3–4 CaPs (OR = 1.91, 95% CI = 1.01–3.61). A cumulative gene interaction influence on disease risk, which approximately doubled for individuals with at least 2 susceptibility genotypes, was also identified (OR = 2.18, 95% CI = 1.10–4.32).ConclusionsThis exploratory analysis suggests that the 5 genetic variants previously described may contribute to prostate cancer risk in Singaporean men.     

C1q肾病的诊断及治疗

C1q肾病是一种以系膜增生为主的肾小球疾病,其特点为免疫荧光染色可见系膜区高强度C1q沉积,电镜下可见系膜区电子致密物沉积,根据组织病理学特点主要分为3类,包括微小病变(MCD)、局灶节段性肾小球硬化(FSGS)和免疫介导的增生性肾小球肾炎。C1q肾病的临床表现具有多样性,可表现为肾炎或肾病范围内蛋白尿,伴有或不伴有血尿和肾功能损伤。虽然目前糖皮质激素是治疗C1q肾病的主要方法,但多数研究认为C1q肾病对糖皮质激素治疗反应较差。中西医结合治疗有望提高C1q肾病的疗效。     

Peak bone mineral density at the hip is linked to chromosomes 14q and 15q

A major determinant of osteoporotic hip fracture is peak hip BMD which is a highly heritable trait. Caucasian American women have lower BMD and higher hip fracture rates than African American women. This study examines linkage of hip BMD in 570 Caucasian sister pairs and 204 African American sister pairs. It compares the results with our published study in a smaller overlapping sample of Caucasian sisters. Hip BMD was measured at neck, trochanter, Wards, shaft, and total hip. Principal component analysis provided a novel BMD phenotype comprising neck and trochanter, common sites of fracture, and Wards, site of lowest BMD. A 9 cM genome scan was performed for these phenotypes. Significant linkage was found at chromosomes 14q and 15q. At 14q, the 774 African American and Caucasian sister pairs together yielded the highest LOD score for trochanter (3.5) and at 15q the highest LOD score for femoral neck (4.3). This linkage study in Caucasian and African American healthy premenopausal sisters demonstrates that chromosomes 14q and 15q harbor genes that affect peak bone mass at the hip in women. Principal component had comparable LOD scores with those of the component phenotypes suggesting pleiotropic effects of these genes on hip phenotypes.     

抗C1q抗体与狼疮性肾炎

系统性红斑狼疮(SLE)患者血清中超过150种自身抗体,研究发现SLE病人血清有另一种重要的补体成分C1q的抗体,即抗C1q抗体.该抗体普遍存在于SLE病人血清中,并与肾脏受累有关,且抗体滴度增加提示肾炎复发.本文就抗C1q抗体在狼疮性肾炎(LN)诊断、随访、早期识别狼疮活动以及复发等方面作用作一综述.     

Allelic losses at 8p, 10q, 11p, 13q, 16q, 17p,and 18q in prostatic carcinomas: The impact of zonal location,Gleason grade,and tumour multifocality

Molecular genetic investigations have made it clear that the development and progression of prostate cancer is associated with losses of genetic material in certain chromosomal arms. However, there are only few data about the question of whether the zonal location, a higher Gleason grade, or multifocality of the tumour have any influence on the pattern of allelic losses. In the present study, 48 tumour foci from 32 radical prostatectomy specimens were investigated for allelic losses at chromosomes 8p, 10q, 11p, 13q, 16q, 17p, and 18q with a set of 20 microsatellite markers. The results were analysed for the zonal location of the tumour foci and the presence of a Gleason grade 4 differentiation. Overall, focal allelic losses at 8p, 10q, 11p, 13q, 16q, 17p, and 18q were observed in 62.5%, 17.2%,. 3.2%, 18.8%, 40%, 9.7%, and 22.6% of the 32 cases, respectively. Comparing the frequencies of allelic losses with the zonal location or the Gleason grade, no highly significant correlations were found at any chromosomal locus investigated. However, the observation of different patterns of allelic losses in 12 of 14 cases containing more than one tumour focus indicates a high rate of genetic heterogeneity. We conclude that allelic losses at the chromosomal loci investigated are not strongly associated with a specific zonal location or a higher Gleason grade of prostatic carcinoma. Genetic heterogeneity of multiple tumour foci within one gland might contribute to the difficulties in predicting the prognosis for this common malignancy.     

