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Results for “Loss of Heterozygosity”

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PubMed1999

Mitotic recombination map of 13cen-13q14 derived from an investigation of loss of heterozygosity in retinoblastomas.

Loss of heterozygosity at tumor-suppressor loci is an important oncogenic mechanism first discovered in retinoblastomas. We explored this phenomenon by examining a set of matched retinoblastoma and leukocyte DNA samples from 158 patients informative for DNA polymorphisms. Loss of heterozygosity at the retinoblastoma locus (13q14) was observed in 101 cases, comprising 7 cases with a somatic deletion causing hemizygosity and 94 with homozygosity (isodisomy). Homozygosity was approximately equally frequent in tumors from male and female patients, among patients with a germ-line vs. somatic initial mutation, and among patients in whom the initial mutation occurred on the maternal vs. paternal allele. A set of 75 tumors exhibiting homozygosity was investigated with markers distributed in the interval 13cen-13q14. Forty-one tumors developed homozygosity at all informative marker loci, suggesting that homozygosity occurred through chromosomal nondisjunction. The remaining cases exhibited mitotic recombination. There was no statistically significant bias in apparent nondisjunction vs. mitotic recombination among male vs. female patients or among patients with germ-line vs. somatic initial mutations. We compared the positions of somatic recombination events in the analyzed interval with a previously reported meiotic recombination map. Although mitotic crossovers occurred throughout the assayed interval, they were more likely to occur proximally than a comparable number of meiotic crossovers. Finally, we observed four triple-crossover cases, suggesting negative interference for mitotic recombination, the opposite of what is usually observed for meiotic recombination.

Chromosome Mapping↗

PubMed1998

Loss of heterozygosity on chromosome 9 and loss of chromosome 9 copy number are separate events in the pathogenesis of transitional cell carcinoma of the bladder.

The most frequent genetic aberration found in transitional cell carcinoma (TCC) of the bladder involves chromosome 9. Loss of heterozygosity (LOH) analyses show deletions of both chromosome 9p and 9q, while in situ hybridization studies suggest a significant percentage of tumours with monosomy 9. To investigate the types of chromosome 9 losses that occur in bladder cancer, we have studied 40 tumours with different techniques such as in situ hybridization (ISH), flow cytometry and LOH analysis. LOH for one or more markers was found in 43% of the tumours. This percentage does not differ from previous reports. With ISH, complete monosomy for chromosome 9 was observed in only 1 of the 40 tumours. Four other tumours had monosomic subpopulations, representing 23-40% of the cells. In 18 cases, an underrepresentation of the chromosome 9 centromere relative to chromosome 6 or to the ploidy of the tumour was observed, including the cases with monosomy. In 5 of these 18 cases, the relative loss could not be confirmed by LOH. In addition, when LOH and a relative underrepresentation were observed in the same tumour, the extent of LOH as measured by the intensity of allele loss, was often not related to the extent of underrepresentation. We therefore conclude that complete monosomy of chromosome 9 is rare in TCCs of the bladder and that a relative loss of centromere signal may not be related to a loss compatible with inactivation of a tumour suppressor gene. LOH was found in TCCs of all stages and grades. Our results suggest that loss of tumour suppressor genes on chromosome 9 is an early event in the pathogenesis of bladder cancer.

Carcinoma, Transitional Cell↗

PubMed2002

[Loss of heterozygosity of tumor suppressor genes at chromosome 3p in transitional cell carcinoma of urinary bladder].

