Clinicopathological features of RER+ colorectal carcinoma

Objective: Replication errors (RER) is related to initiation and development of colorectal carcinoma (CRC). To investigate the different biological behavior of RER⁺ and RER⁻ CRC. Methods: Silver staining PCR-single strand conformation polymorphism (PCR-SSCP) and denatured polyacrylamide gel electrophoresis methods were used to detect microsatellite instability (MSI) at 4 loci on chromosome 2, 5, 17 in paraffin-embedded specimens of 60 colorectal carcinoma (CRC) and their paired normal tissue. RER⁺ was scored if 2 or more loci behaved as gaining extra bands. Results: The results showed that RER⁺ was found in 19/60 CRC, among which 7 cases had a family history. According to the criteria of Amsterdam, 4 were diagnosed as hereditary nonpolyposis colorectal cancer (HNPCC), and of which 3 cases were RER⁺. The ratio RER⁺ in HNPCC (75%) was significantly higher than that among sporadic CRC (28.5%). Most of the RER⁺ CRC have the feature of poorly differentiated adenocarcinoma (P<0.01), the tendency to involve the right side of the colon (P<0.05), a higher proportion with a family history (P<0.05), Duckes' A and B stage (P<0.05). Conclusion: The results indicated that RER⁺ is a relatively common molecular event in CRC. There are different clinico-pathological features and behavior between RER⁺ and RER⁻ CPC.     

Somatically acquired genetic alterations in flat colorectal neoplasias

Somatically acquired mutations in several genes have been reported as playing an important role during colorectal tumorigenesis. Two alternative groups of carcinomas, termed LOH⁺ and RER⁺, have been defined on the basis of their genetic anomalies, a biallelic inactivation of the APC or the TGF-βRII genes, occurring as an alternative, in LOH⁺ or RER⁺ tumors. It is a generally accepted hypothesis that most of colorectal cancers (CRC) develop from a pre-existing adenomatous polyp. Such benign lesions are usually exophytic polyps, a small proportion of adenomas having been described as flat lesions. The latter histological category has thus been proposed to bear specific genetic alterations. In order to examine this hypothesis, we have characterized a series of 44 flat colorectal neoplasias for their RER status and for somatic APC, KRAS and TGF-βRII genes mutations. Flat colorectal neoplasias were found to be of the RER⁺ subtype in 22% of cases, all of them exhibiting a TGF-βRII mutation. A mutation of the APC and KRAS genes has been found in 42% and 4% of tumors, respectively, none of these tumors being of the RER⁺ subtype. With the exception of a low KRAS mutation rate, flat adenomas appear to follow tumorigenesis pathways very similar to those identified in exophytic adenomas and carcinomas. Int. J. Cancer 77:366–369, 1998. © 1998 Wiley-Liss, Inc.     

Microsatellite alterations and p53, TGFβRII,IGFIIR and BAX mutations in sporadic non-small-cell lung cancer

Fifty-two sporadic primary non-small-cell lung carcinomas (NSCLC) were examined for microsatellite instability. Six different microsatellite markers localized on chromosomes 2, 5, 8, 10, 11 and 17 were used. Genomic instability was observed in 35% (18/52) of NSCLC at single or multiple loci. The tumors were also analyzed for p53-gene mutations by PCR-SSCP analysis. Polynucleotide stretch frameshift mutations of TGFβRII (transforming-growth-factor-beta receptor II), IGFIIR (insuline growth-factor II receptor) and BAX genes were also analyzed. RER⁺ (replication-error-positive) tumors appear not to be affected by a higher rate of point mutations in coding sequences: no correlation was found between microsatellite instability and point mutations in the p53 gene, and the RER⁺ tumors showed no alterations in stretches of nucleotide inside TGFβRII, BAX or IGFIIR. Int. J. Cancer 78:606–609, 1998. © 1998 Wiley-Liss, Inc.     

