Ductal carcinoma in situ of the breast with different histopathological grades and corresponding new breast tumour events: Analysis of loss of heterozygosity

Smeds, Johanna; Wärnberg, Fredrik; Norberg, Torbjörn; Nordgren, Hans; Holmberg, Lars; Bergh, Jonas

doi:10.1080/02841860410002842

Cited by 13 publications

(7 citation statements)

References 24 publications

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“…The sequential accumulation of mismatched base pairs and/or LOH from multiple mutations may lead to deregulation of tumor suppressor genes such as TP53, VHL, FHIT, and Rb, which often are found to be inactivated in early precancerous and cancerous cells [49-51]. Our results showed that the occurrence of MSI and LOH was highest in the Tp53-Alu microsatellite among the markers screened , and it was also found to correlate with low or deficient expression of the hMSH2 and P53 proteins in the de novo breast cancer patients after chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

High incidence of microsatellite instability and loss of heterozygosity in three loci in breast cancer patients receiving chemotherapy: a prospective study

Kamat

Khidhir²,

Jaloudi

et al. 2012

BMC Cancer

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BackgroundThe aim of the study was to evaluate potential chemotherapy-induced microsatellite instability, loss of heterozygosity, loss of expression in mismatch repair proteins and associations with clinical findings in breast cancer patients, especially resistance to chemotherapy and/or development of other tumors in the four years following chemotherapy treatment.MethodsA comprehensive study of chemotherapy-related effects with a follow-up period of 48 months post treatment was conducted. A total of 369 peripheral blood samples were collected from 123 de novo breast cancer patients. Microsatellite instability and loss of heterozygosity in five commonly used marker loci (including Tp53-Alu of the tumor suppressor gene TP53) were analyzed in blood samples. Sampling was conducted on three occasions; 4–5 weeks prior to the first chemotherapy session (pre-treatment), to serve as a baseline, followed by two consecutive draws at 12 weeks intervals from the first collection. Mismatch repair protein expression was evaluated in cancer tissues using immunohistochemistry for three mismatch-repair related proteins.ResultsA total of 70.7% of the patients showed microsatellite instability for at least one locus, including 18.6% marked as high-positive and 52.1% as low-positive; 35.8% showed loss of heterozygosity in addition to microsatellite instability, while 29.3% exhibited microsatellite stability. The following incidence rates for microsatellite instability and loss of heterozygosity were detected: 39.1% positive for Tp53-Alu, 31.1% for locus Mfd41, and 25.3% for locus Mfd28. A higher occurrence of loss of heterozygosity was noted with alleles 399 and 404 of Tp53-Alu. The mismatch repair protein expression analysis showed that the chemotherapy caused a loss of 29.3% in hMLH1 expression, and 18.7% and 25.2% loss in hMSH2 and P53 expression, respectively. A strong correlation between low or deficient hMSH2 protein expression and occurrence of mismatch repair/loss of heterozygosity events in Mfd41, Tp53-Alu, and Mfd28 was evident. A significant association between mismatch repair/loss of heterozygosity and incidence of secondary tumors was also established.ConclusionOur results suggest that microsatellite instability, loss of heterozygosity, and deficiency in mismatch repair may serve as early prognostic factors for potential chemotherapy-related side effects in breast cancer patients.

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Section: Discussionmentioning

confidence: 99%

High incidence of microsatellite instability and loss of heterozygosity in three loci in breast cancer patients receiving chemotherapy: a prospective study

Kamat

Khidhir²,

Jaloudi

et al. 2012

BMC Cancer

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“…Thus, the increased frequency of breast cancer in outer quadrants is related to the presence of elevated genomic instabilities [65]. LOH was also studied on samples from 30 women with grade 1 and grade 3 DCIS, and 6 patients who subsequently developed invasive cancer [11]. At four chromosomal loci (6q, 11p, 17p and 17q), there were higher losses in grade 3 compared to grade 1 DCIS, however, the fractional allelic loss at 19 loci was significantly higher in grade 1 than in grade 3 DCIS.…”

Section: Field Cancerization Is Probably a General Phenomenon Of Epitmentioning

confidence: 99%

“…At four chromosomal loci (6q, 11p, 17p and 17q), there were higher losses in grade 3 compared to grade 1 DCIS, however, the fractional allelic loss at 19 loci was significantly higher in grade 1 than in grade 3 DCIS. As well, LOH in DCIS and corresponding invasive breast cancer were heterogeneous [11]. On the contrary, a previous study had indicated the possible progressive nature of DCIS to invasive ductal carcinoma (IDC) using similar LOH analysis.…”

Section: Field Cancerization Is Probably a General Phenomenon Of Epitmentioning

confidence: 99%

“…Multiple tumors in these organs are likely to originate from polyclonal tumor stem cells, although these clones may have identical genetic alterations. For example, loss of heterozygosity (LOH) in primary ductal carcinoma in situ (DCIS) were distinct from those in their corresponding cancers, suggesting that some DCIS and subsequent adenocarcinoma in the same breast developed from genetically divergent clones [11]. Furthermore, a study of microdissected normal glands and their co-existing malignant epithelia from breast cancer specimens demonstrated that only one had identical LOH to the cancer, with the majority harboring LOH at different genetic loci from the tumor [12].…”

Section: Introductionmentioning

confidence: 99%

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Clinical implications and utility of field cancerization

et al. 2007

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Cancer begins with multiple cumulative epigenetic and genetic alterations that sequencially transform a cell, or a group of cells in a particular organ. The early genetic events might lead to clonal expansion of pre-neoplastic daughter cells in a particular tumor field. Subsequent genomic changes in some of these cells drive them towards the malignant phenotype. These transformed cells are diagnosed histopathologically as cancers owing to changes in cell morphology. Conceivably, a population of daughter cells with early genetic changes (without histopathology) remain in the organ, demonstrating the concept of field cancerization. With present technological advancement, including laser capture microdisection and high-throughput genomic technologies, carefully designed studies using appropriate control tissue will enable identification of important molecular signatures in these genetically transformed but histologically normal cells. Such tumorspecific biomarkers should have excellent clinical utility. This review examines the concept of field cancerization in several cancers and its possible utility in four areas of oncology; risk assessment, early cancer detection, monitoring of tumor progression and definition of tumor margins.

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“…However, MFBC behaves more aggressively than unifocal breast cancer of a similar size hence there is a necessity for further research into its biology. It has been previously demonstrated by allelotyping that multiple breast lesions may exhibit distinct clonal patterns at the molecular level [10,11]. A similar study to identify molecular heterogeneity between tumour foci in MFBC, as defined in this paper, is underway.…”

Section: Score For Proportionmentioning

confidence: 91%

Oestrogen and progesterone receptor status of individual foci in multifocal invasive ductal breast cancer

Garimella¹,

Long²,

O’Kane³

et al. 2007

Acta Oncologica

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Ductal carcinoma in situ of the breast with different histopathological grades and corresponding new breast tumour events: Analysis of loss of heterozygosity

Cited by 13 publications

References 24 publications

High incidence of microsatellite instability and loss of heterozygosity in three loci in breast cancer patients receiving chemotherapy: a prospective study

High incidence of microsatellite instability and loss of heterozygosity in three loci in breast cancer patients receiving chemotherapy: a prospective study

Clinical implications and utility of field cancerization

Oestrogen and progesterone receptor status of individual foci in multifocal invasive ductal breast cancer

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