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Results for “Loss of heterozygosity”

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At least 19 recordsLinked to original sources

PubMed2003

Refinement of heterozygosity loss on chromosome 5p15 in sporadic colorectal cancer.

AIM: To refine the loss of heterozygosity on chromosome 5p15 and to identify the new tumor suppressor gene (s) in colorectal tumorigenesis. METHODS: Sixteen polymorphic microsatellite markers were analyzed on chromosome 5 and another 6 markers were applied on chromosome 5p15 in 83 cases of colorectal and normal DNA by PCR. PCR products were electrophoresed on an ABI 377 DNA sequencer. Genescan 3.1 and Genotype 2.1 software were used for LOH scanning and analysis. RESULTS: We observed 2 distinct regions of frequent allelic deletions on Chromosome 5, at D5S416 on 5p15 and D5S428-D5S410 on 5q. Another 6 polymorphric microsatellite markers were applied to 5p15 and the minimal region of frequent loss of heterozygosity was established on 5p15 spanning the D5S416 locus. CONCLUSION: Through our detailed deletion mapping studies, we have found a critical and precise location of 5p deletions, 5p15.2-5p15.3, which must contain one or more unknown tumor suppressor gene (s) of colorectal cancer.

Adult↗

PubMed1999

[Prognostic value of heterozygosity loss in chromosome 3p in non-microcytic bronchogenic carcinoma].

BACKGROUND: Recent advances on carcinogenesis have led to the recognition of different patterns of behaviour of non-small cell lung cancers apart from those guided by the TNM staging system and the histologic subtype. The frequent genetic loss on chromosome 3p in all kinds of lung carcinoma leads to the suspect of the presence of a tumor suppressor gene located in that place. The aim of this work was to compare the different clinical features and evolution after treatment of the patients with non small cell lung carcinoma with and without loss of heterozygosity (LOH) on 3p. PATIENTS AND METHOD: Forty-five operated on non-small cell lung cancer patients were evaluated. The mean age was 64.4 years and all the patients were male. Seven patients had been previously treated for another epithelial neoplasm. 82.2% of the patients were heavy tobacco smokers. Most of the tumors (62.2%) were squamous cell carcinomas. Samples of tumoral and non tumoral lung tissue were immediately frozen after surgery. DNA from the tissue was extracted; then PCR amplification of microsatellites in regions 3p14 and 3p21 was performed. To determine the LOH in the regions analyzed a polyacrylamide gel electrophoresis was performed. RESULTS: Twenty-five percent of the informative samples for 3p14 and 21.9% for 3p21 showed LOH. There was an statistical relationship between the LOH on 3p14 and the history of tobacco smoking and the adenocarcinoma histologic subtype (p < 0.05). There was a higher number of relapses and a shorter disease-free interval in those patients harboring 3p21 LOH. CONCLUSIONS: LOH on 3p can be detected in non-small cell lung carcinoma. Patients with loss of heterozygosity on 3p21 have a worse evolution after a curative intended surgical resection.

Adult↗

PubMedDate not supplied

[Heterozygosity loss and somatic mutations in type I and II dominant autosomal renal polycystic kidney disease: evidence of a recessive mechanism at a cell level in cystogenesis].

Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder mainly characterized by renal cyst formation. Cysts in ADPKD are focal in nature, since only a small fraction of nephrons become cystic. The hypothesis that a second hit may be required for cyst formation has been proposed. This hypothesis suggests that inactivation of the inherited wild-type allele by a somatic mutation triggers cyst formation. In some cases, this second hit eliminates the normal allele and the affected cells remain with a single allele, which is the inherited mutated copy, and we only visualize one allele after the amplification by polymerase chain reaction; this is called loss of heterozygosity (LOH). In this study we have analysed the DNA isolated from epitehlial cells from 164 cysts of 8 kidneys affected by ADPKD type I and 30 cysts form a kidney affected by ADPKD type II. We have demonstrated the presence of LOH in 20.1% of PKD1 cysts and in 10% of PKD2 cysts. We have also found eight other different mutations in PKD2 cysts without LOH; so the percentage of somatic mutations in the PKD2 kidney reaches 36.6% of cysts. In conclusion, our data suggest that a recessive mechanism at the cellular level is implicated in cyst formation in the PKD1 and the PKD2 disease. The loss of both copies of the gene triggers the proliferation of a single cell, resulting in the cyst formation.