Myeloid-derived suppressor cell infiltration is associated with a poor prognosis in patients with hepatocellular carcinoma

The clinicopathological features of myeloid-derived suppressor cell (MDSC) and CD8⁺ T-cell infiltration in hepatocellular carcinoma (HCC) are poorly understood. The present study examined MDSC and CD8⁺ T-cell infiltration in surgically resected primary HCC specimens and investigated the association of MDSC and CD8⁺ T-cell infiltration with clinicopathological features and patient outcomes. Using a database of 466 patients who underwent hepatic resection for HCC, immunohistochemical staining of CD33 (an MDSC marker) and CD8 was performed. High infiltration of MDSCs within the tumor was observed in patients with a poorer Barcelona Clinic Liver Cancer stage, larger tumor size, more poorly differentiated HCC, and greater presence of portal venous thrombosis, microscopic vascular thrombosis and macroscopic intrahepatic metastasis. MDSC infiltration and CD8⁺ T-cell infiltration were independent predictors of recurrence-free survival and overall survival, respectively. Stratification based on the MDSC and CD8⁺ T-cell status of the tumors was also associated with recurrence-free survival (10 year-recurrence-free survival; MDSC^highCD8⁺ T-cell^Low, 3.68%; others, 25.7%) and overall survival (10 year-overall survival; MDSC^highCD8⁺ T-cell^Low, 12.0%; others, 56.7%). In conclusion, the present large cohort study revealed that high MDSC infiltration was associated with a poor clinical outcome in patients with HCC. Furthermore, the combination of the MDSC and tumor-infiltrating CD8⁺ T-cell status enabled further classification of patients based on their outcomes.     

Expression of invasion markers CD44v6/v3, NM23 and MMP2 in laryngeal and hypopharyngeal carcinoma

Twelve laryngeal squamous cell carcinoma cases (7 laryngeal and 5 hypopharyngeal cancer; 15 samples) were analysed by immunohistochemistry for the expression of invasion markers CD44v6/v3, NM23 and matrix metalloproteinase, MMP2. The laryngeal epithelium showed CD44v6⁺v3⁺NM23^- /MMP2^- phenotype. When tumors were grouped into TNM categories the phenotype of the T2 and T3 tumors was similar, characterised by decreased CD44v3⁺ and lack of MMP2 expressions. Meanwhile the NM23 expression was more frequent in T3 tumors. In T4 stage the frequency of NM23 and MMP2 positive cases increased (5/6 and 4/6, respectively) but there was no correlation with the appearence of lymph node metastasis. Comparison of the phenotype of laryngeal and hypopharyngeal tumors, irrespective of the TNM stages, revealed characteristic differences: T2 stage laryngeal tumors showed decreased CD44v3 and occasional NM23 and MMP2 positivity, while in T3 stage these tumors were characterised by increased frequency of NM23 positivity. The phenotype of the hypopharyngeal tumors was significantly different with a high frequency of MMP2 positive cases (5/6) and NM23⁺1ow CD44v3⁺ phenotype. The sharp differences in the phenotypes of laryngeal and hypopharyngeal carcinomas were connected to the differences in their invasive capacity unlike to the size of the tumors, since the T4 stage hypopharyngeal tumors had a significantly smaller size than laryngeal ones, even at lower stages. This work was supported by the Hungarian Ministry of Welfare: ETT No: T-11-100/93     

Microsatellite instability in thyroid tumours and tumour-like lesions

Fifty-one thyroid tumours and tumour-like lesions were analysed for instability at ten dinucleotide microsatellite loci and at two coding mononucleotide repeats within the transforming growth factor β (TGF-β) type II receptor (TβRII) and insulin-like growth factor II (IGF-II) receptor (IGFIIR) genes respectively. Microsatellite instability (MI) was detected in 11 out of 51 cases (21.5%), including six (11.7%) with MI at one or two loci and five (9.8%) with Ml at three or more loci (RER⁺ phenotype). No mutations in the TβRII and IGFIIR repeats were observed. The overall frequency of MI did not significantly vary in relation to age, gender, benign versus malignant status and tumour size. However, widespread MI was significantly more frequent in follicular adenomas and carcinomas than in papillary and Hürthle cell tumours: three out of nine tumours of follicular type (33.3%) resulted in replication error positive (RER⁺), versus 1 out of 29 papillary carcinomas (3.4%, P = 0.01), and zero out of eight Hürthle cell neoplasms. Regional lymph node metastases were present in five MI-negative primary cancers and resulted in MI-positive in two cases. © 1999 Cancer Research Campaign     

