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Biomedical subjects

N Wong

Publications and source records attributed to N Wong.

At least 19 recordsLinked to original sources
PubMed2005

Cyclin E expression in breast cancer: predicting germline BRCA1 mutations, prognosis and response to treatment.

BACKGROUND: Elevated levels of the cell cycle protein cyclin E, and low levels of its inhibitor, p27(Kip1), have been associated with a poor prognosis following breast cancer. Some studies have found that germline mutations in the breast cancer susceptibility gene, BRCA1, are also associated with an inferior survival rate. The relationship between cyclin E/p27(Kip1) levels, BRCA1 status and outcome has not been studied in detail. PATIENTS AND METHODS: We analyzed a historical cohort of 288 Ashkenazi Jewish women who were diagnosed with breast cancer between 1980 and 1995 and were previously tested for BRCA1/2 mutations. Protein levels of cyclin E and p27(Kip1) were assessed by immunohistochemistry. Breast cancer-specific survival (BCSS) was the main outcome measured. RESULTS: The median follow-up was 8 years. Thirty tumors carried germline BRCA1 mutations. These tumors were more likely to have high cyclin E protein levels [odds ratio (OR) 9.5; P <0.001] and low p27(Kip1) protein levels (OR 2.8; P=0.03) than tumors from patients without BRCA1/2 mutations. High cyclin E expression level was the strongest predictor of BRCA1 germline mutations (multivariate OR 4.7; P=0.004). On univariate analysis, high cyclin E protein levels [relative risk (RR) 2.6; P <0.001] and low p27(Kip1) protein levels (RR 2.3; P=0.006) were significant prognostic factors for a poorer BCSS. In Cox multivariate models, high cyclin E levels remained an independent indicator of poor outcome only in the subgroup of patients who did not receive chemotherapy (P=0.002). CONCLUSIONS: In this ethnically restricted cohort, a high level of cyclin E is a characteristic of BRCA1-related breast cancer, and is a marker of poor prognosis following breast cancer, particularly in the absence of adjuvant chemotherapy.

Adult↗
PubMed2005

Novel genomic insertion-- deletion in MLH1: possible mechanistic role for non-homologous end-joining DNA repair.

Hereditary non-polyposis colorectal cancer (HNPCC) is an inherited cancer syndrome caused by a defect in the mismatch repair pathway. The majority of HNPCC mutations have been detected in MLH1 and MSH2. Most reported mutations are substitutions, small insertions and deletions, but standard methods of mutation analysis do not detect large rearrangements. It is now established that large deletions, insertions and rearrangements account for a significant proportion of MLH1 and MSH2 mutations. We report an unusual rearrangement resulting in the deletion of exons 6, 7 and 8 of MLH1, with the retention of part of intron 6 and insertions of two nucleotides each flanking the retained sequence. The 349-bp-retained sequence is made up of two closely spaced Alu sequences. The mutation was initially detected by protein truncation test and cDNA sequencing. Multiplex ligation-dependent probe amplification confirmed the deletion of three exons. PCR and sequencing were used to characterize the breakpoint. Despite the high density of Alu elements in MLH1, there is no homology at the deletion breakpoints or insertion junctions in this case to suggest that homologous recombination has occurred. We propose a mechanism involving non-homologous end joining to explain the occurrence of this complex deletion.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Distinct patterns of genetic alterations in adenocarcinoma and squamous cell carcinoma of the lung.