Chromosomes, Human, Pair 16↗

PubMed2000

16q heterozygosity loss in Wilms' tumour in children and its clinical importance.

INTRODUCTION: The loss of heterozygosity (LOH) of 16q is a structural change detected in about 20-30% of Wilms' tumour cases. Aberrations which result in deletion of 16q are also found in breast cancer, prostate cancer and liver cancer, where they are connected with a worse prognosis. The hypothesis of a bad prognosis in nephroblastomas with LOH 16q was first formulated by scientists from NWTS (National Wilms Tumor Study) on the basis of 232 cases of Wilms' tumour. However, SIOP studies (International Society of Paediatric Oncology) which included 28 cases of Wilms' tumour, did not show any clinico-pathological correlations with LOH 16q. Therefore, we aimed to evaluate the importance of LOH 16q in relation to clinico-pathological factors in a group of children, treated according to the SIOP criteria. AIMS: The aim of this work was to evaluate the frequency of LOH 16q in sporadic unilateral Wilms' tumour and to study the relationship between LOH 16q and selected patho-clinical parameters. The study comprised 66 children (31 girls and 35 boys) aged from 2 days to 13 years. METHODS: LOH 16q was studied by the examination of polymorphism of marker sequences in the region 16q24. DNA was isolated from paraffin sections of tissue for routine microscopic examination by the microdissection method. The method of study involved the amplification of polymorphic sequences from the 16q24 region by polymerase chain reaction (PCR) and separation of the products of amplification by polyacrylamide gel electrophoresis. The results were the subject of statistical analysis in relation to gender, age of child at first diagnosis, stage of clinical advancement and histological type of tumour. The connection between LOH 16q and recurrences, metastases and death, and failure free survival and absolute survival of children followed-up for over 24 months after nephrectomy were studied. RESULTS: The study revealed a lack of correlation between LOH 16q and gender, however LOH 16q was more frequent in children with Wilms' tumour aged >24 months, P<0.05. Also, LOH 16q was more frequent in tumours classified as clinical stage (CS) II or III than in CS I, P<0.05, but there were no differences in the occurrence of LOH 16q in tumours classified as CS II and CS III. We have found no correlation between LOH 16q and the histological type of tumour. However, LOH 16q has been found three times as frequently in tumours from children who died than in tumours of children who survived, P<0.0024.

Adolescent↗

PubMedDate not supplied

Detection of heterozygosity loss in microdissected fine needle aspiration specimens of breast carcinoma.

OBJECTIVE: To use the polymerase chain reaction (PCR) to detect loss of heterozygosity (LOH) in microdissected cells form cytologic smears obtained by fine needle aspiration (FNA) from 20 cases of invasive breast carcinoma. STUDY DESIGN: In each case, histologic sections of the primary tumor were also available. Tumor and nontumor cells were dissected from both the cytologic smear and tissue section in all cases except in three smears that showed only tumor cells. RESULTS: LOH was identified in 10 of 19 informative cases using two polymorphic DNA markers at chromosome 11q13 (INT-2, PYGM). The same results were obtained in both the cytologic and histologic specimens, including three cases that had hypocellular cytologic smears. CONCLUSION: FNA of breast lesions provides adequate samples for direct microdissection of the cytologic smear to detect LOH using PCR amplification.

Biopsy, Needle↗

PubMed1997

[Significance of heterozygosity loss in the long arm of chromosome 5 (5q21) in small cell carcinoma of the lung].