Expression of estrogen,progesterone and epidermal growth factor receptors in primary and metastatic breast cancer

The prognostic value of epidermal growth factor receptor (EGFR) expression and its biological role in estrogen receptor-positive (ER⁺) and ER-negative (ER^?) primary breast cancer is controversial. In this study, distributions of ER, progesterone receptor and EGFR have been established using immunohisto-chemistry in both primary breast tumors and their matched axillary lymph node metastases of 26 patients or their matched distant metastases of 2 patients. In addition, 5 patients with bilateral breast cancer were studied. ER⁺ tumor cells were detected in 22 (69%) and EGFR⁺ tumor cells were detected in 11 (34%) primary breast carcinomas. Expression of ER and EGFR was inverse regarding the individual tumor cells in both primary tumors and metastases. Relationship of EGFR expression with poorly differentiated and large breast tumors was observed. Furthermore, primary tumors with a predominant lobular component were ER⁺ and, with one exception, EGFR^?. Invasive ductal carcinomas were more frequently EGFR⁺. No apparent differences in receptor expression were observed between primary tumors and lymph node metastases or chro-nously or metachronously occurring bilateral breast cancers. Only one ER⁺ primary tumor showed a switch to EGFR expression in the involved lymph node. Our study shows that a shift in receptor phenotype between primary tumors and lymph node metastases is a rare event and, thus, additional analyses of involved lymph nodes will not likely serve as a better predictor for response to anti-estrogen therapy. We conclude that expression of EGFR is not a prerequisite for development of metastases. © 1995 Wiley-Liss, Inc.     

Gastric and intestinal phenotypic marker expression in gastric carcinomas and its prognostic significance: immunohistochemical analysis of 136 lesions

OBJECTIVE: It is well known that both gastric and intestinal phenotypic cell markers are expressed in gastric carcinomas, irrespective of their histologic type. However, the clinicopathologic significance of these expressions has not yet been clarified. METHODS: We analyzed the correlations among gastric and intestinal phenotypic marker expression patterns of the tumor, clinicopathologic findings and the patient's outcome in 136 advanced gastric carcinomas. RESULTS: Phenotypic marker expression was immunohistochemically evaluated using the monoclonal antibodies 45M1 (anti-human gastric mucin; HGM), CLH5 (anti-MUC6), Ccp58 (anti-MUC2) and 56C6 (anti-CD10). All tumors were classified as gastric (G), gastric and intestinal mixed (GI), intestinal (I) or unclassified (UC) phenotype. Of the 136 gastric carcinomas, 50 (36.8%), 56 (41.2%), 21 (15.4%) and 9 (6.6%) were classified as G, GI, I and UC phenotype, respectively. The G-phenotype tumors were associated with a higher rate of undifferentiated-type and infiltrative histology as compared with the I-phenotype tumors (p < 0.05 and p < 0.001, respectively). Furthermore, both univariate and multivariate analysis of survival revealed the G-phenotype tumor to be associated with a significantly poorer outcome than the I-phenotype tumor (p < 0.05). CONCLUSION: Our present results indicate that the gastric and intestinal phenotypic marker expression pattern of tumors, determined by the combination of HGM, MUC6, MUC2 and CD10 expression, is prognostically useful for patients with gastric carcinoma.     

p21-ras-peptide-specific T-cell responses in a patient with colorectal cancer. CD4+ and CD8+ T cells recognize a peptide corresponding to a common mutation (13Gly → Asp)