OBJECTIVE: To investigate the potential effects of three tumor suppressor genes located at chromosome 3p, FHIT, hMLH1 and VHL, in carcinogenesis of transitional cell carcinoma (TCC) of urinary bladder in Chinese. METHODS: PCR was used to examine the heterozygosity and loss of heterozygosity (LOH) of the 6 microsatellite polymorphic markers inside of or flanking to the three genes tumor suppressor genes FHIT, hMLHi, and VHL in TCC tissues of 40 cases. RESULTS: The rates of heterozygosity and LOH were 55.0% (38/40) and 59.1% (22/38) for hMLH1 gene. The rates of heterozygosity and LOH were 90.0% (36/40) and 47.2% (17/36). The rate of heterozygosity of the two microsatellite polymorphic markers in the intron of FHIT gene, D2S1234 and D3S1300, were 70% (28/40) and 67.5% (27/40), The LOH rates of D2S1234 and D3S1300 were 46.4% (13/28) and 37% (10/27) respectively. The rate that at least one the these 2 microsatellite polymorphic markers was heterozygote was 95.0% (38/40), the rate that LOH occurred for at least one of them was 57.8% (22/38). The heterozygosity rate of D3S1561 and D3S1612, two microsatellite polymorphic markers linked to hMLH1 gene, were 42.5% (17/40) and 30% (12/40) respectively, the LOH rates for these two markers were 41.2% (7/17) and 75.0% (9/12) respectively, the rate that at least one of these two markers was heterozygote was 59.1% (13/22). The heterozygosity rate of D3S10368 and D3S1284, two microsatellite polymorphic markers linked to VHL gene, were 70% (28/40) and 47.5% (19/40) respectively, the LOH rates for these two markers were 42.8% (12/28) and 42.1% (8/19) respectively, the rate that at least one of these two markers was heterozygote was 90.0% (36/40). High frequencies of LOH were found in tumor suppressor genes FHIT, hMLH1 and VH. Only the LOH of D3S1284 was positively correlated with the pathological staging of TCC of urinary bladder (P < 0.05). CONCLUSION: LOH in tumor suppressor genes FHIT, hMLH1 and VHL may play an important role in carcinogenesis of human urinary bladder, and may provide new approaches for early detection of TCC. Loss of VHK gene may be a late event of carcinogenesis of TCC.

Acid Anhydride Hydrolases↗

PubMed1998

Chromosome loss with concomitant duplication and recombination both contribute most to loss of heterozygosity in vitro.

Loss of heterozygosity (LOH) plays an important role in the expression of recessive mutations in mammalian cells. To gain insight into the rate and mechanisms of LOH the autosomal HLA-A gene was used as a model system. Spontaneous HLA-A2 mutants originated with a rate of respectively 4.1 x 10(-6) and 6.9 x 10(-6) per cell per generation in TK6 and WI-L2-NS, two isogenic lymphoblastoid cell lines which differ in TP53 status. The rate of loss of HLA-A2 is 10-50 times higher compared to the mutation rate of the X-linked HPRT gene. The homozygous TP53 mutation in WI-L2-NS had no effect on the rate of HLA-A2 loss or the spectrum of these mutations. Microsatellite analysis of most of the HLA-A2 mutants (84%) showed LOH for multiple markers on chromosome arm 6p telomeric of a recombination breakpoint, LOH for all 6p markers, or LOH for markers on both the 6p- and 6q-arms. Cytogenetic analysis showed that these mechanisms gave mutant cells which harbored two intact chromosomes 6 and which were indistinguishable from non-mutant cells. Therefore, loss of HLA-A2 is mainly caused by somatic recombination (33-50%) or chromosome loss with duplication of the remaining chromosome (34-40%). These findings correspond to the mechanisms behind loss of the wild-type RBI allele in retinoblastoma and suggest that both somatic recombination and chromosome loss followed by duplication contribute to tumorigenesis.

Cell Line, Transformed↗

PubMed2002

A Robertsonian translocation suppresses a somatic recombination pathway to loss of heterozygosity.

In mammals, loss of APC/Apc gatekeeper function initiates intestinal tumorigenesis. Several different mechanisms have been shown or proposed to mediate functional loss of APC/Apc: mutation in APC/Apc, non-disjunction, homologous somatic recombination and epigenetic silencing. The demonstration that, in the C57BL/6 (B6) Apc(Min/+) mouse model of inherited intestinal cancer, loss of Apc function can occur by loss of heterozygosity (LOH) through somatic recombination between homologs presents an opportunity to search for polymorphisms in the homologous somatic recombination pathway. We report that the Robertsonian translocation Rb(7.18)9Lub (Rb9) suppresses the multiplicity of intestinal adenomas in this mouse model. As the copy number of Rb9 increases, the association with the interphase nucleolus of the rDNA repeats centromeric to the Apc locus on Chromosome 18 is increasingly disrupted. Our analysis shows that homologous somatic recombination is the principal pathway for LOH in adenomas in B6 Apc(Min/+) mice. These studies provide additional evidence that neoplastic growth can initiate in the complete absence of canonical genomic instability.

