Chromosome 17q12 variants contribute to risk of early-onset prostate cancer

In a recent genome-wide association study by Gudmundsson and colleagues, two prostate cancer susceptibility loci were identified on chromosome 17q. The first locus, at 17q12, was distinguished by two intronic single-nucleotide polymorphisms (SNPs) in the TCF2 gene (rs4430796 and rs7501939). The second locus was in a gene-poor region of 17q24, where the strongest evidence of association was for SNP rs1859962. To determine if these loci were also associated with hereditary prostate cancer, we genotyped them in a family-based association sample of 403 non-Hispanic white families, including 1,015 men with and without prostate cancer. SNPs rs4430796 and rs7501939, which were in strong linkage disequilibrium (r(2) = 0.68), showed the strongest evidence of prostate cancer association. Using a family-based association test, the A allele of SNP rs4430796 was overtransmitted to affected men (P = 0.006), with an odds ratio of 1.40 (95% confidence interval, 1.09-1.81) under an additive genetic model. Notably, rs4430796 was significantly associated with prostate cancer among men diagnosed at an early (<50 years) but not later age (P = 0.006 versus P = 0.118). Our results confirm the prostate cancer association with SNPs on chromosome 17q12 initially reported by Gudmundsson and colleagues. In addition, our results suggest that the increased risk associated with these SNPs is approximately doubled in individuals predisposed to develop early-onset disease. Importantly, these SNPs do not account for a significant portion of our prior prostate cancer linkage evidence on chromosome 17. Thus, there likely exist one or more additional independent prostate cancer susceptibility loci in this region.     

Allelotyping defines minimal imbalance at chromosomal region 17q25 in non-serous epithelial ovarian cancers

Allelic deletions of multiple chromosome 17q loci in sporadic ovarian cancer of epithelial origin suggest that inactivation of tumor suppressor gene(s) in these regions may be important for ovarian tumorigenesis. To further define the pattern of allelic imbalance in epithelial ovarian tumors of different histologies, a PCR-based assay was used to assess loss of heterozygosity (LOH) of polymorphic markers representative of TP53, BRCA1, NME1 and GH1, and region 17q23-25. LOH was observed for at least one marker in 68% of malignant tumors (n=60) and in 18% tumors of borderline malignancy (n=11), but not in benign tumors (n=5). The highest frequency of LOH in malignant tumors (64%) was observed with D17S801 on 17q25. Ten of 39 malignant ovarian tumors displaying LOH of at least one 17q marker, displayed a LOH pattern enabling the determination of a minimal region of overlapping deletion defined by D17S795 and D17S801. One borderline tumor also displayed an interstitial LOH pattern that overlapped this 17q25 minimal region of deletion. The histologies of malignant tumors displaying a pattern indicative of interstitial 17q deletions were of the endometrioid, clear cell and mucinous epithelial types. As the minimal region of overlap defined by these tumors overlap regions deleted in malignant tumors of all histologic types, and in a tumor of borderline malignancy, the 17q25-tumor suppressor may be implicated in the development of all types of epithelial ovarian tumors.     

Multiple genes at 17q23 undergo amplification and overexpression in breast cancer

Studies by comparative genomic hybridization imply that amplification of the chromosomal region 17q22-q24 is common in breast cancer. Here, amplification and expression levels of six known genes located at 17q23 were examined in breast cancer cell lines. Four of them (RAD51C, S6K, PAT1, and TBX2) were found to be highly amplified and overexpressed. To investigate the involvement of these genes in vivo, fluorescence in situ hybridization analysis of a tissue microarray containing 372 primary breast cancers was used. S6K, PAT1, and TBX2 were coamplified in about 10% of tumors, whereas RADS1C amplification was seen in only 3% of tumors. Expression analysis in 12 primary tumors showed that RAD51C and S6K were consistently expressed in all cases in which they were amplified and also in some tumors without amplification. These data suggest that 17q23 amplification results in simultaneous up-regulation of several genes, whose increased biological activity may jointly contribute to the more aggressive clinical course observed in patients with 17q23-amplified tumors.     