Peptides derived from mutated ras are immunogenic in mice and humans, and represent a group of specific tumor antigens that are potential targets for immunotherapy. T-cell responses against mutant p21 ras can be initiated in vitro by repeated stimulation of peripheral-blood mononuclear cells with mutant ras-derived peptides. Patients with tumors commonly harbouring ras mutations may therefore show evidence of in vivo reactivity against such mutations. Peripheral-blood mononuclear cells from 10 patients with colorectal adenocarcinoma were screened for reactivity against synthetic ras-derived peptides corresponding to the most commonly found mutations in this type of cancer. In one patient, T-cell reactivity against the 1–25, 13Gly → Asp peptide was detected. From this patient, both CD4⁺ and CD8⁺ T-cell clones specific for the 1–25, 13Gly → Asp mutation could be raised. We were not, however, able to detect the corresponding mutation in the cancer. The 13Gly → Asp mutation in the ras oncogene is frequent and constitutes 9 to 27% of all K ras mutations found in biopsies from patients with colorectal carcinomas. Our study demonstrates a mutant ras-specific T-cell response of both the CD4⁺ and the CD8⁺ phenotype in a cancer patient. We speculate that in this patient a specific T-cell response resulted in eradication of tumor cells harboring the 13Gly → Asp mutation. © 1994 Wiley-Liss, Inc.     

Characterization and immunotherapeutic potential of γδ T-cells in patients with glioblastoma

Classical immunotherapeutic approaches to glioblastoma multiforme (GBM) have shown mixed results, and therapies focused on innate lymphocyte activity against GBM have not been rigorously evaluated. We examined peripheral blood lymphocyte phenotype, γδ T-cell number, mitogenic response, and cytotoxicity against GBM cell lines and primary tumor explants from GBM patients at selected time points prior to and during GBM therapy. Healthy volunteers served as controls and were grouped by age. T-cell infiltration of tumors from these patients was assessed by staining for CD3 and T-cell receptor γδ. Our findings revealed no differences in counts of mean absolute T-cells, T-cell subsets CD3⁺CD4⁺ and CD3⁺CD8⁺, and natural killer cells from healthy volunteers and patients prior to and immediately after GBM resection. In contrast, γδ T-cell counts and mitogen-stimulated proliferative response of γδ T-cells were markedly decreased prior to GBM resection and throughout therapy. Expanded/activated γδ T-cells from both patients and healthy volunteers kill GBM cell lines D54, U373, and U251, as well as primary GBM, without cytotoxicity to primary astrocyte cultures. Perivascular T-cell accumulation was noted in paraffin sections, but no organized T-cell invasion of the tumor parenchyma was seen. Taken together, these data suggest that γδ T-cell depletion and impaired function occur prior to or concurrent with the growth of the tumor. The significant cytotoxicity of expanded/activated γδ T-cells from both healthy controls and selected patients against primary GBM explants may open a previously unexplored approach to cellular immunotherapy of GBM.     

A clinicopathologic study of primary small intestine lymphoma: prognostic significance of mucosa-associated lymphoid tissue-derived lymphoma

BACKGROUND: It remains unclear whether the presence of mucosa-associated lymphoid tissue (MALT) lymphoma has prognostic implications for patients with primary small intestine lymphoma. METHODS: The clinicopathologic features of 80 patients with primary small intestine lymphoma were examined retrospectively in relation to the presence of MALT lymphoma. Survival was compared univariately and multivariately among the groups divided by clinicopathologic findings. RESULTS: Twenty-one cases (26%) were diagnosed as low grade B-cell lymphoma (15 marginal zone B-cell lymphoma of MALT type, 2 mantle cell lymphoma, and 4 follicle center lymphoma), 46 cases (58%) were diagnosed as high grade B-cell lymphoma (19 secondary large cell lymphoma with a low grade MALT component, 17 diffuse large cell lymphoma without MALT features, 7 Burkitt lymphoma, and 3 lymphoblastic lymphoma), and 13 cases (16%) were diagnosed as T-cell lymphoma. A significantly better survival was noted for patients without colorectal and/or gastric involvement, diffuse infiltration under macroscopy, high grade histology, and perforation. Those patients with MALT type tumors, less advanced stage of disease, B-cell phenotype, benign lymphoid follicular hyperplasia, and radical tumor resectability appeared to have a better survival rate. Based on Cox multivariate analysis, early stage disease and MALT-derived tumors were determined to be independent prognostic factors (P < 0.05). CONCLUSIONS: The presence of MALT-derived lymphoma appears to have a favorable prognosis among patients with primary small intestinal lymphoma.     

