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.
Highlights
The importance of functional wild-type p53 protein is exemplified by the fact that somatic pathogenic variants in TP53 are detected in more than 50% of all cancer types, more aggressive sub-types, which constitute 28% of breast cancers [1,2]
POSH cases were selected based on the following criteria – tissue block available, no known pathogenic variant in BRCA1, BRCA2 or TP53, invasive breast cancer reported as HER2 positive with associated ductal carcinoma in situ (DCIS)
Morphological assessment was included for young onset cases with a germline BRCA1 pathogenic variant, young onset cases with a germline BRCA2 pathogenic variant and 98 young onset breast cancer cases with no identifiable germline high risk pathogenic variant (BRCA1, BRCA2 or TP53) [21]
Summary
The importance of functional wild-type p53 protein is exemplified by the fact that somatic pathogenic variants in TP53 are detected in more than 50% of all cancer types, more aggressive sub-types, which constitute 28% of breast cancers [1,2]. TP53 encodes the p53 protein which has been referred to as ‘the guardian of the genome’ due to its crucial function in maintaining cellular homeostasis including cell cycle arrest, apoptosis, angiogenesis, metabolism, DNA damage and senescence in response to a number of genotoxic stressors [5]. It has been recognised for over two decades that breast cancers associated with BRCA1 pathogenic variants are predominantly triple receptor (ER, PR and HER2) negative, high grade invasive ductal carcinomas with high numbers of tumour infiltrating lymphocytes (TILs) [6,7,8,9,10]. We were interested to describe the tumour features and the characteristics of the tumour microenvironment (TME), the stroma and presence or absence of TILs given the growing interest in the therapeutic barriers and opportunities of the TME
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