Trichorhinophalangeal Syndrome Type Research Articles

A Comprehensive Review of TRPS1 as a Diagnostic Immunohistochemical Marker for Primary Breast Carcinoma: Latest Insights and Diagnostic Pitfalls.

Immunohistochemical expression of TRPS1 (trichorhinophalangeal syndrome type 1) protein is usually used by pathologists to confirm breast origin for triple-negative breast cancers (TNBC) or metastatic carcinomas of unknown primary. However, recent studies have reported TRPS1 expression in a variety of non-breast lesions. This review aims to provide a comprehensive evaluation of TRPS1 expression across various tumor types, highlighting both its diagnostic utility and potential pitfalls that may arise in clinical practice. A thorough search of the PubMed database on TRPS1 immunoexpression in tumor pathology was conducted. While the gene itself has been known for several decades, most studies regarding its use in immunohistochemistry emerged in the late 2010s. Particular emphasis was placed on case reports and cohort studies that examined the implications of TRPS1 expression in non-breast tissues, as well as variations in the results between commercially available TRPS1 clones, which may influence the staining intensity and specificity. TRPS1 demonstrated a strong diagnostic utility in identifying primary breast lesions, particularly in TNBC cases. However, its expression in a growing number of non-breast cancers, such as lung adenocarcinoma, prostate adenocarcinoma, urothelial carcinoma, ovarian high-grade serous carcinoma, and endometrial adenocarcinoma, as well as up to 96% of synovial sarcomas with SS18-SSX fusion, emphasizes the need for caution when interpreting TRPS1 positivity and suggests a multi-marker approach in order to increase the diagnostic accuracy. While TRPS1 remains a highly sensible immunohistochemical marker for confirming breast primary lesions, pathologists should be aware of its low specificity and incorporate complementary diagnostic methods in order to ensure accurate clinical management. Further research should focus on elucidating the molecular pathways regulating TRPS1 expression in various tumor types, which may better define its clinical utility.

TRPS1, a sensitive marker for different histological and molecular types of breast cancer

ObjectivesWe explored Trichorhinophalangeal syndrome type 1 (TRPS1) expression in special types of breast carcinoma, and analyzed the correlation between TRPS1 and androgen receptor (AR) expression in triple-negative breast cancer (TNBC).MethodsTRPS1 expression was analyzed in 801 patients with special types of breast carcinoma. A total of 969 TNBC were used to analyze the correlation between the expression of TRPS1 and AR. TRPS1 expression was evaluated in 1975 cases of breast cancer with different molecular types.ResultsA total of 801 special types of breast cancers were stained with TRPS1.TRPS1 was positive in 100% (63/63) of mucinous carcinoma, 100% (7/7) adenoid cystic carcinomas (4 classic adenoid cystic carcinomas and 3 solid-basaloid adenoid cystic carcinomas), 100% (4/4) tubular carcinomas, 100% (2/2) secretory carcinomas, and 99.59% (243/244) invasive lobular carcinomas, 99.26% (267/269) invasive micropapillary carcinomas, 97.44% (38/39) ER-positive neuroendocrine tumors, 94.44% (34/36) metaplastic breast carcinomas (MBCs), 63.73% (65/102) apocrine carcinomas. TRPS1 was negative in all triple-negative neuroendocrine carcinomas (0/7).TRPS1 was positive in 92.86% (26/28) of metastatic special types of breast cancer. TRPS1 and AR expression were analyzed in 969 cases of TNBC. 90.40% were positive for TRPS1, and 42.41% were positive for AR. A significant inverse correlation between TRPS1 and AR expression was shown in TNBC (p < .001). TRPS1 showed a higher positive rate (93.13%) in TNBC compared to GATA binding protein 3 (GATA3), gross cystic disease fluid protein 15 (GCDFP-15) and forkhead box transcription Factor C 1 (FOXC1).ConclusionsIn conclusion, our study demonstrated that TRPS1 is a highly sensitive marker for most special types of breast carcinoma. TRPS1 was positive in 63.73% of apocrine carcinomas. TRPS1 and AR expression was inversely correlated in TNBC.