MHC-dependent cytolysis of autologous tumor cells by lymphocytes infiltrating urothelial carcinomas

Tumor-infiltrating lymphocytes (TIL) were grown from 23 urothelial carcinomas. Phenotyping analysis showed that the TIL cultures were mainly CD3⁺. Although CD4⁺ and CD8⁺ T-cell sub-sets were grown in culture, CD4⁺ T-cell sub-sets predominated over CD8⁺ T cells. Immunohistochemical studies performed on 5 tumor specimens confirmed this observation, and indicated that CD4⁺ T cells surrounded the tumor islets, whereas CD8⁺ T lymphocytes were localized among the tumor cells. Five short-term carcinoma cell lines established from these urothelial tumors were used as target cells in cytolysis assays in order to investigate the functional anti-tumor activity of autologous TIL. TIL from 4/5 tumors were lytic and 3 TIL lines displayed MHC-class-I-dependent cytotoxicity directed against autologous tumor cells. CD4⁺ T-cell-depletion experiments performed on TIL line 07 confirmed that CD8⁺ MHC-class-I-dependent CTL were the predominant effectors. Finally, experiments performed on 6 allogeneic urothelial-cancer cell lines matched for HLA-class-I molecules showed that TIL07 exhibited selective lytic activity toward tumor 07. These data indicate that CD8⁺ MHC-class-I-dependent CTL present in urothelial carcinomas are functional and may participate in the anti-tumor immune response. Int. J. Cancer 71:585-594, 1997. © 1997 Wiley-Liss, Inc.     

Analysis of radiotherapy-induced alteration of CD8+ T cells and PD-L1 expression in patients with uterine cervical squamous cell carcinoma

Radiotherapy induces an immune response in the cancer microenvironment that may influence clinical outcome. The present study aimed to analyse the alteration of CD8⁺ T-cell infiltration and programmed death-ligand 1 (PD-L1) expression following radiotherapy in clinical samples from patients with uterine cervical squamous cell carcinoma. Additionally, the current study sought to analyse the association between these immune responses and clinical outcomes. A total of 75 patients who received either definitive chemoradiotherapy or radiotherapy were retrospectively analyzed. CD8⁺ T-cell infiltration and PD-L1 expression were determined by immunohistochemistry using biopsy specimens before radiotherapy (pre-RT) and after 10 Gy radiotherapy (post-10 Gy). The PD-L1⁺ rate was significantly increased from 5% (4/75) pre-RT to 52% (39/75) post-10 Gy (P<0.01). Despite this increase in the PD-L1⁺ rate post-10 Gy, there was no significant association between both pre-RT and post-10 Gy and overall survival (OS), locoregional control (LC) and progression-free survival (PFS). On the other hand, the CD8⁺ T-cell infiltration density was significantly decreased for all patients (median, 23.1% pre-RT vs. 16.9% post-10 Gy; P=0.038); however, this tended to increase in patients treated with radiotherapy alone (median, 17.7% pre-RT vs. 24.0% post-10 Gy; P=0.400). Notably, patients with high CD8⁺ T-cell infiltration either pre-RT or post-10 Gy exhibited positive associations with OS, LC and PFS. Thus, the present analysis suggested that CD8⁺ T-cell infiltration may be a prognostic biomarker for patients with cervical cancer receiving radiotherapy. Furthermore, immune checkpoint inhibitors may be effective in patients who have received radiotherapy, since radiotherapy upregulated PD-L1 expression in cervical cancer specimens.     

Association of Replication Error Positive Phenotype with Lymphocyte Infiltration in Endometrial Cancers