Adenoma↗

PubMed2002

Loss of heterozygosity or allele imbalance in histologically normal breast epithelium is distinct from loss of heterozygosity or allele imbalance in co-existing carcinomas.

To better understand early steps in human breast carcinogenesis, we examined allele imbalance or loss of heterozygosity (LOH), in co-existing normal-appearing breast epithelium and cancers. We microdissected a total of 173 histologically normal ducts or terminal ductolobular units (TDLUs) and malignant epithelial samples from 18 breast cancer cases, and examined their DNA for LOH at 21 microsatellite markers on 10 chromosome arms. Fourteen of 109 (13%) normal ducts/TDLUs, from 8 of 18 (44%) cases, contained LOH. The location of these 14 ducts/TDLUs appeared unrelated to distance from the cancer. LOH in normal-appearing epithelium involved only single markers, whereas LOH in cancers commonly encompassed all informative markers on a chromosome arm. In only 1 of 14 (7%) ducts/TDLUs with LOH, was the same LOH seen in the co-existing cancer. Global differences in LOH per arm in normal-appearing tissue were not demonstrated, but less LOH was seen at 11q and 17p than at 1q (P = 0.002), 16q (P = 0.01), and possibly 17q (P = 0.06). These results indicate that in a large fraction of women with breast cancer, histologically normal breast epithelium harbors occult aberrant clones. Individual clones rarely are precursors of co-existing cancers. However, they might constitute a reservoir from which proliferative lesions or second cancers develop once additional genetic abnormalities occur, they could contribute to intratumoral genetic heterogeneity, and they are consistent with a role for genetic instability early in tumorigenesis.

Allelic Imbalance↗

PubMed1994

Molecular genetic analysis of flow-sorted ovarian tumour cells: improved detection of loss of heterozygosity.

Detection of loss of heterozygosity (LOH) is usually performed on homogenised tumour specimens. In this type of analysis samples with a low percentage of tumour cells have to be excluded and possible intra-tumour heterogeneity is obscured. In this study we report the application of polymerase chain reaction (PCR)-driven LOH detection with in total 22 microsatellite markers for chromosome 1q, 3p, 3q, 4p, 6p, 6q, 11p, 11q, 17p, 17q, 18p, 18q, Xp and Xq on flow-sorted cells from fresh and paraffin-embedded ovarian tumour tissue. Titration experiments showed that LOH can be detected with as few as 100 cell equivalents of DNA. Clear examples of LOH could be detected in the sorted aneuploid fractions from one unilateral and two bilateral ovarian tumours from three patients. In two samples the sorted fraction was less than 10% of the total sample. The bilateral tumours from the same patient showed loss of identical alleles for one marker (case OV64) and two markers (case OV69), indicative of their monoclonal origin. Multiparameter flow cytometry using two different ovarian tumour markers (MOv18 and BMA180), an anti-cytokeratin monoclonal antibody (MAb) (M9), an anti-vimentin MAb (V9) and a MAb against the panepithelial antigen 17-1A on the fresh ascites cells of the fourth ovarian cancer patient was used to investigate possible intra-tumour heterogeneity. We showed the presence of at least three phenotypically different populations, of which the diploid, keratin-positive, vimentin-negative population showed a similar LOH pattern as the aneuploid population (DNA index = 1.7), indicative of its neoplastic origin. The same LOH pattern was shown in an omentum metastasis from this patient also having the same aneuploid DNA index of 1.7. The sharing of the same LOH pattern by the diploid and aneuploid tumour cell populations suggests that the observed allele loss events occurred before the development of aneuploidy. PCR on flow-sorted cells is thus an important tool to study clonal diversity in tumours.

Aneuploidy↗

PubMed1996

Refinement of two chromosome 11q regions of loss of heterozygosity in ovarian cancer.

