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4. Clinical Validation of PITX2 DNA Methylation to Predict Outcome in High-Risk Breast Cancer Patients Treated with Anthracycline-Based Chemotherapy

Author

Schmitt, M. (Manfred), Wilhelm, O.G. (Olaf G.), Noske, A. (Aurelia), Schricker, G. (Gabriele), Napieralski, R., Vetter, M. (Martina), Aubele, M. (Michaela), Perkins, J. (Jonathan), Lauber, J. (Jürgen), Ulm, K. (Kurt), Thomssen, C. (Christoph), Martens, J.W.M. (John), Weichert, W. (Wilko), Kiechle, M. (Marion), Schmitt, M. (Manfred), Wilhelm, O.G. (Olaf G.), Noske, A. (Aurelia), Schricker, G. (Gabriele), Napieralski, R., Vetter, M. (Martina), Aubele, M. (Michaela), Perkins, J. (Jonathan), Lauber, J. (Jürgen), Ulm, K. (Kurt), Thomssen, C. (Christoph), Martens, J.W.M. (John), Weichert, W. (Wilko), and Kiechle, M. (Marion)

Abstract

Background: Breast cancer patients at high risk for recurrence are treated with anthracycline-based chemotherapy, but not all patients do equally benefit from such a regimen. To further improve therapy decision-making, biomarkers predicting outcome are of high unmet medical need. Methods: The percent DNA methylation ratio (PMR) of the promoter gene coding for the Paired-like homeodomain transcription factor 2 (PITX2) was determined by a validated methylation-specific real-time polymerase chain reaction (PCR) test. The multicenter study was conducted in routinely collected archived formalin-fixed paraffin-embedded (FFPE) tissue from 205 lymph node-positive breast cancer patients treated with adjuvant anthracycline-based chemotherapy. Results: The cut-off for the PITX2 methylation status (PMR = 12) was confirmed in a randomly selected cohort (n = 60) and validated (n = 145) prospectively with disease-free survival (DFS) at the 10-year follow-up. DFS was significantly different between the PMR ≤ 12 versus the PMR > 12 group with a hazard ratio (HR) of 2.74 (p < 0.001) in the validation cohort and also for the patient subgroup treated additionally with endocrine therapy (HR 2.47; p = 0.001). Conclusions: Early-stage lymph node-positive breast cancer patients with low PITX2 methylation do benefit from adjuvant anthracycline-based chemotherapy. Patients with a high PITX2 DNA methylation ratio, approximately 30%, show poor outcome and should thus be considered for alternative chemotherapy regimens.

Published
2018
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6. Tissue kallikrein-related peptidase 4 (KLK4), a novel biomarker in triple-negative breast cancer

Author

Aubele, M., Walch, A., Gross, E., Napieralski, R., Zhao, S., Ahmed, N., Kiechle, M., Reuning, U., Dorn, J., Sweep, C.G.J., Magdolen, V., Schmitt, M., Aubele, M., Walch, A., Gross, E., Napieralski, R., Zhao, S., Ahmed, N., Kiechle, M., Reuning, U., Dorn, J., Sweep, C.G.J., Magdolen, V., and Schmitt, M.

Abstract

Item does not contain fulltext, Triple-negative breast cancer (TNBC), lacking the steroid hormone receptors ER and PR and the oncoprotein HER2, is characterized by its aggressive pattern and insensitivity to endocrine and HER2-directed therapy. Human kallikrein-related peptidases KLK1-15 provide a rich source of serine protease-type biomarkers associated with tumor growth and cancer progression for a variety of malignant diseases. In this study, recombinant KLK4 protein was generated and affinity-purified KLK4-directed polyclonal antibody pAb587 established to allow localization of KLK4 protein expression in tumor cell lines and archived formalin-fixed, paraffin-embedded TNBC tumor tissue specimens. For this, KLK4 protein expression was assessed by immunohistochemistry in primary tumor tissue sections (tissue microarrays) of 188 TNBC patients, mainly treated with anthracycline- or CMF-based polychemotherapy. KLK4 protein is localized in the cytoplasm of tumor and stroma cells. In this patient cohort, elevated stroma cell KLK4 expression, but not tumor cell KLK4 expression, is predictive for poor disease-free survival by univariate analysis (hazard ratio: 2.26, p=0.001) and multivariable analysis (hazard ratio: 2.12, p<0.01). Likewise, univariate analysis revealed a trend for statistical significance of elevated KLK4 stroma cell expression for overall survival of TNBC patients as well.