Microsatellite instability (MI) has been detected in certain sporadic cancers as well as in hereditary non-polyposis colorectal cancer (HNPCC). In order to determine the precise clinicopathological characteristics of MI in endometrial cancer, we examined 90 sporadic endometrial cancers (83 endometrioid adenocarcinomas, 3 adenosquamous carcinomas, 3 papillary serous carcinomas, and 1 clear cell carcinoma) and eight lesions of endometrial hyperplasia for replication error (RER) using polymerase chain reaction amplification of CA repeated microsatellite sequences at 15 loci. RER was observed in 23 (28%) of the 83 endometrioid adenocarcinomas at at least one locus and in 19 (23%) at two or more loci (RER+ phenotype) in the seven most commonly observed loci, but not in carcinomas of other histological types or in endometrial hyperplasia. Lymphocyte infiltration around carcinoma cells, which is one of the histological features seen in tumors from HNPCC, was severer in RER+ phenotype tumors (79%, 11/14) than in the RER– tumors (25%, 11/44) (marked/moderate infiltration versus slight, P <0.001, χ² test), when 58 tumors with muscular invasion were examined. The RER+ phenotype was associated with a higher parity and gravidity ( P <0.05, Wilcoxon test). However, RER+ phenotype was not associated with tumor stage, histological grade, muscular invasion, lymph node metastasis or patient survival. In conclusion, MI occurs in a subset of endometrial cancers, which often show marked infiltration of lymphocytes around the tumor.     

Differential expression of Pim-3, c-Myc,and p-p27 proteins in adenocarcinomas of the gastric cardia and distal stomach

Gastric cardia adenocarcinoma (GCA) is distinct from adenocarcinoma of the distal stomach because of its different etiological factors, tumor characteristics, and biological behavior. However, its pathogenesis is not fully understood. The purpose of this study is to characterize the role of Pim-3, c-Myc, and p-p27 in the tumorigenesis and progression of different sites of gastric adenocarcinoma by determining its pathogenetic significance. The expression of Pim-3, c-Myc, and p-p27 proteins was evaluated by immunohistochemistry in 140 resection specimens of gastric adenocarcinomas (78 GCAs , 62 DGAs and 20 normal gastric tissues). The level of expression of Pim-3, c-Myc, and p-p27 and the co-expression of all three markers (Pim-3+/c-Myc+/p-p27+) in GCA were significantly lower than that in DGA tumors (P?<?0.05). Detailed analysis of the immunoreactivity patterns showed that in DGA, Pim-3 immunoreactivity was associated significantly with poor tumor differentiation, advanced tumor stage, and presence of lymph node metastasis. In addition, c-Myc overexpression correlated with tumor stage and lymph node metastasis, and positive p-p27 expression correlated with poor differentiation and tumor stage. The phenotype of Pim-3⁺/c-Myc⁺/p-p27⁺ co-expression was closely correlated with tumor stage and lymph node metastasis (P?<?0.05). In contrast, GCA only demonstrated a close correlation of Pim-3 overexpression with poor tumor differentiation and tumor stage (P?<?0.05). Our results demonstrate the presence of different expression patterns of Pim-3, c-Myc, p-p27, and Pim-3⁺/c-Myc⁺/p-p27⁺ and their clinicopathologic significance in GCA and DGA tumors. Our results add support to the notion that distinct molecular mechanisms may be involved in the development and progression of adenocarcinomas from the gastric cardia and distal portion of stomach.     

Clinicopathologic Characteristics of Breast Cancer Stem Cells Identified on the Basis of Aldehyde Dehydrogenase 1 Expression

Purpose

Breast cancer displays varying molecular and clinical features. The ability to form breast tumors has been shown by several studies with aldehyde dehydrogenase 1 (ALDH1) positive cells. The aim of this study is to investigate the association between ALDH1 expression and clinicopathologic characteristics of invasive ductal carcinoma.

Methods

We investigated breast cancer tissues for the prevalence of ALDH1⁺ tumor cells and their prognostic value. The present study included paraffin-embedded tissues of 70 patients with or without recurrences. We applied immunohistochemical staining for the detection of ALDH1⁺ cells. Analysis of the association of clinical outcomes and molecular subtype with marker status was conducted.