染色体8q24和17q24区域与中国人列腺癌的关联分析

目的 探索染色体8q24区域(rs620861C、rs1447295A)和17q24区域(rs185996,G)风险等位基因与北方中国人前列腺癌的关联.了解其基因型与前列腺癌患者表型(年龄、肿瘤分期、PSA水平、Gleason评分、有无良性前列腺肥大)的关联,分析基因之间的交互作用.方法 采用病例-对照设计,收集前列腺癌患者临床表型信息;采用PCR-HRM和测序技术对各位点进行了分型,并对基因型在病例组和正常对照组中的分布进行了年龄匹配的病例-对照间比较(病例组:124人,对照组:138人)及基因交互作用分析;对病例组中基因型在不同临床表型中的分布进行了比较.结果 在病例-对照之间三个风险位点的基因型和等位基因频率分布差异未见有统计学意义;在病例组中各位点与前列腺癌表型之间未见有显著性关联;未能检测到三个风险位点之间有交互作用.结论 染色体8q24区域(rs620861C、rs1447295A)和17q24区域(rs185996G)可能与北方中国人患前列腺癌的遗传风险无关联.     

Expression levels of HER2/neu and those of collocated genes at 17q12-21, in breast cancer

HER2/neu is associated with poorer clinical outcome in breast cancer. Expression patterns of co-localised cancer-associated genes at 17q12-21 were examined using RT-PCR. The study group consisted of a 96-patient cohort. Relative quantity of mRNA expression was calculated using the comparative cycle threshold method and Qbase software. Results were analysed to detect expression patterns among the genes, and to identify associations between expression levels and clinical data. Levels of HER2/neu correlated with those of GRB7 (r=0.551, p<0.001), RARA (r=0.391, p<0.001), RPL19 (r=0.549, p<0.001) and LASP1 (r=0.399, p<0.001). GRB7 was significantly inversely associated with improved DFS at 60 months (p=0.036). RARA levels were greater in HER2/neu-positive as opposed to HER2/neu-negative patients (p=0.021); levels were significantly higher in ER-positive patients, relative to those who were ER-negative (p=0.003). Levels of RPL19 were significantly higher in the HER2/neu-overexpressing (p=0.010) and luminal B subtypes (p=0.007). LASP1 levels were higher in those patients who had been classified clinically as HER2/neu-positive (p=0.004). This study reaffirms the correlation between HER2/neu and the co-localised LASP1 and GRB7; the latter target may hold additional significance in addition to being a surrogate marker for HER2/neu expression. The relationship identified between RARA and ER-positivity may herald an avenue for targeted therapy of these tumours.     

Chromosome rearrangement at 17q25 and xp11.2 in alveolar soft-part sarcoma: A case report and review of the literature.

BACKGROUND: Despite the characteristic histopathologic appearance of alveolar soft-part sarcoma (ASPS), its histogenesis remains unclear, and cytogenetic analysis of ASPS is limited to eight cases so far because of the extreme rarity of this disease. METHODS: The authors document a cytogenetic study of a primary case of ASPS in which a modern spectral karyotyping technique was used. RESULTS: A standard cytogenetic analysis of the primary tumor cells with G-banding revealed 46,XY, add(17)(q25) in 23 of 25 metaphases analyzed. This structural rearrangement of chromosome 17, involving band q25, was also present in 5 of 8 ASPS cases in the literature. Moreover, with the spectral karyotyping technique, the additional part of the long arm of chromosome 17 in the current case was found to originate from chromosome X, resulting in a final tumor karyotype of 46, XY, add(17)(q25).ish der(17)t(X;17) (p11.2;q25)(wcpX+). CONCLUSIONS: This case report documents a clonal chromosome abnormality of der(17)t(X;17)(p11.2;q25) in ASPS. The results of the current study indicate that further molecular analyses focused on 17q25 and Xp11.2 are of interest and could help to elucidate the pathogenesis of ASPS.     

BRCA1 and BRCA2 as ovarian cancer susceptibility genes

Individuals carrying germline mutations in one allele of the BRCA1 or BRCA2 genes are at significantly increased risk of developing cancer. Although the increased risk of breast cancer is often highlighted, cancer at several other sites is also considerably more common in these individuals. Here, we discuss existing knowledge of the role of BRCA1 and BRCA2 mutation in pre-disposition to ovarian cancer. The risk of an individual with a mutation developing cancer of the ovary appears to be influenced by the position of the mutation within the BRCA gene, the presence of allelic variants of modifying genes and the hormonal exposure of the carrier. Once cancer has developed, the pathology and clinical behaviour of BRCA-associated tumours is distinct from sporadic cases. Comparison of the pathogenesis of breast and ovarian cancers caused by BRCA mutation provides insight into the function of BRCA proteins as tumour suppressors in different cellular environments.     