Deciphering Breast Origin in Malignant Effusions: The Diagnostic Utility of an MGP, GATA-3, and TRPS-1 Immunocytochemical Panel

Introduction: Defining the origin of metastatic cancer is crucial for establishing an optimal treatment strategy, especially when obtaining sufficient tissue from secondary malignancies is limited. While cytological examination is often used in this diagnostic setting, morphologic analysis alone often fails to differentiate metastases derived from the breast from other primaries. The hormone receptor, human epidermal growth factor receptor-2, gross cystic disease fluid protein 15, and mammaglobin immunohistochemistry are often used to diagnose metastatic breast cancer. However, their effectiveness decreases in estrogen receptor (ER)-negative breast cancers, including the triple-negative breast cancer (TNBC) subtype. Methods: We conducted a comprehensive evaluation of GATA-binding protein 3 (GATA-3), trichorhinophalangeal syndrome type 1 (TRPS-1), and Matrix Gla Protein (MGP) immunochemistry across 140 effusion cytology specimens with metastatic adenocarcinoma derived from various primaries, including the breast, colon, pancreaticobiliary, lung, tubo-ovarian, and stomach. Results: The expression rates of these immunomarkers were significantly higher in metastatic cancers originating from the breast than other primaries. In TNBC, TRPS-1 (80.00%) and MGP (65.00%) exhibited higher positivity rates compared to GATA-3 (40.00%). Additionally, our data suggest that an immunohistochemical panel comprising MGP, GATA-3, and TRPS-1 significantly enhances the detection of metastatic breast cancer in effusion cytology specimens, including TNBC in particular. When considering dual-marker positivity, the diagnostic accuracy was found to be 89.29% across all breast cancer subtypes and 92.93% for TNBC. Conclusions: MGP appears to be a robust marker for identifying metastatic breast cancer in malignant effusions, especially TNBC. MGP notably enhances diagnostic accuracy when incorporated together with GATA-3 and TRPS-1 in an immunohistochemical panel.

TRPS1 expression in MPNST is correlated with PRC2 inactivation and loss of H3K27me3

Initially described as a highly specific immunohistochemical marker for carcinomas of mammary origin, trichorhinophalangeal syndrome type 1 (TRPS1) has subsequently been detected in a variety of other non-mammary tumors. In this study, we examined the immunohistochemical expression of TRPS1 in 114 peripheral nerve sheath tumors, including 43 malignant peripheral nerve sheath tumors (MPNSTs), 58 schwannomas, including 9 cellular neurofibromas, and 13 neurofibromas, including 1 atypical neurofibroma. Notably, TRPS1 was expressed in 49% of MPNSTs and was absent in all schwannomas and neurofibromas. All MPNSTs showed TRPS1 labeling in >50% of nuclei, with 95% of cases demonstrating diffuse labeling. Most cases (67%) showed weak TRPS1 immunoreactivity, while a smaller subset showed moderate (24%) or strong (9%) intensity staining. Analysis of publicly available gene expression datasets revealed higher levels of TRPS1 mRNA in MPNSTs with PRC2 inactivation. In keeping with this finding, TRPS1 expression was more commonly observed in MPNSTs with loss of H3K27me3, suggesting a potential relationship between TRPS1 and the PRC2 complex. This study further broadens the spectrum of TRPS1-expressing tumors to include MPNST.

Effect of decalcification on immunohistochemical staining of trichorhinophalangeal syndrome type 1

AbstractTo evaluate the effect of different decalcification solutions on the immunohistochemical staining of trichorhinophalangeal syndrome type 1 (TRPS1), and to provide a reliable basis for the accurate diagnosis of bone metastasis of breast cancer. Due to the limited biopsy samples of bone metastatic cancer, 20 cases of invasive breast cancer were selected to simulate bone metastatic biopsy, dividing into four groups: undecalcified group, 30% formic acid group, 10% hydrochloric acid group and 10% nitric acid group. Immunohistochemical staining was performed after treatment for 2, 6, 18 and 24 h. There was no change in the proportion and intensity of TRPS1 cells in the formic acid decalcification group within 18 h, but decreased significantly after 24 h. The staining intensity of TRPS1 and the proportion of stained cells were significantly decreased in the hydrochloric acid decalcification group since 2 h treatment. The percentage and intensity of positive cells in the nitric acid decalcification group changed little or no change within 6 h, and then gradually decreased with the extension of time. Another three invasive breast cancer samples were used to compare the effects of different decalcification solutions on the same case. In brief, we conclude that the effect of 30% formic acid decalcification on TRPS1 staining is small when the time is less than 18 h. 10% nitric acid decalcification should be controlled within 6 h, which has little effect on TRPS1 staining, and 10% hydrochloric acid decalcification will lead to significantly less positive TRPS1 staining, so it is not recommended for breast bone metastasis tissue decalcification.

TRPS1 function beyond breast: A retrospective immunohistochemical study on non-breast cytology specimens.