BACKGROUND: Loss of heterozygosity (LOH) at 5q21, where the APC/MCC genes reside, is one of the genetic alterations that characterizes lung cancer. The aim of this study was to analyse LOH frequency on chromosome 5q21 in patients with non-small cell lung cancer and its relationship with TNM staging and histological subtypes. PATIENTS AND METHODS: Tumor and corresponding normal DNA were isolated from 60 patients with non-small cell lung cancer and a subsequent polymerase chain reaction (PCR) with microsatellite markets within the APC/MCC region was performed. The PCR products were resolved by electrophoresis. The comparison between the normal and tumor DNA patterns allowed us to detect the samples harboring LOH. RESULTS: LOH at 5q21 was detected in 20% of the patients. LOH at 5q21 was found in 16% of stage I patients, 8% in stage II patients and 40% in stage IIIA patients. A trend towards worse survival was detected in stage IIIA patients with LOH at 5q21 (9 months median time survival) in comparison with patients with LOH (21 months), although the difference was not statistically significant (p = 0.11). No significant differences in LOH were observed among histological types. In addition, we found no correlation between LOH and higher frequency of mutations rate affecting K-ras and p53 genes. CONCLUSIONS: LOH at 5q21 is a frequent genetic alteration in non-small cell lung cancer and correlates with locally advanced disease (stage IIIA). Our results suggest that LOH at the 5q21 region could be a prognostic factor in non-small cell lung cancer.

Carcinoma, Non-Small-Cell Lung↗

PubMed1998

Loss of heterozygosity and loss of expression of the DCC gene in gastric cancer.

AIM: To investigate the role of DCC gene inactivation in the development and progression of gastric cancer. METHODS: Loss of heterozygosity and loss of expression of the DCC gene was studied in 51 surgical specimens of gastric cancer using detection based on polymerase chain reaction. RESULTS: Loss of heterozygosity was found in 35.3% (18 of 51) of specimens and was detected more often in stage III and IV (50%) than in stage I and II cancers (14.3%) (p < 0.05). Occurrence of loss of heterozygosity was not correlated with histological type, tumour size, depth of invasion, or lymph node metastasis. Loss of expression was found in 49% of cases (25 of 51). Loss of expression was not significantly correlated with any clinicopathological variable. CONCLUSIONS: Loss of heterozygosity and loss of expression of the DCC gene are often encountered in gastric cancer. Loss of heterozygosity of the DCC gene is a late event and associated with malignant progression.

Gene Expression↗

PubMed1996

Increased expression of the insulin-like growth factor-II gene in Wilms' tumor is not dependent on loss of genomic imprinting or loss of heterozygosity.

Loss of imprinting of insulin-like growth factor-II gene (IGF2) and/or loss of heterozygosity at the 11p15 loci have been postulated to be responsible for IGF2 overexpression in Wilms' tumor. In order to delineate the mechanism of IGF2 overexpression in Wilms' tumors, we have genotyped the 11p15-11p13 chromosomal region and determined allelic expression of IGF2 and H19 in both tumor tissue and in normal adjacent kidney tissue from 40 patients with Wilms' tumor. In five of the eight subjects informative for the ApaI IGF2 polymorphism, loss of imprinting of IGF2 was observed in both normal and tumor tissues. A significant increase (>5-fold) in IGF2 expression in tumor tissues compared to the normal adjacent kidney tissue was observed regardless of the IGF2 imprinting or the chromosome 11p15 heterozygosity status. In each case, the overexpression of IGF2 in the tumors was accompanied by activation of all four IGF2 promoters. Our data indicate that alterations of IGF2 imprinting occurred in normal adjacent kidney tissue before tumorigenesis and that the IGF2 overexpression in Wilms' tumor tissue occurs through a loss of heterozygosity- or loss of imprinting-independent process.

Alleles↗

PubMed2005

Infrequent mutation of TRAIL receptor 2 (TRAIL-R2/DR5) in transitional cell carcinoma of the bladder with 8p21 loss of heterozygosity.

Loss of heterozygosity (LOH) on 8p is a frequent event in many cancers and is often associated with more aggressive disease. Tumour necrosis factor-related apoptosis inducing ligand (TRAIL) receptor 2 (TRAIL-R2) also known as TNFRSF10B (tumour necrosis factor receptor (TNFR) super family 10b) or KILLER/DR5, a member of the TNFR family, is a promising candidate tumour suppressor gene at 8p21-22. Mutations in this gene have been identified in non-small cell lung cancer, head and neck cancer, breast cancer and non-Hodgkin's lymphoma. We carried out mutation analysis of TRAIL-R2 in bladder cancer cell lines and in primary bladder tumours. One novel protein truncating mutation was identified in a bladder cancer cell line. Our results suggest that if TRAIL-R2 is the target of LOH events in these cancers, inactivation of the remaining allele is by a mechanism other than mutation.