Loss of heterozygosity on chromosome 11q23.3-qter is a frequent event in ovarian carcinoma, implying the existence of an important ovarian tumor suppressor gene(s) within the region. To refine a minimum region(s) of loss, 67 ovarian tumors were analyzed for loss of heterozygosity with eight microsatellite markers spanning 11q23.3-qter. Forty tumors (61%) demonstrated allelic losses. Twenty-seven of these had allelic losses on only part of 11q23.3, which enabled the identification of two distinct regions likely to harbor ovarian tumor suppressor genes. The proximal region, flanked by markers D11S925 and D11S1336, is less than two megabases while the second more distal region, flanked by markers D11S912 and D11S439, is approximately eight megabases. The refinement of these candidate tumor suppressor gene loci will facilitate future loss of heterozygosity studies and enable the isolation of candidate genes from these regions.

Alleles↗

PubMed2003

Low microsatellite instability and high loss of heterozygosity rates indicate dominant role of the suppressor pathway in squamous cell carcinoma of head and neck and loss of heterozygosity of 11q14.3 correlates with tumor grade.

Loss of heterozygosity (LOH) and microsatellite instability (MSI) have been recognized as important events in squamous cell carcinoma of the head and neck (HNSCC), suggesting involvement of both suppressor and mutator pathways. We analyzed 153 HNSCC with 8 Bethesda reference panel markers and 14 microsatellite markers selected from chromosomal regions known to harbor either tumor-suppressor genes or oncogenes. A combination of multiplex fluorescence-based polymerase chain reaction and automatic fragment analysis was performed. LOH was observed in 78% of all tumors. 2% to 17% LOH frequency was observed with Bethesda reference panel markers comparing to higher 8% to 48% LOH in chromosomal areas 3p, 9p, 11q, and 17p. LOH of 11q14.3 correlated with tumor grade. The proportions of high- and low-MSI tumors were 3% and 10%, respectively, but no mutation was identified in MLH1 and MSH2 mismatch repair genes. These results indicate the dominant role of the suppressor in comparison with the mutator pathway in HNSCC carcinogenesis.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Loss of heterozygosity reveals non-VHL allelic loss in hemangioblastomas at 22q13.

Hemangioblastomas (HBs) are low-grade (World Health Organization grade I/IV) central nervous system (CNS) tumors that frequently contain VHL (3p26) mutations. They occur sporadically and in von Hippel Lindau (VHL) disease. Encoded pVHL aids degradation of hypoxia-inducible factors (HIFs) in the presence of normal oxygen levels. HBs provide an in vivo view of HIF effects within a CNS tumor. Typically, HBs are cystic tumors containing a mural nodule formed by noninvasive, vacuolated stromal cells that are embedded in a network of capillaries. Nine HBs, consecutively resected from 8 patients at our institution during a recent 2-year time span, were evaluated for additional losses of tumor suppressor genes. Non-VHL microsatellites studied for loss of heterozygosity (LOH) are near tumor suppressor genes lost in gliomas, pituitary adenomas, several CNS tumors on 22q, neurofibromatosis 1, and colon carcinomas (13, 2, 2, 1, and 2 markers for each, respectively). LOH in the region of 3p21.3-3p26.3 occurred in 3 of 8 HBs informative for at least 1 marker (D3S1539, D3S2303, or D3S2373). By using 2 markers (D22S417 and D22S532) for 22q13.2, LOH was found in 5 of 8 informative HBs. All 3 HBs with allelic losses near VHL also showed LOH at 22q13.2. No consistent losses were found with markers for 1p34, LMYC, 5q21, 5q32, 9p21, 10q23, 17p13, and 19q13. LOH for the 22q13.2 region in HBs suggests that the loss of another tumor suppressor gene is involved in the pathogenesis of HBs in addition to VHL. Absence of LOH for glioma markers is consistent with the low-grade behavior of HBs.

Adult↗

PubMed2000

Definition and refinement of chromosome 8p regions of loss of heterozygosity in gastric cancer.