Trichorhinophalangeal syndrome type 1 (TRPS1) has emerged as a reliable immunohistochemistry (IHC) marker for identifying breast origin in metastatic carcinomas. This study investigates the utility of TRPS1 IHC in non-breast cytology specimens. A retrospective search of our pathology database for the year 2021 identified fluids (pleural and peritoneal) and liver, lung and bone fine needle aspirations (FNAs) with surgical follow-up confirming non-breast metastatic carcinomas. Cell blocks from cases with sufficient neoplastic cells underwent immunostaining using a rabbit polyclonal antibody against human TRPS1. Cases lacking tumor on deeper levels after the original work-up were excluded from the study. Two pathologists independently interpreted the TRPS1 staining. Of 136 cases assessed, 31 (22.79%) exhibited positive TRPS1 staining, while 105 (77.21%) were nonreactive. Positivity rates were observed in tumors of Mullerian cell origin, gastrointestinal tract (GIT), and lung origin at 28.85%, 25%, and 21.57%, respectively. Of the tumors of Mullerian cell origin 10 (66.67%) were serous carcinomas, 4 (26.67%) were endometrioid carcinomas, and one (6.67%) was a clear cell carcinoma. Lung tumors comprised seven (63.64%) squamous cell carcinomas and four (36.36%) adenocarcinomas, while the gastrointestinal tumors consisted of 14 (80%) adenocarcinomas and one (20%) squamous cell carcinoma. Although recognized as a sensitive marker for mammary carcinomas, TRPS1 immunostaining was also detected in Mullerian, lung, and GIT carcinomas. This highlights the significance of being cautious when depending solely on TRPS1 immunostaining to distinguish metastatic breast tumors.

Xenopus tropicalis osteoblast-specific open chromatin regions reveal promoters and enhancers involved in human skeletal phenotypes and shed light on early vertebrate evolution

While understanding the genetic underpinnings of osteogenesis has far-reaching implications for skeletal diseases and evolution, a comprehensive characterization of the osteoblastic regulatory landscape in non-mammalian vertebrates is still lacking. Here, we compared the ATAC-Seq profile of Xenopus tropicalis (Xt) osteoblasts to a variety of non mineralizing control tissues, and identified osteoblast-specific nucleosome free regions (NFRs) at 527 promoters and 6747 distal regions. Sequence analyses, Gene Ontology, RNA-Seq and ChIP-Seq against four key histone marks confirmed that the distal regions correspond to bona fide osteogenic transcriptional enhancers exhibiting a shared regulatory logic with mammals. We report 425 regulatory regions conserved with human and globally associated to skeletogenic genes. Of these, 35 regions have been shown to impact human skeletal phenotypes by GWAS, including one trps1 enhancer and the runx2 promoter, two genes which are respectively involved in trichorhinophalangeal syndrome type I and cleidocranial dysplasia. Intriguingly, 60 osteoblastic NFRs also align to the genome of the elephant shark, a species lacking osteoblasts and bone tissue. To tackle this paradox, we chose to focus on dlx5 because its conserved promoter, known to integrate regulatory inputs during mammalian osteogenesis, harbours an osteoblast-specific NFR in both frog and human. Hence, we show that dlx5 is expressed in Xt and elephant shark odontoblasts, supporting a common cellular and genetic origin of bone and dentine. Taken together, our work (i) unravels the Xt osteogenic regulatory landscape, (ii) illustrates how cross-species comparisons harvest data relevant to human biology and (iii) reveals that a set of genes including bnc2, dlx5, ebf3, mir199a, nfia, runx2 and zfhx4 drove the development of a primitive form of mineralized skeletal tissue deep in the vertebrate lineage.

Diagnostic utility and sensitivities of matrix Gla protein (MGP), TRPS1 and GATA3 in breast cancer: focusing on metastatic breast cancer, invasive breast carcinoma with special features, and salivary gland-type tumours

Matrix Gla protein (MGP) and trichorhinophalangeal syndrome type 1 (TRPS1) have recently emerged as novel breast-specific immunohistochemical (IHC) markers, particularly for triple-negative breast cancer (TNBC) and metaplastic carcinoma. The present study aimed to validate and compare the expression of MGP, TRPS1 and GATA binding protein 3 (GATA3) in metastatic breast carcinoma (MBC), invasive breast carcinoma (IBC) with special features, including special types of invasive breast carcinoma (IBC-STs) and invasive breast carcinoma of no special type with unique features, and mammary and non-mammary salivary gland-type tumours (SGTs). Among all enrolled cases, MGP, TRPS1 and GATA3 had comparable high positivity for ER/PR-positive (p=0.148) and HER2-positive (p=0.310) breast carcinoma (BC), while GATA3 positivity was significantly lower in TNBC (p<0.001). Similarly, the positive rates of MGP and TRPS1 in MBCs (99.4%), were higher than in GATA3 (90.9%, p<0.001). Among the IBC-STs, 98.4% of invasive lobular carcinomas (ILCs) were positive for all three markers. Among neuroendocrine tumours (NTs), all cases were positive for TRPS1 and GATA3, while MGP positivity was relatively low (81.8%, p=0.313). In the neuroendocrine carcinoma (NC) subgroup, all cases were positive for GATA3 and MGP, while one case was negative for TRPS1. All carcinomas with apocrine differentiation (APOs) were positive for GATA3 and MGP, while only 60% of the cases demonstrated moderate staining for TRPS1. Among mammary SGTs, MGP demonstrated the highest positivity (100%), followed by TRPS1 (96.0%) and GATA3 (72.0%). Positive staining for these markers was also frequently observed in non-mammary SGTs. Our findings further validate thehigh sensitivity of MGP and TRPS1 in MBCs, IBC-STs, andbreast SGTs. However, none of these markers arecapable of distinguishing between mammary and non-mammary SGTs.