Apoptosis↗

PubMed1998

Comparison of loss heterozygosity in primary and recurrent ductal carcinoma in situ of the breast.

Ductal carcinoma in situ (DCIS) of the breast is often an indolent disease, although some cases are reported to recur many years after a limited surgical resection. It is not known whether these recurrences reflect a resurgence of residual disease or an independent development of a second tumor in susceptible individuals. Therefore, we conducted a longitudinal molecular study of four women with reappearance of DCIS 2 to 15 years after an initial conservative resection. Loss of heterozygosity (LOH) was characterized in both tumors in each case, using several polymerase chain reaction-amplified microsatellite markers on five chromosomal arms commonly affected in breast cancer. In three cases with ipsilateral recurrent disease, all of the allelic losses seen in the initial tumors were also seen in the recurrent lesions, suggesting a common genetic pathway for the development of both lesions and continuous proliferation of residual disease. The presence of at least one additional LOH in all of the three recurrent tumors, however, suggests that the recurrent tumors developed after genetic progression. In contrast, in one case of DCIS that was followed by the development of DCIS in the contralateral breast 7 years later (a case of bilateral DCIS), unrelated LOH patterns were present in the two lesions. These findings suggest that the reappearance of DCIS in the same breast is most commonly the result of a tumor derived from (but not identical to) the original lesion, with acquisition of additional genetic changes, even when the recurrent lesion manifested itself many years (15 years, in one case) after the initial presentation. Furthermore, genetic progression could be detected in tumors recurring in as little as 2 years after the initial resection.

Adult↗

PubMed2002

Poorly differentiated adenocarcinoma and mucinous carcinoma of the colon and rectum show higher rates of loss of heterozygosity and loss of E-cadherin expression due to methylation of promoter region.

Previous studies have reported that poorly differentiated adenocarcinoma and mucinous carcinoma of the colon and rectum (Por & Muc) show a low incidence and poor prognosis. However, genetic alterations and tumourigenesis of Por & Muc remain unclear. In our study, we analyzed the genetic and epigenetic alterations of Por & Muc to clarify the difference from those of well-differentiated adenocarcinoma (WD). First, we evaluated the loss of heterozygosity (LOH) on 4 chromosomes (2p, 5q, 17p, 18q) frequently observed in colorectal cancer. Second, to determine large-scale allelic losses, we performed wide-ranging allelotyping study. Using 27 microsatellite markers spanning every 10 cM on chromosome 17 and 18, we defined the LOH ratio as the proportion of markers that exhibit LOH out of 27 markers. Third, we evaluated the methylation of E-cadherin. With respect to LOH of 4 loci, higher rates of LOH were observed in Por & Muc and a statistical significance was found on the markers adjacent to MSH2 and SMAD4/DCC. Moreover, as the evidence of large-scale allelic imbalance, the average LOH ratio was higher in Por & Muc (0.70) than in WD (0.24) (p = 0.01). Methylation analysis showed that 54.5% of Por & Muc demonstrated hypermethylation of E-cadherin. In immunohistochemistry, 77.8% of Por & Muc exhibited abnormal expression of E-cadherin. Hypermethylation of E-cadherin correlated significantly with abnormal expression (p = 0.047). These results suggest that the higher rates of LOH contribute to Por & Muc tumourigenesis and most of Por & Muc lose normal E-cadherin expression, partly because of the methylation of promoter region.

Adenocarcinoma↗

PubMed2002

Microsatellite instability, loss of heterozygosity, and loss of hMLH1 and hMSH2 protein expression in endometrial carcinoma.