Published
2017

7. Tissue kallikrein-related peptidase 4 (KLK4), a novel biomarker in triple-negative breast cancer

Author

Yang, F, Aubele, M., Walch, A., Gross, E., Napieralski, R., Zhao, S., Ahmed, N., Kiechle, M., Reuning, U., Dorn, J., Sweep, C.G.J., Magdolen, V., Schmitt, M., Yang, F, Aubele, M., Walch, A., Gross, E., Napieralski, R., Zhao, S., Ahmed, N., Kiechle, M., Reuning, U., Dorn, J., Sweep, C.G.J., Magdolen, V., and Schmitt, M.

Abstract

Item does not contain fulltext, Triple-negative breast cancer (TNBC), lacking the steroid hormone receptors ER and PR and the oncoprotein HER2, is characterized by its aggressive pattern and insensitivity to endocrine and HER2-directed therapy. Human kallikrein-related peptidases KLK1-15 provide a rich source of serine protease-type biomarkers associated with tumor growth and cancer progression for a variety of malignant diseases. In this study, recombinant KLK4 protein was generated and affinity-purified KLK4-directed polyclonal antibody pAb587 established to allow localization of KLK4 protein expression in tumor cell lines and archived formalin-fixed, paraffin-embedded TNBC tumor tissue specimens. For this, KLK4 protein expression was assessed by immunohistochemistry in primary tumor tissue sections (tissue microarrays) of 188 TNBC patients, mainly treated with anthracycline- or CMF-based polychemotherapy. KLK4 protein is localized in the cytoplasm of tumor and stroma cells. In this patient cohort, elevated stroma cell KLK4 expression, but not tumor cell KLK4 expression, is predictive for poor disease-free survival by univariate analysis (hazard ratio: 2.26, p=0.001) and multivariable analysis (hazard ratio: 2.12, p<0.01). Likewise, univariate analysis revealed a trend for statistical significance of elevated KLK4 stroma cell expression for overall survival of TNBC patients as well.

Published
2017

10. High-resolution MALDI-FT-ICR MS imaging for the analysis of metabolites from formalin-fixed, paraffin-embedded clinical tissue samples

Author

Buck, A., Ly, A., Balluff, B., Sun, N., Gorzolka, K., Feuchtinger, A., Janssen, K.P., Kuppen, P.J.K., Velde, C.J.H. van de, Weirich, G., Erlmeier, F., Langer, R., Aubele, M., Zitzelsberger, H., Aichler, M., and Walch, A.

Subjects
Male, Time Factors, Tissue Fixation, metabolite, imaging mass spectrometry, Disease-Free Survival, Diagnosis, Differential, Fixatives, Predictive Value of Tests, Formaldehyde, Germany, Neoplasms, Biomarkers, Tumor, Cluster Analysis, Humans, Metabolomics, cancer, 610 Medicine & health, formalin-fixed paraffin-embedded tissue, MALDI, Netherlands, Proportional Hazards Models, Paraffin Embedding, Imaging Mass Spectrometry, Maldi, Cancer, Formalin-fixed Paraffin-embedded Tissue, Metabolite, Fourier Analysis, Computational Biology, Reproducibility of Results, Cyclotrons, Treatment Outcome, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, 570 Life sciences, biology, Female
Abstract

We present the first analytical approach to demonstrate the in situ imaging of metabolites from formalin-fixed, paraffin-embedded (FFPE) human tissue samples. Using high-resolution matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry imaging (MALDI-FT-ICR MSI), we conducted a proof-of-principle experiment comparing metabolite measurements from FFPE and fresh frozen tissue sections, and found an overlap of 72% amongst 1700 m/z species. In particular, we observed conservation of biomedically relevant information at the metabolite level in FFPE tissues. In biomedical applications, we analysed tissues from 350 different cancer patients and were able to discriminate between normal and tumour tissues, and different tumours from the same organ, and found an independent prognostic factor for patient survival. This study demonstrates the ability to measure metabolites in FFPE tissues using MALDI-FT-ICR MSI, which can then be assigned to histology and clinical parameters. Our approach is a major technical, histochemical, and clinicopathological advance that highlights the potential for investigating diseases in archived FFPE tissues.