Loss of heterozygosity at several chromosomal loci is a common feature of the malignant progression of human tumors. These regions are thought to harbor one or more putative tumor suppressor gene(s) playing a role in tumor development. Allelic losses on the short arm of chromosome 8 (8p) have been reported as frequent events in several cancers, and three commonly deleted regions have been defined at 8p11.2-12, 8p21-22, and 8p23.1. To evaluate the possible involvement of these regions in gastric cancer, we used eight microsatellite markers to perform an extensive analysis of allele loss at 8p21-22 in 52 cases of primary gastric adenocarcinoma. We found that 44% of tumors showed allelic loss for at least one marker at 8p21-22. The critical region of loss was found to be between markers LPL and D8S258, which displayed loss of heterozygosity in 39% and 33% of cases, respectively. This region is centromeric to the LPL locus and centered on the D8S258 locus. We conclude that 8p22 deletion is a frequent event in gastric cancer and suggest the presence of a putative tumor suppressor gene near the D8S258 locus. Initial steps were taken toward the identification of this gene, which is likely to play an important role in the pathogenesis of gastric cancer and of other tumors as well.

Chromosome Mapping↗

PubMed1996

Major role for a 3p21 region and lack of involvement of the t(3;8) breakpoint region in the development of renal cell carcinoma suggested by loss of heterozygosity analysis.

In a loss of heterozygosity analysis of 3p, we examined 44 sporadic cases of renal cell carcinoma (RCC) and matched normal tissue with 18 markers distributed over the whole p-arm. The majority of these markers clustered in three regions that have been suggested to be involved in the development of RCC, namely the p25 region, where the von Hippel Lindau (VHL) gene is located; the p21 region, which has been identified as a common region of overlap (SRO) of heterozygous deletions; and the p14 region, which is the location of the constitutional t(3;8) breakpoint occurring in an RCC family. Thirty-one out of these 44 tumors were analyzed with 9 additional markers from the 3p12-14 region to further delimit the SRO in this region. Our analysis shows that when deletions were detected the 3p21 region was always included. The 3p21 markers D3F15S2 and UBEIL were always contained within these 3p21 deletions. The t(3;8) breakpoint region showed the lowest percentage of loss of heterozygosity. Moreover, in three cases the t(3;8) breakpoint region retained heterozygosity, whereas a region more proximal to the breakpoint showed allelic losses. This supports exclusion of the t(3;8) region from a role in the development of sporadic RCC. In a number of tumors, two or three 3p regions with allelic losses were present separated by a region of retention of heterozygosity. In these tumors, deletions at 3p21 occurred in combination with deletions of either the VHL region, or the region proximal to the t(3;8), or both, suggestive of multiple gene involvement in the development of sporadic RCC with a primary role of the 3p21 region.

Carcinoma, Renal Cell↗

PubMed2003

Detection of loss of heterozygosity by high-resolution fluorescent system in non-small cell lung cancer: association of loss of heterozygosity with smoking and tumor progression.

BACKGROUND: We recently developed a novel system for detecting microsatellite alteration, which is an important process in carcinogenesis. In patients with non-small cell lung cancer (NSCLC), loss of heterozygosity (LOH) is frequently observed and causes functional disorders of tumor suppressor genes. PATIENTS AND METHODS: In a consecutive series of 51 patients with NSCLC who had undergone a surgical resection, microsatellite instability (MSI) and LOH in tumors were analyzed by polymerase chain reaction using five fluorescence-labeled dinucleotide markers (D2S123, D5S107, D10S197, D11SS904, and D13S175) and an autosequencer. RESULTS: MSI was detected in only one patient (2.0%) with only one marker. LOH was detected in at least one chromosomal region that was tested in 39 patients (76%). The mean (+/- SD) number of LOHs detected by each marker was 1.74 +/- 1.40, with 1 LOH detected in 10 patients, 2 LOHs detected in 15 patients, 10 LOHs detected in 3 patients, 1 LOH detected in 4 patients, and 3 LOHs detected in 5 patients. The number of LOHs detected in each patient was significantly associated with the pack-year index (rho = 0.501; p = 0.0004), although there was no relationship with having a history of multiple cancers and familial cancer. Patients with stage IA disease showed a significantly lower number of LOHs than did patients with other stages of disease (1.15 vs 2.38, respectively; p = 0.0013). CONCLUSION: LOH is very common in patients with NSCLC, and the number of LOHs increases with increases in smoking, suggesting the presence of an important event in lung carcinogenesis.