Squamous cell carcinoma (SqC) and adenocarcinoma (AdC) are the two most common subtypes of non-small cell lung cancer (NSCLC). Cumulative information suggests that the SqC and AdC subtypes progress through different carcinogenic pathways, but the genetic aberrations promoting such differences remain unclear. Here we have assessed the overall genomic imbalances and structural abnormalities in SqC and AdC. By parallel analyses with comparative genomic hybridisation (CGH) on tumorous lung tissues and spectral karyotyping (SKY) on short-term cultured primary tumours, genome-wide characterisation was carried out on 69 NSCLC (35 SqC, 34 AdC). Molecular cytogenetic characterisation indicated common and distinct genetic changes in SqC and AdC. Common events of +1q21-q24, +5p15-p14, and +8q22-q24.1, and -17p13-p12 were found in both groups, although hierarchical clustering simulation on CGH findings depicted +2p13-p11.2, +3q25-q29, +9q13-q34, +12p, +12q12-q15 and +17q21, and -8p in preferential association with SqC pathogenesis (P<0.05). Corresponding SKY analysis suggested that these changes occur in simple and complex rearrangements, and further indicated the clonal presence of translocation partners leading to chromosomal over-representations. These recurring rearrangements involved chromosome pairs of t(1;13), t(1;15), t(7;8), t(8;15), t(8;9), t(2;17) and t(15;20). Of particular interest was the finding that the t(8;12) translocation partner was exclusive to AdC. The combined application of SKY and CGH has thus uncovered the genome-wide chromosomal aberrations in NSCLC. Specific chromosomal imbalances and translocation partners found in SqC and AdC have highlighted regions for further molecular investigation into gene(s) that may hold importance in the carcinogenesis of NSCLC.

Adenocarcinoma↗
PubMed2004

Putative common origin of two MLH1 mutations in Italian-Quebec hereditary non-polyposis colorectal cancer families.

Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited cancer syndromes, accounting for 3-5% of all cases of colorectal cancer. In most HNPCC families, the disease is caused by a germline mutation in MLH1 or MSH2. In some populations, founder mutations appear to explain a substantial fraction of HNPCC. We report here the identification and preliminary characterization of two putative MLH1 founder mutations. The mutation MLH1c.1831delAT was shown to segregate in two Quebec families of Italian origin who fulfilled the Amsterdam criteria for HNPCC. Haplotype analysis using five intragenic microsatellite/single nucleotide polymorphism markers spanning MLH1 on chromosome 3 showed that these two unrelated families share an identical haplotype. In addition, two other Italian kindred whose affected members carry MLH1g.IVS6 + 3A>G also share a common haplotype, suggesting that, similarly, the latter mutation has a common origin. These mutations are the first putative founder MLH1 mutations to be identified in HNPCC kindred of Italian origin.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Glomeruloid microvascular proliferation is associated with p53 expression, germline BRCA1 mutations and an adverse outcome following breast cancer.

Glomeruloid microvascular proliferation (GMP) in breast cancer independently adversely affected survival (relative risk 1.9, 95% CI: 1.2-3.0), particularly among women who received adjuvant chemotherapy (10-year survival 27 vs 69%, P=0.0003), and was significantly associated with p53 overexpression and BRCA1 germline mutations. The presence of GMP may influence treatment decisions.

Adult↗
PubMed2001

Nonrandom chromosomal imbalances in human ovarian surface epithelial cells immortalized by HPV16-E6E7 viral oncogenes.

We had previously immortalized human ovarian surface epithelial (HOSE) cells using HPV16E6E7 ORFs. In order to identify crucial genetic events involved during cell immortalization, the genomic profile of immortalization of five HOSE cell lines was analyzed by comparative genomic hybridization. Our results showed that chromosomal imbalance was common in HOSE cells after immortalization. The common chromosomal imbalances identified in immortal HOSE cells are: +19q13.1 (5/5 lines), -13q12 approximately qter (4/5 lines), +5q15 approximately q33 (3/5 lines), +20q11.2 approximately q13.2 (3/5 lines) and -22q11.2 approximately qter (3/5 lines). Other chromosomal imbalances, which were detected in two of the five immortal HOSE cell lines, included gains on chromosome 1 and 11q12 approximately q13, and losses on 2p, 4q, 8p, 10p and 11q14 approximately qter. The chromosomal imbalances observed in HOSE cells before immortalization include -8pter approximately p11.2, -11q23 approximately qter, -13q12 approximately qter and +19 which may represent early genetic events during cell immortalization. The genomic profile was examined in one HOSE cell line (HOSE 6-3) at various stages of immortalization. The genomic profiles of HOSE 6-3 cells after crisis were largely stable. A few additional chromosomal imbalances were detected in the immortalized HOSE cells after an extensive culture period including +11pter approximately q23, -15q23 approximately qter, and +17q12 approximately qter. Identification of nonrandom chromosomal imbalance in immortalized HOSE cells may facilitate the identification of specific chromosomes harboring genes involved in the immortalization of human ovarian surface epithelial cells.