Published
2015
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11. Lifetime Study in mice: 24 months follow up after low doses of ionizing radiation with Scheimpflug imaging and OCT

Author

Dalke, C., primary, Rößler, U., additional, Neff, F., additional, Greiter, M., additional, Gomolka, M., additional, Hornhardt, S., additional, Garrett, L., additional, Kunze, S., additional, Unger, K., additional, Rosemann, M., additional, Kempf, S.J., additional, Azimzadeh, O., additional, Wurst, W., additional, Aubele, M., additional, Zitzelsberger, H., additional, Hölter, S.M., additional, Tapio, S., additional, Hoeschen, C., additional, Kulka, U., additional, Atkinson, M., additional, and Graw, J., additional

Published
2016
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13. Lifetime study in mice for radiation-induced cataracts

Author

Dalke, C., primary, Rößler, U., additional, Neff, F., additional, Greiter, M., additional, Gomolka, M., additional, Hornhardt, S., additional, Unger, K., additional, Garrett, L., additional, Rosemann, M., additional, Kempf, S., additional, Azimzadeh, O., additional, Wurst, W., additional, Aubele, M., additional, Zitzelsberger, H., additional, Hölter, S., additional, Tapio, S., additional, Hoeschen, C., additional, Kulka, U., additional, Atkinson, M., additional, and Graw, J., additional

Published
2015
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20. Somatic copy number changes in DPYD are associated with lower risk of recurrence in triple-negative breast cancers.

Author

Gross, E, Meul, C, Raab, S, Propping, C, Avril, S, Aubele, M, Gkazepis, A, Schuster, T, Grebenchtchikov, N, Schmitt, M, Kiechle, M, Meijer, J, Vijzelaar, R, Meindl, A, van Kuilenburg, ABP, Gross, E, Meul, C, Raab, S, Propping, C, Avril, S, Aubele, M, Gkazepis, A, Schuster, T, Grebenchtchikov, N, Schmitt, M, Kiechle, M, Meijer, J, Vijzelaar, R, Meindl, A, and van Kuilenburg, ABP

Abstract

BACKGROUND: Genomic rearrangements at the fragile site FRA1E may disrupt the dihydropyrimidine dehydrogenase gene (DPYD) which is involved in 5-fluorouracil (5-FU) catabolism. In triple-negative breast cancer (TNBC), a subtype of breast cancer frequently deficient in DNA repair, we have investigated the susceptibility to acquire copy number variations (CNVs) in DPYD and evaluated their impact on standard adjuvant treatment. METHODS: DPYD CNVs were analysed in 106 TNBC tumour specimens using multiplex ligation-dependent probe amplification (MLPA) analysis. Dihydropyrimidine dehydrogenase (DPD) expression was determined by immunohistochemistry in 146 tumour tissues. RESULTS: In TNBC, we detected 43 (41%) tumour specimens with genomic deletions and/or duplications within DPYD which were associated with higher histological grade (P=0.006) and with rearrangements in the DNA repair gene BRCA1 (P=0.007). Immunohistochemical analysis revealed low, moderate and high DPD expression in 64%, 29% and 7% of all TNBCs, and in 40%, 53% and 7% of TNBCs with DPYD CNVs, respectively. Irrespective of DPD protein levels, the presence of CNVs was significantly related to longer time to progression in patients who had received 5-FU- and/or anthracycline-based polychemotherapy (hazard ratio=0.26 (95% CI: 0.07-0.91), log-rank P=0.023; adjusted for tumour stage: P=0.037). CONCLUSION: Genomic rearrangements in DPYD, rather than aberrant DPD protein levels, reflect a distinct tumour profile associated with prolonged time to progression upon first-line chemotherapy in TNBC.

Published
2013

21. Her-2/neu gene amplification, elevated mRNA expression, and protein overexpression in the metaplasia-dysplasia-adenocarcinoma sequence of Barrett's esophagus

Author

Walch, A.K., Specht, K., Bink, K., Zitzelsberger, H., Braselmann, H., Bauer, M., Aubele, M., Stein, H., Siewert, J.R., Höfler, H., and Werner, M.