Adult↗

PubMed1994

Loss of heterozygosity at the RB locus correlates with loss of RB protein in primary malignant neuro-endocrine lung carcinomas.

RB protein expression and loss of heterozygosity (LOH) in the RB gene were studied in 77 primary lung carcinomas of all histological types. RB protein expression was studied by immunohistochemistry with 3 anti-RB antibodies, and was found altered in 23/29 (79%) neuro-endocrine (NE) carcinomas and in 18/48 (37%) non-NE carcinomas. RB gene allele status was studied with 3 probes detecting RFLP in RB locus. Fifty-five patients were informative, and loss of heterozygosity was detected in 29 (52%) of the corresponding tumors with 1 of the 3 probes used; 89% of the informative NE carcinomas, excluding carcinoids, and only 13% of the non-NE carcinomas exhibited LOH and loss of RB-protein expression. LOH at the RB locus was strongly correlated with the absence of RB protein in malignant NE carcinomas, and this association was strongly correlated with the neuro-endocrine phenotype. Inactivation of the RB protein in primary NE carcinomas, excluding carcinoids, therefore seems to imply in the majority of cases the mutation of one allele and loss of the remaining allele of the RB gene, leading to loss of RB-protein expression. In contrast, RB-protein expression was independent of allele status in non-NE carcinomas and carcinoids.

Gene Deletion↗

PubMed2005

Single-cell analysis of loss of heterozygosity at the ATM gene locus in Hodgkin and Reed-Sternberg cells of Hodgkin's lymphoma: ATM loss of heterozygosity is a rare event.

Hodgkin's lymphoma (HL) is a lymphoid malignancy characterized by the presence of rare neoplastic cells, Hodgkin and Reed-Sternberg (HRS) cells, scattered among a predominant population of inflammatory cells. On the basis of previously reported cytogenetic analyses, the ATM (ataxia-telangiectasia mutated) gene at 11q22-23 has been implicated in the etiology of HL. We therefore developed a single-cell PCR approach to detect ATM loss of heterozygosity (LOH) in HRS cells. Three microsatellites were investigated; 1 localized inside the ATM gene and the remaining 2 in close proximity. In 2 of the 15 lymph node samples, an allelic loss of the ATM gene locus was detected. ATM protein expression was examined in 8 cases (including 1 of the 2 cases with LOH) by immunohistochemistry. In the case associated with an allelic loss, the ATM protein was absent in the HRS cells, whereas in the 7 remaining cases, without detectable LOH at the ATM locus, nuclear ATM expression was observed. In the 2 HL cases with LOH, the ATM gene was sequenced following whole genome amplification of DNA isolated from microdissected HRS cells. In 1 of these 2 cases, a splice site mutation in the second ATM allele was found. This mutation could generate a premature termination codon leading to a marked instability and a rapid degradation of the resulting ATM mRNA transcripts. This latter event could explain the loss of the expression of the ATM protein in HRS cells as detected by immunohistochemistry in this particular case. As previously reported in some B-cell lymphomas, our results suggest that ATM genetic anomalies could play a role in the pathogenesis of a subset of HL cases.

Ataxia Telangiectasia Mutated Proteins↗

PubMed2005

Mass spectrometry-based loss of heterozygosity analysis of single-nucleotide polymorphism loci in paraffin embedded tumors using the MassEXTEND assay: single-nucleotide polymorphism loss of heterozygosity analysis of the protein tyrosine phosphatase receptor type J in familial colorectal cancer.

As the number of identified single-nucleotide polymorphisms (SNPs) increases, high-throughput methods are required to characterize the informative loci in large patient series. We investigated the feasibility of MassEXTEND LOH analysis using Sequenom's MassArray RT software, a mass spectrometry method, as an alternative to determine loss of heterozygosity (LOH). For this purpose, we studied the c.827A>C SNP (1176A>C p.Gln276Pro) in protein tyrosine phosphatase receptor type-J (PTPRJ), which is frequently deleted in human cancers. In sporadic colorectal cancer (CRC), c.827A>C showed allele-specific LOH of the c.827A allele, which is important because LOH of PTPRJ may be an early event during sporadic CRC. To elucidate the impact of this low-penetrance gene on familial CRC, we studied c.827A>C in 222 familial CRC cases and 156 controls. In 6.2% of the A/C genotyped CRC samples, LOH of c.827A was observed with MassEXTEND LOH analysis and confirmed by conventional sequencing. Furthermore, a case with LOH of c.827A showed no LOH in 22 synchronously detected adenomas, including one with malignant transformation. The importance of the PTPRJ- c.827A>C SNP appears to be limited in familial CRC. We conclude that MassEXTEND LOH analysis (using Sequenom's MassARRAY RT software) is a sensitive, high-throughput, and cost-effective method to screen SNP loci for LOH in formalin-fixed paraffin-embedded tissue.