TRPS1 expression in non-melanocytic cutaneous neoplasms: an immunohistochemical analysis of 200 cases.

Although trichorhinophalangeal syndrome type 1 (TRPS1) was initially thought to be highly sensitive and specific for carcinomas and mesenchymal tumors of mammary origin, more recent data suggest its expression is not limited to breast neoplasms but also can be seen in other cutaneous neoplasms, such as extramammary Paget disease and squamous cell carcinoma (SCC) in situ. Two-hundred cases of non-melanocytic cutaneous neoplasm, including basal cell carcinomas (BCCs) (n = 41), SCCs (n = 35), Merkel cell carcinomas (MCCs) (n = 25), and adnexal neoplasms (n = 99), were tested for TRPS1 expression using a monoclonal anti- TRPS1 rabbit anti-human antibody. TRPS1 expression was present in almost all cases of SCC (94%), with a median H-score of 200, while it was either absent or only focally present in most BCCs (90%), with a median H-score of 5. The difference between BCCs and SCCs in H-score was significant (p < .001). All MCCs (100%) lacked TRPS1 expression. TRPS1 expression was frequently seen in most adnexal neoplasms, benign and malignant, in variable intensity and proportion but was consistently absent in apocrine carcinomas. All endocrine mucin-producing sweat gland carcinomas (EMPSGCs) (100%, 6/6) showed diffuse and strong TRPS1 immunoreactivity, with a median H-score of 300, which was significantly different (p < .001) than that of BCCs. Our study shows that TRPS1 may be an effective discriminatory marker for BCCs and SCCs. It also has a role in distinguishing BCCs from EMPSGCs.

Trichorhinophalangeal Syndrome Type 1 Immunohistochemical Expression in Carcinomas of Gynecologic Origin.

Trichorhinophalangeal syndrome type 1 (TRPS1) is a new reportedly sensitive and specific immunohistochemical marker for carcinomas of breast origin, including triple-negative (estrogen receptor, progesterone receptor, and HER2) tumors. In our practice, we have observed a subset of cases of nonmammary carcinomas that are positive for TRPS1, with higher frequency in cytology effusion samples with metastatic gynecologic malignancies. This study aimed to evaluate the expression of TRPS1 in a large tissue cohort of Müllerian carcinomas. We retrospectively retrieved 105 cases of formalin-fixed paraffin-embedded gynecologic tumors from our surgical pathology archives. Cases corresponded to tumors of tubo-ovarian (17 high-grade serous carcinomas, 3 low-grade serous carcinomas, 2 clear cell carcinomas, and 8 endometrioid adenocarcinomas), endometrial (25 endometrioid adenocarcinomas, 8 serous carcinomas, 6 clear cell carcinomas, 12 carcinosarcomas, 1 dedifferentiated carcinoma, and 1 mesonephric-like adenocarcinoma), cervical (6 human papillomavirus [HPV]-associated squamous cell carcinomas [SCCs], 11 HPV-associated endocervical adenocarcinomas, and 2 HPV-independent gastric-type endocervical adenocarcinomas), and vulvar (2 HPV-independent SCCs and 1 HPV-associated SCC) origins. Immunohistochemistry for TRPS1 was performed in whole tissue sections and assessed for positivity (≥5% of nuclear labeling), distribution (focal: 5% to 49%, diffuse: 50% to 100%), and intensity (1+, 2+, 3+) in tumor cells. Positive TRPS1 staining was observed in 51.4% (54/105) of cases. Most tumors (64.8%) demonstrated diffuse labeling, while focal in 35.2%. Among positive cases, the intensity was predominantly 1+ (57.4%), followed by 2+ (33.3%) and 3+ (9.2%). Tumors with a high percentage of positivity overall consisted of tubo-ovarian (70%) and endometrial carcinomas (58.4%). TRPS1 immunostain is often expressed in gynecologic carcinomas. Awareness of this phenomenon is crucial when evaluating challenging cases in which the differential diagnosis includes a malignancy of breast origin, to avoid misclassification of the primary site.