Polymorphisms of the estrogen-metabolizing genes CYP17 and catechol-O-methyltransferase and risk of epithelial ovarian cancer

Because some studies have linked polymorphic variants of the estrogen-metabolizing genes CYP17 and catechol O-methyl transferase (COMT) with risk for hormonally related cancers, we sought to determine whether selected polymorphisms of these genes differed between women with and without ovarian cancer. From a population-based study of ovarian cancer, we analyzed DNA from a total of 480 cases and controls. PCR amplification was performed using primers that amplify restriction sites for MspAI (A2 polymorphism-CYP17) and NlaIII (Val/Met polymorphism-COMT). Digestion of the PCR products was performed. Genotypes identified by gel electrophoresis were assigned as homozygous wild type (WW), heterozygous variant (Wv), and homozygous variant (vv). Frequencies were compared using chi(2) or Fisher's exact tests. Logistic regression was used to calculate crude and adjusted relative risks (RRs) for ovarian cancer associated with possession of any variant allele overall, and within demographic, weight, and smoking history categories, and by histological subtype of ovarian cancer. A portion (68.9%) of cases either carried or was homozygous for the A2 variant of CYP17 compared with 53.9% of controls, for a RR (and 95% confidence interval) of 1.86 (1.26, 2.75; P = 0.003), adjusted for age, parity, oral contraceptive use, site of study, and family history of breast or ovarian cancer. The increased risk was most apparent for women >50 and women with invasive serous cancers. A portion (71.9%) of cases either carried or was homozygous for the Val/Met variant of COMT, compared with 76.9% of controls (P = 0.27). Although the inverse association of ovarian cancer with possession of a Val/Met variant was not significant overall, it was for mucinous tumors of the ovary, with an adjusted RR of 0.28 (0.13, 0.61; P = 0.0012). Possession of the A2 variant of CYP17 appears to increase risk for ovarian cancer, whereas possession of the Val/Met variant of COMT decreases the risk for mucinous tumors. Confirmation in other populations and further exploration of potential pathogenetic mechanisms will be necessary.     

Chromosome 11q13 markers and D-type cyclins in breast cancer

Summary One in six primary human breast cancers has DNA amplification centered on the cyclin D1 gene (CCND1) on chromosome 11q13. This genetic abnormality is preferentially associated with estrogen-receptor positive tumors and may define a sub-class of patients with an adverse prognosis. AlthoughCCND1 has the credentials of a cellular oncogene, being a target for chromosomal translocation and retroviral integration, the 11q13 amplicon encompasses several other markers andCCND1 is not the only candidate for the key gene on the amplified DNA. To assess their relative importance, we have constructed a physical map of the amplified DNA and compared the extent and frequency of amplification across the region. Since it is likely that the gene providing the selective force for amplification will be expressed at elevated levels, we have also examined expression of both RNA and protein. By these criteria, cyclin D1 remains the strongest candidate for the key oncogene on the amplicon and we are currently investigating the functional consequences of its over-expression.Presented by Gordon Peters at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, USA, November 4, 1993; Minisymposium on Molecular Genetics in Breast Cancer.     

Frequent loss of heterozygosity on chromosomes 6q, 11, and 17 in human ovarian carcinomas

Recently, tumor-specific allele loss has been shown to be an important characteristic of some tumors. When such loss includes one or more growth-regulatory genes, it may allow the expression of tumorigenicity. Using Southern blots, we analyzed normal and tumor DNA samples from 19 ovarian cancer patients, using a series of polymorphic DNA probes that map to a variety of chromosomal loci. Of 14 informative cases, tumor-specific allelic loss was observed in nine (64%) at the estrogen receptor (ESR) gene locus on chromosome 6q. On chromosome 17p at the D17S28 and D17S30 loci, allelic losses were also detected in 6 of 8 (75%) and 9 of 14 (64%) cases, respectively. Allelic loss at the HRAS1 gene locus on chromosome 11p occurred in 5 of 11 (46%) informative cases. The relatively high incidence of these allelic losses observed on chromosome 6q represents the first implication by molecular genetic analysis of this chromosomal region in a human malignancy, and it thus appears to be a genetic change specific to ovarian carcinoma. DNA sequence losses on 11p and 17p, also reported for other cancers, may reflect the presence of tumor- or growth-suppressor genes on these chromosomes that are important in the genesis of many tumor types, including ovarian malignancies.     