Aged↗

PubMed2001

High-resolution chromosome 3p allelotyping of breast carcinomas and precursor lesions demonstrates frequent loss of heterozygosity and a discontinuous pattern of allele loss.

We performed high-resolution allelotyping for loss of heterozygosity (LOH) analysis on microdissected samples from 45 primary breast cancers, 47 mammary preneoplastic epithelial foci, and 18 breast cancer cell lines, using a panel of 27 polymorphic chromosome 3p markers. Allele loss in some regions of chromosome 3p was detected in 39 of 45 (87%) primary breast tumors. The 3p21.3 region had the highest frequency of LOH (69%), followed by 3p22-24 (61%), 3p21.2-21.3 (58%), 3p25 (48%), 3p14.2 (45%), 3p14.3 (41%), and 3p12 (35%). Analysis of all of the data revealed at least nine discrete intervals showing frequent allele loss: D3S1511-D3S1284 (U2020/DUTT1 region centered on D3S1274 with a homozygous deletion), D3S1300-D3S1234 [fragile histidine triad (FHIT)/FRA3B region centered on D3S1300 with a homozygous deletion], D3S1076-D3S1573, D3S4624/Luca2.1-D3S4597/P1.5, D3S1478-D3S1029, D3S1029 (with a homozygous deletion), D3S1612-D3S1537, D3S1293-D3S1597, and D3S1597-telomere; it is more than likely that additional localized regions of LOH not examined in this study also exist on chromosome 3p. In multiple cases, there was discontinuous allele loss at several 3p sites in the same tumor. Twenty-one of 47 (45%) preneoplastic lesions demonstrated 3p LOH, including 12 of 13 (92%) ductal carcinoma in situ, 2 of 7 (29%) apocrine metaplasia, and 7 of 25 (28%) usual epithelial hyperplasia. The 3p21.3 region had the highest frequency of LOH in preneoplastic breast epithelium (36%), followed by 3p21.2-21.3 (20%), 3p14.2/FHIT region (11%), 3p25 (10%), and 3p22-24 (5%). In 39 3p loci showing LOH in both the tumor and accompanying preneoplasia, 34 (87%) showed loss of the same parental allele (P = 1.2 x 10(-6), cumulative binomial test). In addition, when 21 preneoplastic samples showing LOH were compared to their accompanying cancers, 67% were clonally related, 20% were potentially clonally related but were divergent, and 13% were clonally unrelated. Overall this demonstrated the high likelihood of clonal relatedness of the preneoplastic foci to the tumors. We conclude that: chromosome 3p allele loss is a common event in breast carcinoma pathogenesis; involves multiple, localized sites that often show discontinuous LOH with intervening markers retaining heterozygosity; and is seen in early preneoplastic stages, which demonstrate clonal relatedness to the invasive cancer.

Adult↗

PubMed1998

[Prognostic significance of loss of heterozygosity in breast cancer].

Loss of heterozygosity (LOH) was analyzed in 113 cases of sporadic breast cancer using 35 microsatellite markers on 20 chromosomes. LOH was frequently seen in 17p (44%), 16q (31%), 17q (29%) and 13q (23%). Individual patients were scored according to the incidence of LOH at the above four chromosomal markers; with no LOH as 1, with one or two LOH as 2, and with three of four LOH as 3. A high LOH score was well associated with high histological grade (p = 0.019) and a significantly poor prognosis (p = 0.0035). These data suggest that accumulation of LOH occurs at a later stage of breast cancer progression, and that the LOH score may be a useful prognostic marker of breast cancer.

Breast Neoplasms↗