P-15 A rare case of Trichorhinophalangeal Syndrome Type I

Abstract Introduction Trichorhinopharyngeal syndrome (TRPS) type 1 is a rare autosomal dominant genetic disorder due to defects of the TRPS1 gene. Clinical findings include short stature, fine hair, craniofacial and skeletal malformations, and deformities in phalangeal joints. This rare disease has a wide clinical spectrum and careful investigation on suspected cases should be made. Clinical Case A 19-year-old female patient, after application to the rheumatology clinic of our center with hand deformities, was referred to our endocrinology clinic after initial examination revealed no rheumatologic disorder; with a pre-diagnosis of a possible bone mineral disorder. She had no co-morbid disease, but her history revealed admissions to a pediatric endocrinology unit and investigations of a possible mucopolysaccharidosis, though no diagnosis had been made. There was no kinship between her parents. In her physical examination, she had fine hair, the fifth metacarpal bone of her right hand was short, she had palpable bone cysts on both of her third phalanges, and a high palatal arch. She had a short stature of 149 cm. From her history, it was learned that none of her relatives showed similar phenotypic properties. Her laboratory findings, listed in Table 1, showed no definitive defect other than a mild vitamin D deficit. The X-ray of her hands (Figure 1) showed shortening of the right fifth metacarpal bone. Her bone mineral density scan was normal. From this point, due to her clinical and radiological findings, a possible diagnosis of pseudo-pseudohypoparathyroidism was assumed, and the patient was referred to the department of genetics. The result of the genetic analysis revealed a heterozygous c.2894G&amp;gt;A (p.Arg965His) variant in the TRPS1 (NM_014112/5) gene. As a result, the patient was diagnosed with trichorhinophalangeal syndrome type 1, and was referred to the department of physical medicine and rehabilitation for physiotheraphy program for her hand deformities and possible future deformities in the skeletal system. Because the disease has an autosomal dominant inheritance, she was also informed about genetic consultancy for her possible future conception. Conclusion Trichorhinophalangeal syndrome type 1 is a rare disease and can mimic a variety of disorders including pseudo-pseudohypoparathyroidism, rheumatoid arthritis and other rheumatological diseases. Though there is no definite treatment, suspected cases should be evaluated both clinically and genetically to avoid misdiagnosis. Financial disclosures: None Funding resources: NoneFigure 1.X-ray of the patient's handsArrow shows shortening of the right fifth metacarpal bone Table 1.Laboratory findings of the patientALT: alanine aminotransferase, ALP: alkaline phosphatase, PTH: parathormone

TRPS1 expression in primary and metastatic prostatic adenocarcinoma, muscle invasive bladder urothelial carcinoma, and breast carcinoma: Is TRPS1 truly specific and sensitive for a breast primary?

Trichorhinophalangeal syndrome type 1 (TRPS1) has been reported to be a sensitive and specific immunohistochemical (IHC) marker for breast carcinomas, especially when determining primary site of origin. However, there is limited data on TRPS1 expression in prostate and bladder cancers.A two-phase study was performed with 1) an exploratory cohort analyzing TRPS1 gene alterations in prostate, bladder, and breast carcinoma and TPRS1 mRNA expression data in prostate and bladder carcinoma; and 2) TRPS1 and GATA3 IHC in a confirmatory cohort in prostate, bladder, and breast carcinoma samples.Gene alterations were identified in a subset of breast, bladder, and prostate carcinomas and mRNA was consistently detected. In the IHC cohort, 183/210 (87.1 %) of breast, 22/69 (31.9 %) of prostate, and 20/73 (27.4 %) of urothelial carcinomas showed staining with TRPS1. Intermediate to high expression of TRPS1 was observed in 173/210 (82.8 %) of breast, 17/69 (24.6 %) of prostate, and 15/73 (20.5 %) of urothelial carcinomas. Furthermore, in prostate cancer, 26.9 % of pelvic lymph node metastases and 50 % in sites of distant metastases showed expression. Increased TRPS1 mRNA expression (p = 0.032) and IHC expression (p = 0.040) correlated with worse overall survival in bladder cancer. By comparison, GATA3 IHC stained 136/210 (64.8 %) of breast, 0/69 (0 %) of prostate, and 63/73 (93 %) of bladder carcinomas. Intermediate to high expression of GATA3 was seen in 131/210 (62.4 %) of breast and 63/73 (93 %) of bladder carcinomas.This study shows there is significant staining of TRPS1 in bladder and prostate cancers. As a result, comprehensive studies are needed to establish the true specificity of TRPS1 IHC stain across various tumor types before its widespread clinical adoption.