Cell Line↗
PubMed2001

CD44-initiated cell spreading induces Pyk2 phosphorylation, is mediated by Src family kinases, and is negatively regulated by CD45.

CD44 is a cell adhesion molecule implicated in leukocyte adhesion and migration, co-stimulation of T cells, and tumor metastasis. CD45 is a leukocyte-specific protein tyrosine phosphatase that dephosphorylates the Src family kinases, Lck and Fyn, in T cells. Positive regulation of Lck by CD45 is required for its effective participation in T cell receptor signaling events. Here, immobilized CD44 antibody induced a distinctive cell spreading in CD45(-), but not CD45(+), T cells, and this correlated with the induction of tyrosine-phosphorylated proteins. Two focal adhesion family kinases, Pyk2 and, to a lesser extent, FAK were inducibly phosphorylated, as was a potential substrate, Cas. CD44-mediated cell spreading and induced tyrosine phosphorylation were prevented by the Src family kinase inhibitor, PP2. Furthermore, 2-fold more Lck associated with CD44 in the low density sucrose fraction from CD45(-) T cells compared with CD45(+) T cells, suggesting that CD45 may regulate the association of Lck with CD44 in this fraction. Therefore, in CD45(-) T cells, CD44 signaling is mediated by Src family kinases, and this leads to Pyk2 phosphorylation, cytoskeletal changes, and cell spreading. This implicates CD45 in the negative regulation of Src family kinase-mediated CD44 signaling leading to T cell spreading.

Animals↗
PubMed2001

Establishment and characterization of a new xenograft-derived human esophageal squamous cell carcinoma cell line SLMT-1 of Chinese origin.

A new human esophageal cancer cell line, named SLMT-1, was established from a nude-mouse xenograft of a well-differentiated esophageal squamous cell carcinoma (ESCC) of the lower esophagus from a male Hong Kong Chinese patient. SLMT-1, passaged over 34 times and with a doubling time of 31 hours, has the microscopic features of epithelial cells with adherent growth as a monolayer. The general biologic properties of SLMT-1 cells were characterized by (1) a positive test of tumorigenicity obtained by injecting cells subcutaneously into athymic nude mice and observing their development into well-differentiated squamous cell carcinoma; (2) immunohistochemical staining using antibodies (AE1/AE3, CAM5.2 and MAK 6) which show the presence of cytokeratin intermediate filaments; and (3) electron microscopy demonstrating the morphologic features of epithelial cells with the presence of desmosomes. The cytogenetic abnormalities found in both the primary culture and SLMT-1 included der(1;14)(q10;q10), add(1)(p1?), +1, +2, del(3)(q11), +6, +7, i(8)(q10), +8, +10, +11, -13, -15, +16, +17, -18, -19, -Y and marker chromosomes. Additional changes observed in the 34th passage included gains as well as losses of both numerical and structural abnormalities. Comparative genomic hybridization (CGH) indicated copy number gains on chromosomal regions 3q32-qter, 5p, 8p12-p11.2, 11q13-q22 and 13q22-qter, and loss of the Y. The gains of 8p12-p11.2 in SLMT-1 cells are novel to ESCC. Based on its distinct and common characteristics, the SLMT-1 cell line serves as a useful tool for studying the molecular and genetic basis of the pathogenesis of ESCC.