Current status and issues of C1q nephropathy

C1q nephropathy, first proposed by Jennette and Hipp [Am J Clin Pathol 83:415-420, 1985; Am J Kidney Dis 6:103-110, 1985], was described as a distinct glomerular disease entity characterized by extensive mesangial deposition of C1q, with associated mesangial immune complexes, and the absence of any clinical and laboratory evidence of systemic lupus erythematosus. Now, 20 years since the first report, the disease entity is gradually attaining recognition, particularly in the field of pediatrics. C1q is the subcomponent of C1 in the classical pathway of complement activation. Generally, C1q deposition is caused by the activation of C1 by immunoglobulin G (IgG) and IgM; therefore, C1q nephropathy is considered as an immune complex glomerulonephritis. However, in C1q nephropathy, it remains unclear whether the deposition of C1q in the glomeruli is in response to the deposition of immunoglobulin or immune complex, or whether deposition is non-specific trapping that accompanies increased glomerular protein trafficking associated with proteinuria. Since not only the pathogenesis of C1q deposition in glomeruli but also its significance are still uncertain, it has not yet been established as an independent disease. From recent publications of the clinical and pathological characterizations, C1q nephropathy has been thought to be a subgroup of primary focal segmental glomerular sclerosis. However, many reports describe different symptoms, histopathologies, therapeutic responses and prognoses, suggesting that C1q nephropathy is not a single disease entity, but that it may be a combination of several disease groups. There are many uncertain areas requiring further investigation, though it is hoped that a detailed examination of future cases will clarify the subgroups making up C1q nephropathy and their clinicopathological characteristics, and will lead to the establishment of C1q nephropathy as an independent disease entity.     

Association between sequence variants at 17q12 and 17q24.3 and prostate cancer risk in European and African Americans

BACKGROUND: Three SNPs at 17q12 and four SNPs at 17q24.3 were recently identified to be associated with prostate cancer risk using a genome-wide association study. METHODS: We evaluated these 7 SNPs in two hospital-based case-control study populations, including European Americans (EA; 1,563 cases and 576 controls) and African Americans (AA; 364 cases and 353 controls). RESULTS: Each of the reported risk alleles of these seven SNPs were more common in cases than in controls among EA and AA. The differences were highly significant in EA (P = 10(-4)) and marginally significant in AA (P = 0.04) for SNPs at 17q12. In contrast, the differences were not statistically significant in EA or AA for SNPs at 17q24.3, but were marginally significant for two SNPs (P = 0.04-0.06) when EA and AA subjects were combined. Similar results were obtained when genotype and haplotype frequencies between cases and controls were analyzed. These risk variants were not associated with more aggressive prostate cancer or other clinical variables such as TNM stage, pre-operative PSA, or age at diagnosis. CONCLUSIONS: Results from our study provide the first confirmation of these 17q SNPs as novel prostate cancer susceptibility loci in EA and the first indication that these two loci may also play roles in prostate cancer risk among AA.     

Linkage and linkage disequilibrium mapping of genes influencing human obesity in chromosome region 7q22.1-7q35

Linkage results suggest that the region of chromosome 7 containing the leptin gene cosegregates with extreme obesity; however, leptin coding region mutations are rare. To investigate whether the leptin flanking sequence and/or a larger 40-cM region (7q22.1-7q35) contributes to obesity, we genotyped individuals from 200 European American families segregating extreme obesity and normal weight (1,020 subjects) using 21 microsatellite markers and two single nucleotide polymorphisms (SNPs) and conducted nonparametric linkage (NPL) analyses. We also carried out transmission disequilibrium tests for 135 European American triads using 27 markers (including eight SNPs). Both quantitative (MERLIN-regress) and qualitative (GENEHUNTER and MERLIN-npl) analyses provided evidence for linkage for BMI (GENEHUNTER NPL = 2.98, 20 cM centromeric to leptin at the marker D7S692; MERLIN Z score = 3.56). Results for several other regions in 7q gave weak linkage. Transmission disequilibrium test (TDT) and quantitative TDT (and quantitative pedigree disequilibrium test) analyses suggest linkage disequilibrium near leptin and other regions of 7q. Our results suggested that there could be two or more genes in chromosome region 7q22.1-7q35 that influence obesity. A new region found by this study (D7S692-D7S523, 7q31.1) has the most consistent linkage results and could harbor obesity-related genes.     