Mucinous cystadenocarcinoma of the breast harbours TRPS1 expressions and PIK3CA alterations.

Breast mucinous cystadenocarcinoma (BMCA) is a rare tumour recently recognised as a distinct entity by the World Health Organisation Tumour Classification Series. BMCA is a triple-negative tumour that lacks specific immunohistochemical markers; therefore, distinguishing it from mimickers such as ovarian and pancreatic cystadenocarcinomas requires careful clinicopathological correlation. Due to its rarity, little is known about the molecular alterations that underlie BMCA. In this study, we used immunohistochemical staining methods to investigate TRPS1 (trichorhinophalangeal syndrome type 1) expression in BMCA and compare it to expression in ovarian and pancreatic mucinous cystadenocarcinomas. We also collected tumour samples from three BMCA patients for molecular analysis by MALDI-TOF mass spectrometry, real-time polymerase chain reaction, whole exome sequencing and fluorescence in-situ hybridisation. TRPS1 immunoreactivity was found only in BMCA tumour cells and not in the ovarian and pancreatic counterparts. One of the three BMCA tumours also showed a PIK3CA hot-spot mutation, which was confirmed by whole genome next-generation sequencing (NGS). No KRAS, NRAS, BRAF or AKT mutations were found. To our knowledge, this is the first demonstration of TRPS1 expression in BMCA patients and the first identification of a PIK3CA hotspot mutation in these tumours. These findings provide insights into the molecular mechanisms underlying BMCA tumorigenesis and suggest a potential drug target for this rare and poorly understood cancer.

Diagnostic Utility of Trichorhinophalangeal Syndrome Type 1 (TRPS1) immunostain in breast carcinoma compared to GATA3

Diagnostic Utility of Trichorhinophalangeal Syndrome Type 1 (TRPS1) immunostain in breast carcinoma compared to GATA3

Trichorhinophalangeal Syndrome Type 1 Is a Highly Sensitive and Specific Marker for Diagnosing Triple-Negative Breast Carcinomas on Cytologic Samples.

Definitive diagnosis of metastatic triple-negative breast carcinoma (TNBC) is challenging on cytologic samples. Recent studies demonstrated that trichorhinophalangeal syndrome type 1 (TRPS1) is a highly sensitive and specific marker for diagnosing breast carcinomas, including TNBC, on surgical specimens. To evaluate TRPS1 expression in TNBCs on cytologic samples and a large series of nonbreast tumors on tissue microarray sections. Immunohistochemical (IHC) analysis of TRPS1 and GATA-binding protein 3 (GATA3) was performed on 35 TNBC cases on surgical specimens, and 29 consecutive TNBC cases on cytologic specimens. IHC analysis of TRPS1 expression was also performed on 1079 nonbreast tumors on tissue microarray sections. Of the surgical specimens, 35 of 35 TNBC cases (100%) were positive for TRPS1, all with diffuse positivity, whereas 27 of 35 (77%) were positive for GATA3, with diffuse positivity in 7 cases (26%). Of the cytologic samples, 27 of 29 TNBC cases (93%) were positive for TRPS1, with diffuse positivity in 20 cases (74%), whereas 12 of 29 (41%) were positive for GATA3, with diffuse positivity in 2 cases (17%). Of the nonbreast malignant tumors, TRPS1 expression was seen in 9.4% (3 of 32) of melanomas, 10.7% (3 of 28) of small cell carcinomas of the bladder, and 9.7% (4 of 41) of ovarian serous carcinomas. Our data confirm that TRPS1 is a highly sensitive and specific marker for diagnosing TNBC cases on surgical specimens as reported in the literature. In addition, these data demonstrate that TRPS1 is a much more sensitive marker than GATA3 in detecting metastatic TNBC cases on cytologic samples. Therefore, inclusion of TRPS1 in the diagnostic IHC panel is recommended when a metastatic TNBC is suspected.

Trichorhinophalangeal syndrome type 1 (TRPS1) expression in male breast carcinoma

Currently, there is a paucity of highly specific and sensitive markers to identify breast carcinoma in male patients. Immunohistochemical stains commonly used for unmasking primary breast carcinomas include estrogen receptor (ER) and GATA3. However, these markers are commonly expressed in carcinomas originating from other organ systems and can be reduced in breast carcinomas with higher histologic grades. Androgen receptor (AR) may be used to highlight primary male breast cancer, but this marker can also be expressed in other carcinomas. We evaluated TRPS1, a highly sensitive and specific marker for female breast carcinoma, in cases of male breast carcinoma. Through an institutional database search, we identified 72 cases of primary invasive breast carcinoma in male patients. Among ER/progesterone receptor (PR)-positive cancers, 97% showed intermediate or high positivity for both TRPS1 and GATA3. Among HER2-positive cancers, 100% showed intermediate or high positivity for TRPS1 and GATA3. One case of triple-negative breast cancer was collected, showing high positivity for TRPS1 and negativity for GATA3. AR staining was non-specific and heterogeneous: 76% showed high positivity, but the remaining 24% showed low or intermediate positivity. Additionally, among 29 cases of metastatic carcinoma to male breast tissue, 93% were negative for TRPS1, and the remaining 2 cases (7%), which were carcinomas from salivary gland primary tumors, were intermediate positive. TRPS1 is a sensitive and specific marker in the unmasking of male primary invasive breast carcinoma across different subtypes. Additionally, TRPS1 is not expressed in metastatic carcinomas of multiple primaries, with the exception of salivary gland primaries.