Microsatellite instability (MSI) due to replication errors occurs frequently in hereditary tumors. Association with functional inactivation of the mismatch repair (MMR) genes and lack of protein expression has been described. In endometrial carcinoma (EC), the prevalence and clinical significance of these phenomena are not well known. Therefore, DNA samples from 89 EC and 5 metachronous tumors were analyzed with polymerase chain reaction, using 5 microsatellite markers and a DNA sequencer for amplicon detection. The results were correlated with immunohistochemistry of hMLH1 and hMSH2. MSI at >or=2 loci (MSI-H) was detected in 10/89 EC (11%); 1 of 10 showed loss of both hMLH1 and hMSH2, and 5 of 10 showed loss of hMLH1 (P < 0.0001). MSI-H was observed frequently in tumors with mucinous differentiation (P = 0.048), >10% of solid-cribriform pattern (P = 0.037), International Federation of Obstetrics and Gynecology (FIGO) stage III to IV (4 of 13; P = 0.016), and necrosis >5% (P = 0.07). Loss of heterozygosity (LOH) in >or=1 loci was found in 17 of 156 (11%). Survival (Kaplan-Meier) was longer for patients with endometrioid tumors with predominant glandular pattern, <5% necrosis, low FIGO stage and grade, superficial myometrial infiltration, no lymph-vascular invasion (LVI), and loss of hMLH1 expression (all P <or= 0.04). Cox analysis showed independent value for stage, grade, histologic type and pattern, LVI, and hMLH1 expression (all P < 0.05). Age, MSI status, LOH, peritumoral inflammatory reaction, hMSH2, and development of metachronous tumors did not influence survival. In conclusion, MSI phenotype was observed in a small subset of mainly advanced-stage EC, frequently showing mucinous differentiation, areas of solid-cribriform pattern, and necrosis. It is often associated with loss of hMLH1 expression, which may be a prognostic marker, but only rarely with defects of hMSH2.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Frequent loss of heterozygosity without loss of genetic material in acute myeloid leukemia with a normal karyotype.

We performed a whole-genome loss of heterozygosity (LOH) analysis of 32 cases of acute myeloid leukemia with normal karyotype using high-density single nucleotide polymorphism arrays. LOH was found in 20% of cases. We identified two types of LOH: (i) interstitial, characterized by small deletions of genomic DNA (2-8 Mb), and (ii) terminal, involving large (30-90 Mb) telomeric regions. Surprisingly, terminal LOH occurred without loss of genetic material because of deletion of large chromosome regions and their substitution through the duplication of the corresponding regions from the homologous chromosomes (acquired partial uniparental disomy).

Acute Disease↗

PubMed1996

Clinical relevance of loss heterozygosity of the short arm of chromosome 1 in neuroblastoma: a single-institution study.

Neuroblastoma is characterized by a wide variability of its clinical course, and considerable effort has been made to identify factors determining outcome in this disease. In a series of 82 patients from a single institution, we have investigated the prognostic impact of multiple clinical, biological and genetic parameters. Univariate testing showed that advanced stage of disease, abdominal localization of the primary tumor, elevated urinary dopamine levels, N-myc amplification (NMA) and loss of heterozygosity of chromosome lp (LOH lp) were related to a poor outcome. Most of these parameters were strong indicators of treatment failure in children younger than 12 months of age but none of them, apart from stage, had a significant prognostic impact in patients older than 12 months at diagnosis. Interestingly, the shorter survival time associated with the presence of lp deletions or NMA appears to be more strongly linked to a poorer outcome after relapse or progression than to a shorter progression-free interval. Although different types of LOH lp have been described in neuroblastoma and may be associated with different biological features, as suggested by a different pattern of catecholamine secretion, tumors with LOH lp present an aggressive clinical behavior, regardless of the type of LOH lp. In this study, LOH lp is an indicator of poor prognosis and identifies a larger population at risk than NMA alone.

Chromosomes, Human, Pair 1↗

PubMed2000

Molecular alterations of p73 in human esophageal squamous cell carcinomas: loss of heterozygosity occurs frequently; loss of imprinting and elevation of p73 expression may be related to defective p53.

p73 is structurally and functionally related to p53 and is possibly a tumor suppressor gene. Using 15 surgically resected frozen esophageal specimens containing both squamous cell carcinomas (ESCC) and neighboring normal epithelia, we studied p73 gene alterations and mRNA expression. Loss of heterozygosity of the p73 loci was found in nine of 14 informative cases (64%). A polymorphism at codon 173 (Thr) of p73 was identified (eight samples had ACC and seven had ACT), but mutation was not detected in tumor samples. Nine of the 15 ESCC samples (60%) displayed significantly elevated expression of p73 over the neighboring normal epithelium; of these nine samples, four displayed loss of imprinting (LOI) and one switched the expressed allele. Hypermethylation of exon 1 of the p73 gene was not detected, using the bisulfite modification method, in normal or tumor samples. Twelve of the 15 (80%) ESCC samples contained p53 defects, including missense mutation, non-frameshift small deletion or insertion, non-detectable transcripts and protein accumulation. The ESCC samples with p53 defects were significantly correlated with those which had elevated expression of p73 (Fisher's exact test, P < 0.05). The results suggest that increased expression of p73, including that by LOI, could be a partial compensatory mechanism for defective p53.

