Breast cancer : Multifocality, heterogeneity, and related genetic signatures

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Abstract: 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.

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