Packwood, Katie, Martland, Guy, Sommerlad, Matthew, Shaw, Emily, Moutasim, Karwan, Thomas, Gareth, Bateman, Adrian, Jones, Louise, Haywood, Linda, Evans, D. Gareth, Birch, Jillian, Alsalmi, Ohud Abdullah, Henderson, Alex, Poplawski, Nicola and Eccles, Diana (2019) 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). The Journal of Pathology: Clinical Research, 1-10. (doi:10.1002/cjp2.133).
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, αvβ6 integrin, α-SMA and pSMAD2/3 was performed on tissue microarrays (TMA) of invasive carcinoma. We confirmed a previously reported high prevalence of HER2-amplified, ductal no special type (NST) invasive breast carcinoma amongst known TP53 germline pathogenic variant carriers 20/36 (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 TGFβ signalling.
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