Matrix Gla protein (MGP), GATA3, and TRPS1: a novel diagnostic panel to determine breast origin

Abstract

Background Metastatic breast carcinoma is commonly considered during differential diagnosis when metastatic disease is detected in females. In addition to the tumor morphology and documented clinical history, sensitive and specific immunohistochemical (IHC) markers such as GCDFP-15, mammaglobin, and GATA3 are helpful for determining breast origin. However, these markers are reported to show lower sensitivity in certain subtypes, such as triple-negative breast cancer (TNBC). Materials and methods Using bioinformatics analyses, we identified a potential diagnostic panel to determine breast origin: matrix Gla protein (MGP), transcriptional repressor GATA binding 1 (TRPS1), and GATA-binding protein 3 (GATA3). We compared MGP, TRPS1, and GATA3 expression in different subtypes of breast carcinoma of (n = 1201) using IHC. As a newly identified marker, MGP expression was also evaluated in solid tumors (n = 2384) and normal tissues (n = 1351) from different organs. Results MGP and TRPS1 had comparable positive expression in HER2-positive (91.2% vs. 92.0%, p = 0.79) and TNBC subtypes (87.3% vs. 91.2%, p = 0.18). GATA3 expression was lower than MGP (p < 0.001) or TRPS1 (p < 0.001), especially in HER2-positive (77.0%, p < 0.001) and TNBC (43.3%, p < 0.001) subtypes. TRPS1 had the highest positivity rate (97.9%) in metaplastic TNBCs, followed by MGP (88.6%), while only 47.1% of metaplastic TNBCs were positive for GATA3. When using MGP, GATA3, and TRPS1 as a novel IHC panel, 93.0% of breast carcinomas were positive for at least two markers, and only 9 cases were negative for all three markers. MGP was detected in 36 cases (3.0%) that were negative for both GATA3 and TRPS1. MGP showed mild-to-moderate positive expression in normal hepatocytes, renal tubules, as well as 31.1% (99/318) of hepatocellular carcinomas. Rare cases (0.6–5%) had focal MGP expression in renal, ovarian, lung, urothelial, and cholangiocarcinomas. Conclusions Our findings suggest that MGP is a newly identified sensitive IHC marker to support breast origin. MGP, TRPS1, and GATA3 could be applied as a reliable diagnostic panel to determine breast origin in clinical practice.

Mucinous cystadenocarcinoma of the breast harbours TRPS1 expressions and PIK3CA alterations

“…TRPS1 is a highly specific marker for breast origin tumours, especially in triple-negative breast cancer compared with GATA3. [20][21][22] In this study, we found that TRPS1 immunoreactivity in all cases was superior to GATA3 immunostaining and supported a breast origin, which could aid in routine clinical practice. Further studies are needed to better understand the role of TRPS1 in the development and progression of BMCAs and to explore the potential for targeted therapies.…”

“…TRPS1 is a highly specific marker for breast origin tumours, especially in triple‐negative breast cancer compared with GATA3 20–22 . In this study, we found that TRPS1 immunoreactivity in all cases was superior to GATA3 immunostaining and supported a breast origin, which could aid in routine clinical practice.…”

“…20 Recent studies have shown that TRPS1 is a specific and sensitive marker for primary or metastatic breast cancers, especially in triplenegative phenotypes. [20][21][22] Although no study has yet examined TRPS1 expression in BMCA, the question arises of whether TRPS1 could be a good marker for the diagnosis of BMCA as with other TNBCs.…”

“…Trichorhinophalangeal syndrome type 1 (TRPS1) is a novel GATA transcriptional factor that plays a role in the differentiation of normal breast epithelial cells and possibly in breast tumorigenesis 20 . Recent studies have shown that TRPS1 is a specific and sensitive marker for primary or metastatic breast cancers, especially in triple‐negative phenotypes 20–22 . Although no study has yet examined TRPS1 expression in BMCA, the question arises of whether TRPS1 could be a good marker for the diagnosis of BMCA as with other TNBCs.…”

TRPS1 expression in cytokeratin 5 expressing triple negative breast cancers, its value as a marker of breast origin

“…Du et al have also analysed several subsets of breast carcinomas with TRPS1, and found that altogether, only 8% of 1201 breast carcinomas were completely negative for this marker, and further 13% were weakly positive (≤ 10% staining, i.e., negative according to our criteria) [ 37 ]. In contrast to the previously cited studies, metaplastic carcinomas were those that showed the highest positivity rate (129/140, 92% demonstrating over 10% staining), and non-metaplastic TNBCs being the less frequently positive (in 69% of 144 cases).…”