胶质母细胞瘤染色体10q可能存在多个肿瘤抑制基因

目的寻找胶质母细胞瘤10号染色体长臂(10q)上可能存在肿瘤抑制基因的杂合性缺失(LOH)区域,为发现和定位肿瘤抑制基因提供线索和依据。方法应用聚合酶链反应(PCR)方法分析10例胶质母细胞瘤(GBM)染色体10q上9个微卫星多态性标记的LOH。结果在90%(9/10)肿瘤组织染色体10q上检出LOH,在71%(35/49)可提供信息的位点上观察到LOH。以在10q     

The 17q23 amplicon and breast cancer

A novel region of amplification in breast tumors was recently identified on chromosome 17q23. Extensive mapping of the amplicon by Southern blotting and fluorescence in situ hybridization (FISH) in breast cancer cell lines determined that the amplicon can be up to 4 Mbp in size and may contain 50 genes. Copy number analysis at 50–75 kb resolution in breast cancer cell lines and breast tumors identified several independently amplified regions within the amplicon, suggesting that a number of genes are selected for amplification because they independently contribute to tumor formation and progression. Support for this hypothesis comes from studies demonstrating that many of the amplified genes are over-expressed in breast cancer cell lines and tumors, and that the RPS6KB1, TBX2, and PPM1D genes from the region, that are amplified and over-expressed in breast tumors and cell lines, contribute to tumor formation and/or tumor progression. In this review we summarize the structural studies of the amplicon that have been carried out, we outline the evidence implicating the RPS6KB1, TBX2, and PPM1D genes as oncogenes, and we describe some of the other candidate oncogenes from the region.     

Patterns of expression of chromosome 17 genes in primary cultures of normal ovarian surface epithelia and epithelial ovarian cancer cell lines

Oligonucleotide microarray analysis was applied to assess the expression profile of 332 probe sets representing 308 genes or expressed sequence tags (ESTs) that map to chromosome 17 in order to address epigenetic events that result in alterations in gene expression in epithelial ovarian cancer (EOC). Expression profiles were generated from 12 primary cultures derived from normal ovarian surface epithelium (NOSE) and four long-term cultures (TOV-81D, TOV-112D, TOV-21G and OV-90) derived from EOCs that have been previously characterized and shown to mimic features of the tumoral cells from which they were derived. The expression values of all 332 probe sets is highly correlated across the 12 NOSEs (89% correlation coefficients >0.90). In two-way comparisons, differential patterns of gene expression were observed for 157 probe sets for which the expression value of at least one EOC cell line fell outside the limits of the range of expression of the 12 NOSEs. When compared to NOSEs, four genes displayed similar differential patterns of gene expression across all four EOC cell lines, and 26 genes displayed similar differential patterns of gene expression across the three EOC cell lines (TOV-112D, TOV-21G and OV-90) representing tumoral cells derived from the most aggressive disease. A total of 17 genes displayed differential patterns of gene expression greater than threefold in at least one EOC cell line in comparison to NOSE, and three genes were differentially expressed greater than threefold across all aggressive cell lines. The analysis of a selected number of genes by RT-PCR revealed patterns of gene expression comparable to those observed by microarray analysis in the majority of samples tested. Comparison of expression profiles of differentially expressed genes identified by microarray analysis in two-way comparisons of the EOC cell lines and the NOSEs with published reports revealed 10 genes previously implicated in ovarian tumorigenesis and 18 in tumorigenesis of other types of cancer. The differential pattern of gene expression of genes that map to both the p and q arm of chromosome 17 is consistent with the hypothesis that a number of genes that map to this chromosome are implicated in the etiology of ovarian cancer.     

Chromosome 15q24-25.1 variants,diet, and lung cancer susceptibility in cigarette smokers

Background  

Studying gene–environment interactions may provide insight about mechanisms underpinning the reported association between chromosome 15q24-25.1 variation and lung cancer susceptibility.     

Early loss of heterozygosity on 17q in ovarian cancer. The Abe Ovarian Cancer Genetics Group.

We have studied 146 ovarian tumours (94 carcinomas, 22 tumours of low malignant potential and 30 benign tumours) for evidence of allele loss on chromosome 17p and 17q sufficient to imply the proximity of a tumour-suppressor gene. We have examined two polymorphic loci (YNZ22.2 and BHP53) on 17p13 and one on chromosome 17q (17q23-qter). Loss of heterozygosity (LOH) was detected in 34/63 (54%) informative malignant tumours at YNZ22.2 and 22/47 (47%) at BHP53; on 17q, 45/64 (70%) had LOH. Allele loss was detected in a small number of benign and borderline tumours. There was a statistically significant difference between the patterns of allele loss in serous and endometrioid groups of tumours, and allele loss occurred with significantly greater frequency on 17q than on 17p. Comparison of all malignant tumours presenting with either localized (FIGO stage I/II) or widespread (FIGO stage III/IV) disease showed that, particularly on 17q, allele loss increases in the more advanced stages. The p53 tumour-suppressor gene is implicated in ovarian carcinogenesis, and our findings suggest that an important tumour-suppressor gene may be located in the region 17q23-qter. Loss of function in this gene may be responsible for the frequently observed rapid progression of serous-type adenocarcinomas to an advanced stage.