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Full sequencing of TP53 identifies identical mutations within in situ and invasive components in breast cancer suggesting clonal evolution
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
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2009 (English)In: Molecular Oncology, ISSN 1574-7891, Vol. 3, no 3, 214-219 p.Article in journal (Refereed) Published
Abstract [en]

In breast cancer, previous studies have suggested that somatic TP53 mutations are likely to be an early event. However, there are controversies regarding the cellular origin and linear course of breast cancer. The purpose of this study was to investigate tumor evolution in breast cancer by analyzing TP53 mutation status in tumors from various stages of the disease. The entire coding sequence of TP53 was sequenced in a cohort of pure ductal carcinoma in situ (DCIS), pure invasive cancer (</=15mm) and mixed lesions (i.e. invasive cancer with an in situ component). Of 118 tumor samples, 19 were found to harbor a TP53 mutation; 5 (15.6%) of the pure DCIS, 4 (10.5%) of the pure invasive cancers and 10 (20.8%) of the mixed lesions. In the mixed lesions, both the invasive and the DCIS components showed the same mutation in all 5 cases where the two components were successfully microdissected. Presence of the same mutation in both DCIS and invasive components from the same tumor indicates same cellular origin. The role of mutant TP53 in the progression of breast cancer is less clear and may vary between subtypes.

Place, publisher, year, edition, pages
2009. Vol. 3, no 3, 214-219 p.
Keyword [en]
TP53 mutation, Breast cancer, DCIS
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-113745DOI: 10.1016/j.molonc.2009.03.001ISI: 000266853200004PubMedID: 19403344OAI: oai:DiVA.org:uu-113745DiVA: diva2:291838
Available from: 2010-02-03 Created: 2010-02-03 Last updated: 2012-02-15Bibliographically approved
In thesis
1. Aspects of Progression in Breast Carcinoma: from ductal carcinoma in situ to invasive cancer
Open this publication in new window or tab >>Aspects of Progression in Breast Carcinoma: from ductal carcinoma in situ to invasive cancer
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the past decades our knowledge concerning breast cancer progression from ductal carcinoma in situ (DCIS) to invasive cancer has grown rapidly. However, molecular factors driving the progression are still largely unknown.

In the first study, we investigated tumor evolution in breast cancer by analyzing TP53 mutation status in tumors from various stages of the disease. Presence of the same TP53 mutations in both DCIS and invasive components from the same tumor indicates same cellular origin. The role of mutant TP53 in the progression of breast cancer is less clear and may vary between subtypes.

In the second study, we studied the prognosis of basal-like DCIS in a large population-based cohort. Basal-like DCIS was associated with about doubled but not statistically significant risk for local recurrence compared with the other molecular subtypes. Molecular subtype was a better prognostic parameter than histopathological grade.

In the third study, we studied markers in primary DCIS in relation to type of recurrence. Interestingly, recurrences after an ER-/HER2+, ER negative or EGFR positive primary DCIS were more often of the in situ type. The molecular subtype ER+/HER2+, FOXA1 positivity and FOXC1 positivity were risk factors for any recurrence.

In the fourth study, we proposed a histological classification system for a new entity: neoductgenesis. We also evaluated histologic criteria for neoductgenesis. According to our criteria, good agreements among pathologists were achieved. Neoductgenesis was related to more aggressive tumor biology and to mammographic features. The result indicates potential benefits for women earlier considered having pure DCIS but later diagnosed as breast carcinoma with neoductgenesis, suggesting a need to develop appropriate treatment regiments. Our findings have to be repeated and the relation to prognosis warrants further studies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 38 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 735
Keyword
progression, ductal carcinoma in situ, breast cancer
National Category
Cancer and Oncology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-166745 (URN)978-91-554-8256-5 (ISBN)
Public defence
2012-02-25, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:00 (English)
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Supervisors
Available from: 2012-02-06 Created: 2012-01-13 Last updated: 2012-02-15Bibliographically approved

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