Animals↗
PubMed2001

Genetic imbalances in pT2 breast cancers of southern Chinese women.

While much information has been reported on the genetic alterations in breast cancers of Caucasians, little is known about the Oriental populations where breast cancers currently rank the second most common neoplasm. As a first step toward understanding the underlying genetics changes in this population, we used comparative genomic hybridization (CGH) to the genome-wide analysis of forty pT2 tumors from patients of a racially homogenous population in southern China. A complex pattern of genetic alterations emerged with the commonest chromosomal gains identified on 1q (58%), 8q (55%), 11q13 (25%), 16p (28%), 17q (53%) and 20q (35%), and frequent losses on 8p (38%), 11q (28%), 13q (30%) and 18q (25%). When breast cancers with and without lymph-node metastasis were compared, a higher copy gain of 10p was identified in the node-positive group (P=.036). An overall increase in the average number of genetic aberrations was also identified in the late onset group (>45 years)(P=.042) with a higher incidence of genetic losses noted (P=.035). In particular, losses on 16q were detected in 30% of the late onset patients but none in the early onsets (P=0.049). In this study, we have illustrated the pattern of genetic changes in breast tumors of southern Chinese females. While frequent 1q, 8q, 17q and 20q gains, and common 8p and 13q deletions detected were consistent to those aberrations reported from the Caucasian populations, the difference in genetic changes associated in lymph-node metastasis and age of onset identified should provide the basis for additional investigations into the underlying tumorigenesis in the Oriental population.

Adult↗
PubMed2001

Genetic counseling and interpretation of genetic tests in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer.

PURPOSE: Genetic counseling and interpreting genetic test results can be complex. Moreover, without knowing the limitations of the methods used and the lifetime probability of developing cancer in individuals who carry a gene that predisposes to cancer, misinterpretation may lead to false assurance. The purpose of this review is to discuss how genetic counseling will benefit patients and their family, the genetic tests available for hereditary colorectal cancer syndromes, and the interpretation of results. METHODS: Current literature was reviewed and our clinical and research experiences were incorporated. RESULTS: This review serves as a guide to enable various health care providers to better counsel patients in their quest for advice on prevention, early detection, and surveillance for colorectal cancer. Notable topics of discussion are who should undergo genetic counseling and consider testing and how the interpretation of test results can be misleading; for example, understanding the difference between a no mutation detected vs. a negative test result. CONCLUSIONS: Genetic counseling is of paramount importance for patients to fully understand the limitations of genetic testing and will aid in the management of patients who are susceptible to colorectal cancer.

Adenomatous Polyposis Coli↗
PubMed2001

Role of molecular diagnostic testing in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer families.

PURPOSE: Genetic tests are available for familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. The goal of this review was to develop an algorithm for application of molecular diagnostic techniques to the management of hereditary colorectal carcinoma and to familiarize the clinician with the vocabulary of molecular genetic testing for hereditary colorectal carcinoma. METHODS: Studies examining the clinical use of genetic testing for hereditary colorectal carcinoma syndromes are evaluated. Recent advances in molecular genetic technology are reviewed, and clinical management as practiced here and elsewhere is outlined. RESULTS: This review is a guide to the most reliable molecular diagnostic techniques. Three key questions are answered: who, when, and how to test. CONCLUSIONS: When integrated with existing testing protocols for colorectal carcinoma and when applied with appropriate caveats, particularly regarding interpretation of negative results, genetic testing can result in improved management of patients and families.

Adenomatous Polyposis Coli↗
PubMed2001

Hypomethylation of chromosome 1 heterochromatin DNA correlates with q-arm copy gain in human hepatocellular carcinoma.