Subjects
skin and connective tissue diseases
Abstract

SUMMARY: The importance of alterations of the Her-2/neu oncogene in the tumorigenesis of Barrett's adenocarcinoma (BCA) is discussed controversially. In the present study, we evaluated for the first time the Her-2/neu status in the metaplasia-dysplasia-adenocarcinoma sequence of BCA simultaneously at the DNA, mRNA, and protein level using resection specimens of 25 patients. The locus-specific Her-2/neu gene status was quantified by performing fluorescence in situ hybridization, and information about the ploidy status of chromosome 17 was obtained. Tissue sections from the same areas were used for quantitative RT-PCR (TaqMan RT-PCR) of laser-microdissected tumor cells and for immunohistochemistry to quantify Her-2/neu mRNA and oncoprotein expression. Her-2/neu gene amplification was observed in 35% of BCA, and all of these samples showed strong overexpression of both mRNA and oncoprotein. A polysomy 17 without Her-2/neu gene amplification was observed in 52% of BCA, showing a normal or moderately elevated mRNA expression and no or weak immunopositivity. From 13 areas of high-grade dysplasia (HGD) we found four to be amplified for the Her-2/neu locus, whereas five showed a polysomy 17. All four samples of HGD areas with Her-2/neu gene amplification displayed mRNA and strong oncoprotein overexpression; however, lower mRNA levels were seen than in the amplified BCA areas. None of the samples with low-grade dysplasia (LGD) showed a locus-specific Her-2/neu amplification, but polysomy 17 was present in four of eight cases. No changes were detected in BCA-associated intestinal metaplasia and squamous epithelium. In summary, only a locus-specific Her-2/neu gene amplification was associated with strong mRNA overexpression and strong membranous Her-2/neu immunostaining in BCA and HGD. A chromosome 17 polysomy, as found in the majority of BCA, led to no or weak mRNA overexpression and no or weak immunopositivity. In the metaplasia-dysplasia-adenocarcinoma sequence, a chromosome 17 polysomy without Her-2/neu gene amplification was already present in LGD. This may be a result of an early polyploidization, preceding the later genetic events, such as Her-2/neu gene amplification in HGD and BCA.

Published
2001

22. Chromosomal imbalances in Barrett's adenocarcinoma and the metaplasia-dysplasia-carcinoma sequence

Author

Walch, A.K., Zitzelsberger, H., Bruch, J., Keller, G., Angermeier, D., Aubele, M., Müller, J., Stein, H., Braselmann, H., Siewert, J.R., Höfler, H., and Werner, M.

Abstract

To characterize cytogenetic alterations found in Barrett's adenocarcinoma (BA) and, more importantly, its premalignant stages, we studied chromosomal imbalances in various lesions in the histologically proposed metaplasia-dysplasia-carcinoma sequence using comparative genomic hybridization (CGH). Using 30 esophageal adenocarcinoma resection specimens, we were able to study 30 areas of Barrett's adenocarcinoma and 8 lymph node metastases (LN). In addition, we investigated 25 premalignant lesions adjacent to BA derived from a subset of 14 resection specimens including 11 areas of high grade dysplasia (HGD), 8 areas of low grade dysplasia (LGD), and 6 areas of intestinal metaplasia (IM), which were laser-microdissected and studied with CGH. To validate the CGH findings, fluorescence in situ hybridization analysis on 13 BA with probes specific for HER-2/neu and 20q13.2 were performed. The chromosomal alterations most often identified in BA were: gains on 8q (80%), 20q (60%), 2p, 7p and 10q (47% each), 6p (37%), 15q (33%) and 17q (30%). Losses were observed predominantly on the Y-chromosome (76%), 4q (50%), 5q and 9p (43% each), 18q (40%), 7q (33%) and 14q (30%). High-level amplifications were observed on 8q23-qter, 8p12-pter, 7p11-p14, 7q21-31, 17q11-q23. Recurrent chromosomal changes were also identified in metaplastic (gains on 8q, 6p, 10q, losses on 13q, Y, 9p) and dysplastic epithelium (gains on 8q, 20q, 2p, 10q, 15q, losses on Y, 5q, 9p, 13q, 18q). Novel amplified chromosomal regions on chromosomes 2p and 10q were detected in both Barrett's adenocarcinoma and premalignant lesions. An increase of the average number of detected chromosomal imbalances from IM (7.0 +/- 1.7), to LGD (10.8 +/- 2.2), HGD (13.4 +/- 1.1), BA (13.3 +/- 1.4), and LN (22 +/- 1.2) was seen. Although the detection of common chromosomal alterations in premalignant lesions and adjacent carcinomas suggest a process of clonal expansion, the occurrence of several chromosomal changes in an apparently random order relative to one another is striking evidence that clonal evolution is more complex than would be predicted by linear models. This is probably a reflection of the existence of many divergent neoplastic subpopulations and highlights one of the main problems associated with surveillance of Barrett's patients, namely sampling error.