Results

ALDH1⁺ and ALDH1^- tumors were more frequent in triple-negative breast cancers and in luminal A breast cancers, respectively (p<0.01). ALDH1 expression was found to exert significant impact on disease free survival (DFS) (ALDH1⁺ vs. ALDH1^-, 53.1±6.7 months vs. 79.2±4.7 months; p=0.03) and overall survival (OS) (ALDH1⁺ vs. ALDH1^-, 68.5±4.7 months vs. 95.3±1.1 months; p<0.01). In triple-negative breast cancer (TNBC) patients, DFS and OS showed no statistical differences according to ALDH1 expression (ALDH1⁺ vs. ALDH1^-, 45.3±9.4 months vs. 81.3±7.4 months, p=0.52; 69.0±7.5 months vs. 91.3±6.3 months, p=0.67). However, non-TNBC patients showed significant OS difference between ALDH1⁺ and ALDH1^- tumors (ALDH1⁺ vs. ALDH1^-, 77.6±3.6 months vs. 98.0±1.0 months; p=0.04) with no statistical difference of DFS (ALDH1⁺ vs. ALDH1^-, 60.5±8.0 months vs. 81.8±4.6 months; p=0.27).

Conclusion

Our findings suggest that the expression of ALDH1 in breast cancer may be associated with TNBC and poor clinical outcomes. On the basis of our findings, we propose that ALDH1 expression in breast cancer could be correlated with poor prognosis, and may contribute to a more aggressive cancer phenotype.     

Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer

Summary The role of caveolin 1 (CAV1), a structural component of caveolae in breast cancer is controversial, although most studies suggest that it functions as a tumor-suppressor gene. In addition, some studies have identified CAV1 as a marker of myoepithelial cells. Since myoepithelial markers are frequently expressed in breast carcinomas with a basal-like phenotype, which are frequently occurring tumors in women with BRCA1 germline mutations, we evaluated whether CAV1 was associated with a basal-like phenotype in 509 sporadic and 47 hereditary BRCA1-/BRCA2-associated carcinomas. Immunohistochemistry was performed on tissue microarrays and cases were classified as having a basal-like-phenotype if they were estrogen-receptor- and HER2-negative but cytokeratin 5/6- and/or epidermal growth factor receptor-positive. In sporadic carcinomas, CAV1 expression was found in 21 out of 496 valuable cases (4.2%). A basal-like-phenotype was found in 53 out of 498 (10.6%) cases. A strong association was found between CAV1 expression and a basal-like-phenotype, since 52% of tumors that expressed CAV1 had this phenotype, compared with only 9% of CAV1-negative carcinomas (p<0.001). CAV1 was expressed in six (12.8%) familial cases, five of which had a basal-like-phenotype (p = 0.009). Moreover, these six CAV1-positive cases were BRCA1 tumors. The difference in the frequency of CAV1 expression between BRCA1- and BRCA2-associated tumors was statistically significant (p = 0.024). In conclusion, this study reports for the first time CAV1 expression in BRCA1 and BRCA2 hereditary breast cancer and identifies CAV1 as a marker associated with a basal-like-phenotype in both hereditary and sporadic breast cancer.     

Tumor β-catenin expression is associated with immune evasion in non-small cell lung cancer with high tumor mutation burden

β-catenin expression by tumor cells suppressed dendritic cell recruitment to the tumor microenvironment in a melanoma model, resulting in fewer tumor-infiltrating lymphocytes. Immunohistochemistry was used in the present study to examine the association between the expression of β-catenin and tumor infiltrating lymphocytes and CD11c⁺ cells in 122 patients with non-small cell lung cancer (NSCLC), who underwent radical surgery. β-catenin was positive in 24% of NSCLC tumors compared with 59% of squamous cell carcinomas and 11% of adenocarcinomas. There was no significant association between the expression of β-catenin and the frequency of CD8⁺ cell infiltration into tumor tissues, including the stroma. Conversely, the infiltration of CD8⁺ cells into tumor nests was significantly lower in β-catenin-positive cases compared with that in negative β-catenin cases. Similarly, CD11c⁺ cell infiltration was significantly lower in the β-catenin-positive group. The β-catenin-positive group had shorter overall survival and recurrence-free survival times compared with that in the negative group. Furthermore, β-catenin-positive NSCLC had a high tumor mutation burden, but tended to have a low expression of programmed death-ligand 1. In conclusion, the expression of β-catenin in NSCLC was negatively associated with CD11c⁺ cells and cytotoxic T cell infiltration at the tumor site and had a tendency towards a poor prognosis.