TRPS1: A Marker of Follicular Differentiation.

The trichorhinophalangeal syndrome type 1 (TRPS1) immunohistochemical (IHC) stain has increased in use in recent years as a marker for breast carcinomas. The TRPS1 gene is involved in various tissues, including the growth and differentiation of hair follicles. This article seeks to evaluate the IHC expression of TRPS1 in cutaneous neoplasms with follicular differentiation, such as trichoblastoma (TB), trichoepithelioma (TE), and basal cell carcinoma (BCC). IHC studies were performed on 13 TBs, 15 TEs, and 15 BCCs with an antibody against TRPS1. The study found a variable staining expression of TRPS1 in the tumor nests of TB, TE, and BCC. BCCs were distinct in that none of the BCCs demonstrated intermediate or high positivity, while TBs and TEs showed intermediate-to-high positivity in 5/13 (38%) and 3/15 (20%) of cases, respectively. We observed a distinct staining pattern among the mesenchymal cells of TB and TE. We found that TRPS1 highlighted perifollicular mesenchymal cells adjacent to the nests of TB and TE tumor cells. This staining pattern was absent in BCCs, where only scattered stromal cells were positive for TRPS1. Papillary mesenchymal bodies were also highlighted by TRPS1 in TB and TE. TRPS1 stained various parts of the normal hair follicle, including the nuclei of cells in the germinal matrix, outer root sheaths, and hair papillae. TRPS1 may be a useful IHC marker for follicular differentiation.

Trichorhinophalangeal syndrome type 1 (Giedion syndrome): A case report with literature review

Trichorhinophalangeal syndrome (TRPS) is a rare multisystem disorder characterized by abnormalities in the hair (tricho), nose (rhino), and digits (phalangeal). A variety of nonspecific intraoral findings have been reported in the literature, including hypodontia, delayed tooth eruption, malocclusion, a high-arched palate, mandibular retrognathia, midface hypoplasia, and multiple impacted teeth. In addition, supernumerary teeth have been detected in several persons with TRPS, especially type 1. This report describes the clinical manifestations and dental management of a TRPS 1 patient with multiple impacted supernumerary and permanent teeth. A 15-year-old female patient visited our clinic with a known medical history of TRPS 1 with laceration of the tongue caused by teeth eruption in the palate. Radiographic images showed a total of 45 teeth: two deciduous, 32 permanent, and 11 supernumerary teeth. Six permanent teeth and 11 supernumerary teeth in the posterior quadrants were impacted. Four impacted third molars, supernumerary teeth, retained deciduous teeth, and impacted maxillary premolars were removed under general anaesthesia. This case suggests that all patients with TRPS should undergo full clinical and radiographic oral examination and should be informed about the disease and the importance of dental counselling. El síndrome tricorrinofalángico (TRPS) es un trastorno multisistémico raro caracterizado por anomalías en el pelo (trico), la nariz (rino) y los dedos (falángico). En la literatura se han reportado una variedad de hallazgos intraorales inespecíficos, incluyendo hipodontia, demora de la erupción dental, maloclusión, paladar muy arqueado, retrognatia mandibular, hipoplasia en la sección media del rostro y múltiples dientes impactados. Además, se han detectado dientes supernumerarios en diversas personas con TRPS, en especial de tipo 1. Este informe describe las manifestaciones clínicas y el manejo dental de una paciente con TRPS 1 con múltiples dientes impactados, supernumerarios y permanentes. Una paciente de 15 años con historia médica conocida de TRPS 1 se presentó en nuestra clínica quejándose de laceración de la lengua causada por dientes erupcionados. Las imágenes radiográficas mostraron un total de 45 dientes: 2 deciduos, 32 permanentes y 11 supernumerarios. Seis dientes permanentes y 11 dientes supernumerarios de los cuadrantes posteriores resultaron impactados. Se extrajeron 4 terceros molares y dientes supernumerarios impactados, dientes deciduos retenidos y premolares maxilares impactados bajo anestesia general. Este caso evidencia que todos los pacientes con TRPS deberían someterse a exámenes orales completos a nivel clínico y radiográfico, y ser informados sobre la enfermedad y la importancia del asesoramiento dental.