Published
2000

23. Extensive ductal carcinoma in situ with small foci of invasive ductal carcinoma: Evidence of genetic resemblance by CGH

Author

Aubele, M., Mattis, A., Zitzelsberger, H., Walch, A.K., Kremer, M., Welzl, G., Höfler, H., and Werner, M.

Subjects
body regions, skin and connective tissue diseases, neoplasms
Abstract

Although ductal carcinoma in situ (DCIS) of the breast is accepted as a potential precursor lesion for invasive ductal cancer (IDC), the critical genetic events associated with the tumor progression remain unknown. Since some extensive DCIS may show a small focus of IDC, these cases seem to be particularly suitable to investigate the primary abnormalities that determine the progression from in situ to early invasive cancer. We combined laser-microdissection with degenerative oligonucleotide-primed PCR (DOP-PCR) and comparative genomic hybridization (CGH) to detect copy number changes in 7 cases of extensive (>4 cm) DCIS with 1 small adjacent invasive focus. In 3 of the cases, single lymph node metastases (LN) were already present and were also investigated. Analysis of DCIS, IDC and LN components in the same patients revealed several consistent chromosomal changes present at all 3 sites: 1q, 7q, 8q, 16, 17, 19, 20q, 21q and 22q, the most frequent losses on 4q, 11q and 13q. DNA gain on 3p and 12q were more frequently found in IDC than in DCIS, suggesting the presence of proto-oncogenes activated during the progression to invasive cancer on these regions. Using paired analysis, resemblence of alterations found in DCIS and IDC could be quantified (odds ratio 7.0, p< or = 0.01). Gains on 6p, 10q, 14q and 15q and losses on 9p were identified in DCIS and IDC but not in LN, which may, therefore, represent early events in the carcinogenic process. Additional losses were found in the LNs on 2q, 3q, 5q, 6q, 12q and 16q. CGH results on chromosome 1 and 20 were confirmed by FISH and on chromosomal region 9p by microsatellite analyses. Our findings strongly underline the precursor status of high-grade DCIS, in which most of the chromosomal changes identified in IDC are already present. However, although the early stages of breast cancer, i.e., DCIS and the small foci of IDC were mainly characterized by DNA gains, the progression to metastatic tumor (LN) must have involved additional DNA losses on several regions.

Published
2000

25. Somatic copy number changes in DPYD are associated with lower risk of recurrence in triple-negative breast cancers

Author

Gross, E, primary, Meul, C, additional, Raab, S, additional, Propping, C, additional, Avril, S, additional, Aubele, M, additional, Gkazepis, A, additional, Schuster, T, additional, Grebenchtchikov, N, additional, Schmitt, M, additional, Kiechle, M, additional, Meijer, J, additional, Vijzelaar, R, additional, Meindl, A, additional, and van Kuilenburg, A B P, additional

Published
2013
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30. Specific steps in aneuploidization correlate with loss of heterozygosity of 9p21, 17p13 and 18q21 in the progression of pre-malignant laryngeal lesions.

Author

Veltman, I.M., Weert, I. van, Aubele, M., Bot, F.J., Ramaekers, F.C.S., Manni, J.J., Hopman, A.H.N., Veltman, I.M., Weert, I. van, Aubele, M., Bot, F.J., Ramaekers, F.C.S., Manni, J.J., and Hopman, A.H.N.

