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Breast cancer: Multifocality, heterogeneity, and related genetic signatures
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Dep. of Immunoloy, Genetics and Pathology (IGP))
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Breast carcinoma often exhibits a complex subgross morphology and may occupy a large volume of the breast tissue and show unifocal, multifocal or diffuse growth patterns. Expression of estrogen- and progesterone receptors, HER2 overexpression, tumor grade, and proliferative activity allows us to classify breast carcinoma into molecular subgroups (Luminal A, Luminal B, HER2-type, triple negative, and basal-like).

We studied the relation of the spatial distribution of the lesions and their molecular phenotype in a consecutive series of 444 invasive breast carcinomas documented in large-format histology slides (paper I). The cumulative survival of patients diagnosed with unifocal cancer was significantly better than those who had multifocal or diffuse tumors in the luminal A, HER2-positive, and basal-like subgroups.

We also studied the influence of intertumoral heterogeneity on survival in110 multifocal breast carcinomas (paper II). Patients with phenotypically heterogeneous multifocal cancers had a greater risk of dying from the disease (HR=2.879; 95%CI=1.08–7.65; P=0.034) and significantly shorter survival compared to non-heterogeneous cancers.

The methodological issues regarding tissue sampling in multifocal breast carcinomas were addressed in paper III. A single 2 mm core from tumors contained sufficient DNA (> 2 µg) in most samples. Three cores using a 4-mm device were needed to obtain sufficient DNA from normal breast tissue.

In paper IV, we focused on copy number aberrations in cancer-free breast tissue in a series of 282 breast cancer patients. Genome-wide Illumina SNP analysis was performed on fresh frozen samples and the results were morphologically confirmed in tissue samples adjacent to the fresh sample holes from large-section blocks using ERBB2/HER2 gene–protein assay. We observed genetic aberrations in normal breast tissue from 38.3% of patients. Gain of ERBB2 gene was the most common but additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR and NGFR) also showed recurrent gains.

In conclusion, multifocality and phenotypical heterogeneity has an impact on patient survival. Post-zygotic structural genetic aberrations can often be observed in cancer-free breast tissue. Low copy number gain of ERBB2 is the most common aberration in normal breast cells and represents a cancer-predisposing mutation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 56 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1204
Keyword [en]
breast, breast cancer multifocality, molecular phenotypes, intertumoral heterogeneity, biobanking, gene copy number aberrations
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-282336ISBN: 978-91-554-9531-2OAI: oai:DiVA.org:uu-282336DiVA: diva2:916873
Public defence
2016-05-18, Högskolan Dalarna, Högskolegatan 2, 791 31 Falun, Falun, 13:00 (English)
Opponent
Supervisors
Available from: 2016-04-27 Created: 2016-04-05 Last updated: 2016-04-27
List of papers
1. Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer
Open this publication in new window or tab >>Signatures of post-zygotic structural genetic aberrations in the cells of histologically normal breast tissue that can predispose to sporadic breast cancer
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2015 (English)In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 25, no 10, 1521-1535 p.Article in journal (Refereed) Published
Abstract [en]

Sporadic breast cancer (SBC) is a common disease without robust means of early risk prediction in the population. We studied 282 females with SBC, focusing on copy number aberrations in cancer-free breast tissue (uninvolved margin, UM) outside the primary tumor (PT). In total, 1162 UMs (1-14 per breast) were studied. Comparative analysis between UM(s), PT(s), and blood/skin from the same patient as a control is the core of the study design. We identified 108 patients with at least one aberrant UM, representing 38.3% of cases. Gains in gene copy number were the principal type of mutations in microscopically normal breast cells, suggesting that oncogenic activation of genes via increased gene copy number is a predominant mechanism for initiation of SBC pathogenesis. The gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional growth factor receptor genes (EGFR, FGFR1, IGF1R, LIFR, and NGFR) also showed recurrent gains, and these were occasionally present in combination with the gain of ERBB2. All the aberrations found in the normal breast cells were previously described in cancer literature, suggesting their causative, driving role in pathogenesis of SBC. We demonstrate that analysis of normal cells from cancer patients leads to identification of signatures that may increase risk of SBC and our results could influence the choice of surgical intervention to remove all predisposing cells. Early detection of copy number gains suggesting a predisposition toward cancer development, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine for breast cancer.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-265683 (URN)10.1101/gr.187823.114 (DOI)000362157400016 ()26430163 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilSwedish Heart Lung FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2015-11-04 Created: 2015-11-02 Last updated: 2016-09-08Bibliographically approved
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4. Biobanking multifocal breast carcinomas: sample adequacy with regard to histology and DNA content
Open this publication in new window or tab >>Biobanking multifocal breast carcinomas: sample adequacy with regard to histology and DNA content
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2016 (English)In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 68, no 3, 411-421 p.Article in journal (Refereed) Published
Abstract [en]

AIMS: To determine the volume of tumoral and normal breast tissue containing sufficient DNA (>2 μg/sample) for genetic platforms and biobanking, with a focus on multifocality, tumoral heterogeneity, and factors that critically influence sample acceptability.

METHODS AND RESULTS: We examined 57 breast surgical specimens with multifocal (46/57) and unifocal (11/57) cancers. Punch biopsies were obtained from tissue slices under multimodal radiological guidance, and the colour-coded sampling sites were identified in large-format histology slides. The study comprised 415 DNA isolations from tumour (n = 105) and normal (n = 283) tissue, including skin (n = 27) samples. A single 2-mm core from invasive tumour contained sufficient DNA in 91.4% (96/105) of cases, depending on tumour type (3.8-108.2 μg/sample), number and size of additional foci in multifocal cases (P = 0.001), tumour consistency, and degree of necrosis. Three biopsies obtained with a 4-mm device were required from normal breast tissue, at least 10 mm from the tumour. Cold ischaemia for up to 82 min did not influence the yield of DNA.

CONCLUSIONS: Radiological disease mapping is useful for guiding optimal specimen slicing and for targeting breast lesions. A single 2-mm core from tumour and multiple 4-mm cores from normal breast tissue yield adequate DNA in the majority of samples.

Keyword
biobanking; breast cancer; DNA quality and quantity; heterogeneity; multifocality
National Category
Medical and Health Sciences Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-271418 (URN)10.1111/his.12758 (DOI)000367819400011 ()26083274 (PubMedID)
Available from: 2016-01-07 Created: 2016-01-07 Last updated: 2016-09-08Bibliographically approved

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