Carcinoma, Squamous Cell↗

PubMed2004

Loss of heterozygosity at 12p13 and loss of p27KIP1 protein expression contribute to melanoma progression.

Little is known about the mechanisms causing p27KIP1 decrease in melanomas. Therefore, we performed loss of heterozygosity (LOH) analysis with polymerase chain reaction at seven different loci surrounding the p27KIP1/CDKN1B gene at 12p13 and direct DNA sequencing analysis of all exons. Furthermore, the immunohistochemical expression of p27KIP1 and Ki-67 was investigated. Only two mutations in the sequence of p27KIP1/CDKN1B were detected, but the number of tumours showing LOH at 12p13 increased significantly with the parameters of tumour progression (pT level, P=0.018; Breslow index, P=0.01; Clark level, P<0.001), with a more aggressive tumour growth (radial versus vertical growth, P=0.018) and tumour subtype (superficial spreading melanomas versus nodular melanomas versus metastases, P<0.001). p27KIP1 protein expression decreased with the Clark level ( P=0.026) and the pT level ( P=0.045). No correlation between LOH affecting 12p13 and p27KIP1 protein decrease in melanomas was stated. This does not exclude the participation of p27KIP1/CDKN1B in p27KIP1 protein decrease, since protein expression is regulated at various cellular levels; but it could also suggest that other tumour suppressors are situated in the same region as p27KIP1/CDKN1B. Taken together, our data shows that loss of p27KIP1 protein expression and LOH at 12p13 contribute to tumour progression in melanoma.

Carrier Proteins↗

PubMed1998

Mapping loss of heterozygosity at chromosome 13q: loss at 13q12-q13 is associated with breast tumour progression and poor prognosis.

Several chromosome regions exhibit loss of heterozygosity (LOH) in human breast carcinoma and are thought to harbour tumour suppressor genes (TSG). At chromosome 13q, two TSGs have been identified, RB1 at 13q14 and BRCA2 at 13q12-q13. In this study, 139 sporadic breast tumours were analysed with 18 polymorphic microsatellite markers for detailed mapping of LOH at chromosome 13q and evaluation of an association with known progression factors. LOH with at least one marker was observed in 71 (51%) of the tumours analysed. The deletion mapping indicated three LOH target regions, 13q12-q13, 13q14 and 13q31-q34. LOH at chromosome 13q12-q13 was associated with low progesterone receptor content, a high S phase fraction and aneuploidy. Multivariate analysis adjusting for lymph node involvement and S phase fraction showed that patients with tumours exhibiting LOH at 13q12-q13 have a 3-4-fold increased risk of recurrence and death compared with other patients. Our results suggest there are at least three separate LOH target regions at chromosome 13q and inactivation of one or more genes at chromosome 13q12-q13 results in poor prognosis for breast cancer patients.

Aneuploidy↗

PubMed2004

Loss of heterozygosity of chromosome 9p and loss of p16INK4A expression are associated with malignant gastrointestinal stromal tumors.

Gastrointestinal stromal tumors GISTs are distinctive KIT-positive mesenchymal neoplasms. The genetic alterations leading to the malignant behavior of these tumors are not well characterized. In this study, 21 cases of GISTs (eight low malignant potential, nine primary malignant and four intra-abdominal recurrences) were characterized by immunohistochemistry and evaluated for loss of heterozygosity of the short arm of chromosome 9, using six microsatellite markers. Loss of heterozygosity with at least one microsatellite marker at 9p region was a common finding in high-risk GISTs (malignant and recurrent group) but was absent in the low malignant potential group. Recurrent GISTs showed more frequent deletions than their primary tumors. All cases with loss of heterozygosity showed deletions at 9p21. Similarly, all low malignant potential GISTs were immunoreactive for p16, whereas malignant tumors were negative for p16. These results suggest that loss of p16(INK4A) gene on 9p may contribute to the progression and/or malignant transformation of GISTs.

Adult↗