Abstract

Item does not contain fulltext, Laryngeal squamous-cell carcinoma is often preceded by pre-malignant lesions. In this study, pre-malignant as well as malignant laryngeal lesions were analyzed using p53 immunohistochemistry and in situ hybridization for chromosomes 1, 7, 9, 17 and 18. Microsatellite analysis was performed on laser-microdissected tissue fragments with the aim of studying loss of heterozygosity (LOH) of 9p21, 17p13 and 18q21. Sequential biopsies were analyzed from a few cases to study genetic progression in more detail. The following genetic progression patterns were observed: (i) histologically normal mucosa and hyperplastic lesions without malignant progression were typically disomic for all chromosomes tested and showed no or only basal cell layer positivity for p53 and no allelic loss; (ii) hyperplastic lesions preceding dysplastic/invasive growth frequently showed trisomy for chromosome 7 and LOH of 9p21 and 17p13, and small foci within these lesions sometimes showed tetraploidization and p53 positivity; (iii) dysplastic lesions were characterized by a tetraploid chromosome content, LOH of 9p21 and 17p13 and p53 positivity; (iv) carcinoma in situ lesions and invasive laryngeal carcinomas showed a more unbalanced chromosome pattern and an additional 18q21 LOH. These results show that different steps in aneuploidization correlate with LOH of 9p21, 17p13 and 18q21 in early laryngeal carcinogenesis. These genomic changes could be of potential use in the diagnosis and prognosis of pre-malignant laryngeal lesions.

Published
2001

31. Specific steps in aneuploidization correlate with loss of heterozygosity of 9p21, 17p13 and 18q21 in the progression of pre-malignant laryngeal lesions.

Author

Veltman, J.A., Veltman, J.A., van Weert, I, Aubele, M., Bot, F.J., Ramaekers, F.C.S., Manni, J.J., Hopman, A.H.N., Veltman, J.A., Veltman, J.A., van Weert, I, Aubele, M., Bot, F.J., Ramaekers, F.C.S., Manni, J.J., and Hopman, A.H.N.

Abstract

Laryngeal squamous-cell carcinoma is often preceded by pre-malignant lesions. In this study, pre-malignant as well as malignant laryngeal lesions were analyzed using p53 immunohistochemistry and in situ hybridization for chromosomes 1, 7, 9, 17 and 18. Microsatellite analysis was performed on laser-microdissected tissue fragments with the aim of studying loss of heterozygosity (LOH) of 9p21, 17p13 and 18q21. Sequential biopsies were analyzed from a few cases to study genetic progression in more detail. The following genetic progression patterns were observed: (i) histologically normal mucosa and hyperplastic lesions without malignant progression were typically disomic for all chromosomes tested and showed no or only basal cell layer positivity for p53 and no allelic loss; (ii) hyperplastic lesions preceding dysplastic/invasive growth frequently showed trisomy for chromosome 7 and LOH of 9p21 and 17p13, and small foci within these lesions sometimes showed tetraploidization and p53 positivity; (iii) dysplastic lesions were characterized by a tetraploid chromosome content, LOH of 9p21 and 17p13 and p53 positivity; (iv) carcinoma in situ lesions and invasive laryngeal carcinomas showed a more unbalanced chromosome pattern and an additional 18q21 LOH, These results show that different steps in aneuploidization correlate with LOH of 9p21, 17p13 and 18q21 in early laryngeal carcinogenesis. These genomic changes could be of potential use in the diagnosis and prognosis of pre-malignant laryngeal lesions

Published
2001

44. 20q13.2 amplification in intraductal hyperplasia adjacent to in situ and invasive ductal carcinoma of the breast.

Author

Werner, M., Mattis, Anita, Aubele, Michaela, Cummings, Margaret, Zitzelsberger, Horst, Hutzler, Peter, Höfler, Heinz, Mattis, A, Aubele, M, Cummings, M, Zitzelsberger, H, Hutzler, P, and Höfler, H