TRPS1 outperforms GATA3 in pleural effusions with metastatic breast carcinoma versus mesothelioma.

In evaluating malignant pleural fluid cytology, metastatic adenocarcinomas and mesotheliomas are often differential diagnoses. GATA binding protein 3 (GATA3) has historically been used to confirm metastatic breast carcinomas; however, GATA3 has low specificity if mesothelioma is included in differential diagnoses. Trichorhinophalangeal syndrome type 1 (TRPS1) protein is expressed in all types of breast carcinomas, with reported high specificity and sensitivity. We investigated the performance of TRPS1 immunohistochemistry (IHC) and compared it to GATA3 in pleural fluids diagnosed with metastatic breast carcinoma and mesothelioma. Thirty-six consecutive ThinPrep pleural fluids and 4 pleural fine needle aspirations (FNAs) with diagnoses of metastatic breast carcinoma (21) and mesothelioma (19) were retrieved, and IHC with TRPS1 and GATA3 was performed on all. Immunoreactivity scores for TRPS1 were calculated by multiplying percentage of immunoreactive cells by staining intensity. Immunoreactivity scores were negative if 0 or 1, low positive if 2, intermediate positive if 3 or 4, or high positive if 6 or 9. Nuclear immunoreactivity of ≥10% with at least moderate intensity was judged GATA3 positive. GATA3 showed immunoreactivity in all metastatic breast carcinomas and 84% of mesotheliomas. TRPS1 was immunoreactive in all breast carcinoma cases (18 with a score of 9 and 3 with a score of 6). TRPS1 showed low positivity in 5% of mesothelioma cases with all other cases being negative. When cytomorphologic differential diagnoses of mesothelioma exist, TRPS1 is a more specific marker than GATA3 for confirmation of metastatic breast carcinoma in pleural fluid cytology.

Abstract 4607: TRPS1 inhibits angiogenesis in triple negative breast cancer down regulating JAG1 and TYMP genes involved in angiogenesis pathways

Abstract Background. Triple-negative breast cancer (TNBC), the most difficult subtype to treat, is defined as estrogen receptor, HER2, and progesterone receptor negative. TNBC constitutes 10-20% of all breast cancer and has a higher rate of distal recurrence and a poorer prognosis than other breast cancer subtypes. Less than 30% of women with metastatic TNBC survive 5 years and almost all die from their disease despite adjuvant chemotherapy. Angiogenesis is a critical factor in the development of tumors and metastases in numerous cancers. Clinical trials with anti-angiogenic drugs showed to be inadequate, with moderate response rates and insignificant survival gains for patients. To understand the genetic forces involved in TNBC, we performed a transposon mutagenesis screen in Pten mutant mice that identified several candidate trunk drivers and progression genes. A major finding of our screen was the discovery and functional validation of, Trichorhinophalangeal syndrome type 1 (TRPS1), a GATA-like transcription factor, which functions as a transcriptional repressor or activator, depending on cell type, stage of development, or pathological conditions. Based on this data, we explored the role of TRPS1 in angiogenesis. Methods and Results. Tube formation and sprouting assays were performed using overexpression and inactivation of TRPS1 in MDA-MD-231 and HCC70 cells, respectively. Interestingly, inactivation of TRPS1 expression accelerates tube formation structures compared to the vector control as well as cell branching in the sprouting assay. Overexpression of TRPS1 prevents tubing and branching formation in vitro assays. Moreover, immunohistochemistry staining of CD31 detected a reduced number of blood vessels in MDA-MB-231 tumor xenografts overexpressing TRPS1, and an increase of angiogenic vasculature in HCC70 TRPS1-shRNA tumor xenografts. In vitro and in vivo assays demonstrate the role of TRPS1 in tumor angiogenesis. Furthermore, human ChIP qPCR angiogenesis array identified 10 top candidate genes potentially regulated by TRPS1 transcription factor. Of these candidates, JAG1 and TYMP showed to have a higher fold enrichment compared to other angiogenic related genes. Finally, we validated its direct functional binding by using luciferase reporter assay, such demonstrated that TRPS1 is a direct transcriptional regulator of JAG1 and TYMP. Conclusion. TRPS1 is a tumor suppressor involved in the mechanisms regulating tumor angiogenesis by repressing the expression of JAG1 and TYMP genes in TNBC. Citation Format: Liliana Guzman. TRPS1 inhibits angiogenesis in triple negative breast cancer down regulating JAG1 and TYMP genes involved in angiogenesis pathways. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4607.