Using comparative genomic hybridization (CGH) analysis, we, and others, have shown that there is a high and consistent incidence of chromosome 1q copy gain in human hepatocellular carcinoma (HCC). Chromosome 1 rearrangements, that involved peri-centromeric breakpoints, have also been frequently reported in karyotypic studies of HCC. Satellite DNA hypomethylation has been postulated as the mechanism underlying the induction of chromosome 1 peri-centromeric instability in many human cancers and in individuals with the rare recessive disorder ICF (immunodeficiency, centromeric heterochromatin instability, facial anomalies). In this study, we have investigated the role of DNA hypomethylation in 1q copy gain in HCC by examining the methylation status of chromosome 1 heterochromatin DNA (band 1q12). Thirty-six histologically confirmed samples of HCC were studied (24 paired tumor and adjacent nontumorous liver tissues, and 12 tumor only). Hypomethylation of satellite 2 (Sat2) DNA in 1q12 was analyzed by Southern blotting using methyl-sensitive enzyme digestion. In parallel, all cases were analyzed by CGH. A strong correlation between hypomethylated Sat2 sequences and 1q copy gain with a 1q12 breakpoint was found (P < 0.001). We postulate that such hypomethylation alters the interaction between the CpG-rich satellite DNA and chromatin proteins, resulting in heterochromatin decondensation, breakage and aberrant 1q formation. Spectral karyotyping further supported the presence of fragile 1q12 in HCC. Of particular interest was the finding of Sat2 DNA hypomethylation in 5 of 24 adjacent nontumorous liver tissues examined. These tissues showed no evidence of malignancy on histological examination nor did they display any CGH abnormalities. Our findings suggest a role for Sat2 demethylation in the early stages of the stepwise progression of liver carcinogenesis.

Adult↗
PubMed2001

Sinonasal angiosarcoma with marrow involvement at presentation mimicking malignant lymphoma: cytogenetic analysis using multiple techniques.

Angiosarcoma of the head and neck most commonly involves the skin of the scalp or face; primary involvement of the sinonasal region is exceedingly rate. We report a patient with sinonasal angiosarcoma who showed marrow involvement at presentation. Marrow aspiration smears showed many large, often segregated blast-like cells, mimicking malignant lymphoma. However, trephine biopsy revealed formation of anastomosing vascular spaces by the tumor cells and immunoreactivity for CD31, supporting a diagnosis of angiosarcoma. DNA ploidy analysis showed an apparent diploidy. Nevertheless, conventional cytogenetics demonstrated very complex chromosomal abnormalities with the presence of multiple hypodiploid clones, together with several near-triploid to near-tetraploid clones showing structural abnormalities involving chromosomes 1, 3, 4, 9, 14, 16, 17, 18, and 22. The identification of these karyotypic changes has been facilitated by the application of comparative genomic hybridization and spectral karyotyping.

Adult↗
PubMed2001

Recurrent chromosomal rearrangements involving breakpoints 3p21 and 19q13 in Chinese IgD multiple myeloma detected by G-banding and multicolor spectral karyotyping: a review of IgD karyotype literature.

Immunoglobulin D multiple myeloma (IgD MM) is a rare subtype that accounts for 1% to 3% of MM and shows higher aggressiveness with distinctive clinical and laboratory features. However, there is little information in the literature on their karyotypes, which are mainly derived from G-banding results. Our current study on 2 Chinese IgD MM thus represents the first description of cytogenetic data on this subtype based on an integrated analysis with G-banding and multicolor spectral karyotyping (SKY). Both of our cases showed some usual features of MM, as well as a few novel translocations including t(3;22), t(6;19), t(X;19) and the 3 whole-arm translocations namely t(1;6)(q10;p10), t(4;9)(q10;p10), and t(16;18)(q10;q10). We also identified recurrent chromosomal rearrangements involving breakpoints 3p21 and 19q13, which may suggest to be unique aberrations that may underline the pathogenesis of this distinctive biological MM subtype.

Aged↗