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J Pathol Clin Res. 2019 Apr 30. doi: 10.1002/cjp2.133. [Epub ahead of print]

Breast cancer in patients with germline TP53 pathogenic variants have typical tumour characteristics: the Cohort study of TP53 carrier early onset breast cancer (COPE study).

Author information

1
Faculty of Medicine, University of Southampton, Southampton, UK.
2
Cellular Pathology Department, Poole Hospital NHS Foundation Trust, Poole, UK.
3
Cellular Pathology Department, University Hospital NHS Foundation Trust, Southampton, UK.
4
Centre for Tumour Biology Department, Barts Cancer Institute, Queen Mary University of London, London, UK.
5
Department of Genomic Medicine, Division of Evolution and Genomic Science, University of Manchester, Manchester, UK.
6
School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
7
Northern Genetics Service, Newcastle upon Tyne Hospitals, Newcastle, UK.
8
Discipline of Paediatrics, Adelaide Medical School, University of Adelaide, Adelaide, Australia.

Abstract

Germline TP53 pathogenic variants are rare but associated with a high risk of cancer; they are often identified in the context of clinically diagnosed Li-Fraumeni syndrome predisposing to a range of young onset cancers including sarcomas and breast cancer. The study aim was to conduct a detailed morphological review and immuno-phenotyping of breast cancer arising in carriers of a germline TP53 pathogenic variant. We compared breast cancers from five defined groups: (1) TP53 carriers with breast cancer (n = 59), (2) early onset HER2-amplified breast cancer, no germline pathogenic variant in BRCA1/2 or TP53 (n = 55), (3) BRCA1 pathogenic variant carriers (n = 60); (4) BRCA2 pathogenic variant carriers (n = 61) and (5) young onset breast cancer with no known germline pathogenic variant (n = 98). Pathologists assessed a pre-agreed set of morphological characteristics using light microscopy. Immunohistochemistry (IHC) for HER2, ER, PR, p53, integrin alpha v beta 6 (αvβ6) integrin, α-smooth muscle actin (α-SMA) and pSMAD2/3 was performed on tissue microarrays of invasive carcinoma. We confirmed a previously reported high prevalence of HER2-amplified, ductal no special type invasive breast carcinoma amongst known TP53 germline pathogenic variant carriers 20 of 36 (56%). Furthermore we observed a high frequency of densely sclerotic tumour stroma in cancers from TP53 carriers (29/36, 80.6%) when compared with non-carriers, 50.9% (28/55), 34.7% (50/144), 41.4% (65/157), 43.8% (95/217) in groups 2-5 respectively. The majority of germline TP53 gene carrier breast tumours had a high intensity of integrin αvβ6, α-SMA and pSMAD2/3 expression in the majority of cancer cells. In conclusion, aggressive HER2 positive breast cancers with densely sclerotic stroma are common in germline TP53 carriers. High levels of αvβ6 integrin, α-SMA and pSMAD2/3 expression suggest that the dense stromal phenotype may be driven by upregulated transforming growth factor beta signalling.

KEYWORDS:

TP53 pathogenic variant; breast cancer; germline; stroma

PMID:
31041842
DOI:
10.1002/cjp2.133
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