Loss of heterozygosity at 13q14 and 13q21 in high grade, high stage prostate cancer.

BACKGROUND: Loss of heterozygosity (LOH) at chromosome 13q has been frequently detected in prostate cancer, and three regions (i.e., 13q14, 13q21, and 13q33) may harbor tumor suppressor genes important in this neoplasm. In this study, we examined the frequency of 13q LOH in advanced prostate cancers, in order to determine the clinicopathologic relevance of 13q LOH. METHODS: LOH was determined by analyzing microsatellite markers in 41 cases of microdissected predominantly high grade prostate cancer tissues and their matched nonneoplastic cells. The results were compared with those generated previously for lower grade, asymptomatic cancers. RESULTS: The frequencies of LOH at 13q14, 13q21, and 13q33 were 62% (21/34), 57% (20/35), and 34% (11/32), respectively. In comparison to previous results, LOH at 13q14 and 13q21 but not 13q33 was more frequent in prostate cancers that produced local clinical symptoms (bladder outlet obstruction) than those that did not (P < 0.05). LOH at 13q14 was also significantly more frequent in high grade and high stage cancers than those that were lower grade and lower stage (P < 0.05). CONCLUSIONS: Although the target genes on 13q have not been identified in carcinomas of the prostate, LOH at 13q14 in particular is associated with clinically significant prostate cancers. Further fine mapping of these loci may lead to identification of tumor suppressor genes that are deleted in aggressive carcinomas of the prostate.     

Genome-wide association meta-analyses identified 1q43 and 2q32.2 for hip Ward's triangle areal bone mineral density

Aiming to identify genomic variants associated with osteoporosis, we performed a genome-wide association meta-analysis of bone mineral density (BMD) at Ward's triangle of the hip in 7175 subjects from 6 samples. We performed in silico replications with femoral neck, trochanter, and inter-trochanter BMDs in 6912 subjects from the Framingham heart study (FHS), and with forearm, femoral neck and lumbar spine BMDs in 32965 subjects from the GEFOS summary results. Combining the evidence from all samples, we identified 2 novel loci for areal BMD: 1q43 (rs1414660, discovery p = 1.20 × 10^− 8, FHS p = 0.05 for trochanter BMD; rs9287237, discovery p = 3.55 × 10^− 7, FHS p = 9.20 × 10^− 3 for trochanter BMD, GEFOS p = 0.02 for forearm BMD, nearest gene FMN2) and 2q32.2 (rs56346965, discovery p = 7.48 × 10^− 7, FHS p = 0.10 for inter-trochanter BMD, GEFOS p = 0.02 for spine BMD, nearest gene NAB1). The two lead SNPs rs1414660 and rs56346965 are eQTL sites for the genes GREM2 and NAB1 respectively. Functional annotation of GREM2 and NAB1 illustrated their involvement in BMP signaling pathway and in bone development. We also replicated three previously reported loci: 5q14.3 (rs10037512, discovery p = 3.09 × 10^− 6, FHS p = 8.50 × 10^− 3, GEFOS p = 1.23 × 10^− 24 for femoral neck BMD, nearest gene MEF2C), 6q25.1 (rs3020340, discovery p = 1.64 × 10^− 6, GEFOS p = 1.69 × 10^− 3 for SPN-BMD, nearest gene ESR1) and 7q21.3 (rs13310130, discovery p = 8.79 × 10^− 7, GEFOS p = 2.61 × 10^− 7 for spine BMD, nearest gene SHFM1). Our findings provide additional insights that further enhance our understanding of bone development, osteoporosis, and fracture pathogenesis.