Abstract

The 20q13 region harboring recently described putative oncogenes is frequently amplified in invasive ductal carcinoma (IDC). The aim of this study was to examine the 20q13 copy number in intraduct hyperplasia (IH), atypical duct hyperplasia (ADH), and ductal carcinoma in situ (DCIS) adjacent to IDC. In 5 patients, comparative genomic hybridization (CGH) after laser microdissection revealed 20q13 amplification in four of five cases of IH, in all of three cases of IH with atypia, all five of DCIS, and all five of IDC. Fluorescence in situ hybridization (FISH) confirmed the amplification at 20q13.2 in IH in the two specimens analyzed. The amplification rate, however, was higher in DCIS and IDC. In phenotypically normal ductal epithelium normal values were found for 20q13 copy number by FISH (n=2) and CGH (n=5). Although the number of cases presented here is small, our results suggest that mutations in the 20q13.2 region in IH may be associated with accelerated proliferation and hyperplasia of the ductal epithelium. Progression to DCIS and ICD is accompanied by a further increase in the 20q13.2 copy number. [ABSTRACT FROM AUTHOR]

Published
1999
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45. Genetic heterogeneity in a prostatic carcinoma and associated prostatic intraepithelial neoplasia as demonstrated by combined use of laser-microdissection, degenerate oligonucleotide primed PCR and comparative genomic hybridization.

Author

Zitzelsberger, H., Kulka, Ulrike, Lehmann, Lars, Walch, Axel, Smida, J., Aubele, Michaela, Lörch, Thomas, Höfler, Heinz, Bauchinger, Manfred, Werner, Martin, Kulka, U, Lehmann, L, Walch, A, Aubele, M, Lörch, T, Höfler, H, Bauchinger, M, and Werner, M

Abstract

We combined laser-assisted microdissection from H&E-stained paraffin sections, degenerated oligonucleotide-primed polymerase chain reaction (DOP-PCR), and comparative genomic hybridization (CGH) to analyse chromosomal imbalances in small tumour areas consisting of 50–100 cells. This approach was used to investigate intratumour genetic heterogeneity in a case of metastatic prostatic adenocarcinoma and chromosomal changes in areas of prostatic intraepithelial neoplasia (PIN) adjacent to the invasive tumour. In four microdissected invasive tumour areas with different histological patterns (acinar, cribriform, papillary and solid) marked intratumour heterogeneity was found by CGH. Recurrent chromosomal imbalances detected in at least two microdissected tumour areas were gains on 1p32→p36, 2p22, 3q21, 7, 8q21→q24, 11q12→q13, 16p12→p13, 17, 19 and loss on 16q23. Additional chromosomal changes were found in only one of the microdissected areas (gains on 16q21→q23, 20q22 and losses on 8p21→p23, 12p11→q12, 12q21→q26, 13q21→q34, 16q12, and 18q22). In PIN, gains on chromosomes 8q21→q24 and 17 were found in both samples investigated (low and high grade PIN), while gains on chromosomes 7, 11q, 12q, 16p, and 20q and losses on 2p, 8p21→p23, 12q were found only in one PIN area. Controls to ensure reliable CGH results consisted in CGH analyses of (i) approximately 80 microdissected normal epithelial cells, which showed no aberrations after DOP-PCR and (ii) larger cell numbers (approximately 105 or 107 cells) of the primary tumour investigated without DOP-PCR and partially displaying the chromosomal imbalances (gain on 16p12→p13, losses on 2p25, 8p21→p23, 12p11→p12, 12q21→q26, 18q22) found in the small microdissected areas. Microsatellite and FISH analyses further confirmed our CGH results from microdissected cells. The combined approach of laser-assisted microdissection, DOP-PCR and CGH is suitable to identify early genetic changes in PIN and chromosomal imbalances associated with the particular histological patterns of invasive prostatic adenocarcinoma. [ABSTRACT FROM AUTHOR]

Published
1998
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49. Cytometric prognostic parameters in breast cancer

Author

Aubele, M., Gert Auer, and Hofler

Subjects
Adult, Aged, 80 and over, Analysis of Variance, Lymphatic Metastasis, Humans, Breast Neoplasms, Female, DNA, Neoplasm, Middle Aged, Prognosis, Diploidy, Aged
Abstract

Prognostic parameters were examined in a retrospective survey of 730 cases of overt distant metastasis-free invasive breast cancer. A multivariate combination of cytometric and clinical parameters allowed the stratification of patients into five prognostic categories. In the low-risk group the distant recurrence rate was only 3.3%, In the highest risk group 57%. We conclude that cytometric parameters can increase the precision of prognostic evaluation in invasive breast cancers, and thus aid in decisions.

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