Yoon Jin Cha

Screening of ROS1 rearrangements in lung adenocarcinoma by immunohistochemistry and comparison with ALK rearrangements.

ROS1 rearrangement is a predictive biomarker for response to the tyrosine kinase inhibitor, crizotinib. We investigated the usefulness of ROS1 immunohistochemistry (IHC) for the detection of patients who harbor ROS1 rearrangements in two separate cohorts. We also compared ROS1 IHC with ALK IHC in terms of diagnostic performance to predict each gene rearrangement. In a retrospective cohort, IHC was performed in 219 cases of lung adenocarcinoma with already known genetic alterations. In a prospective cohort, we performed IHC for 111 consecutive cases of lung adenocarcinoma and confirmed the results by subsequent FISH. In the retrospective cohort, all 8 ROS1-rearranged tumors were immunoreactive, and 14 of 211 ROS1-wild cases were immunoreactive (sensitivity 100% and specificity 93.4%). In the prospective cohort, all IHC-negative cases were FISH-negative, and 5 of 34 ROS1 immunoreactive cases were ROS1-rearranged (sensitivity 100% and specificity 72.6%). In ROS1-wild tumors, ROS1 protein was more expressed in the tumors of ever-smokers than in those of never-smokers (p = 0.003). ALK IHC showed 100% sensitivity and 98.1 to 100% specificity in both patient cohorts. In conclusion, ROS1 IHC is highly sensitive, but less specific compared with ALK IHC for detection of the corresponding rearrangement. ROS1 IHC-reactive tumors, especially when the tumor is stained with moderate to strong intensity or a diffuse pattern, are recommended to undergo FISH to confirm the gene rearrangement.

Clinicopathological and prognostic significance of programmed cell death ligand-1 expression in lung adenocarcinoma and its relationship with p53 status.

INTRODUCTION PD-L1 expression is a predictive biomarker for response to anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors and can be evaluated by immunohistochemistry. Results of the clinicopathologic characteristics of PD-L1-positive lung adenocarcinoma have been inconsistent in previous studies, and there are no reports on the relationship between PD-L1 expression and p53 status in lung adenocarcinoma. METHODS We examined PD-L1 and p53 expression in a total of 323 surgically resected lung adenocarcinoma cases using anti-PD-L1 (clone SP142) and anti-p53 (clone DO-7) antibodies, and analyzed the clinicopathologic characteristics of PD-L1-positive cases and their relationship with p53 status. RESULTS PD-L1 expression in tumor cells was positive in 60 of 323 cases (18.6%). Higher PD-L1 expression (≥50%) was more prevalent in former or current smokers (p=0.026) and was associated with more pack-years (p=0.016). PD-L1-positive tumors were significantly associated with solid predominant type (p<0.001), p53 aberrant expression (p<0.001), and PD-L1 expression in tumor-infiltrating immune cells (p<0.001). Patients with stage I to III tumors harboring PD-L1-positive tumor cells showed poor recurrence-free survival (p<0.001) and overall survival (p<0.001) on univariate analysis. CONCLUSIONS PD-L1 expression in tumor cells, solid predominant histology, p53 aberrant expression, and PD-L1 expression in tumor-infiltrating immune cells are closely related. These variables should be considered when analyzing the clinical outcomes of patients with lung adenocarcinomas treated with anti-PD1/PD-L1 immune checkpoint inhibitors.

Unique Genetic and Survival Characteristics of Invasive Mucinous Adenocarcinoma of the Lung

Introduction: Invasive mucinous adenocarcinoma is a unique histologic subtype of lung cancer, and our knowledge of its genetic and clinical characteristics is rapidly evolving. Here, we present next- generation sequencing analysis of nucleotide variant and fusion events along with clinical follow-up in a series of lung mucinous adenocarcinoma. Methods: We collected 72 mucinous adenocarcinomas from the United States and Korea. All had been previously assessed for KRAS and EGFR mutations. For KRAS wild-type cases (n = 30), we performed deep targeted next-generation sequencing for gene fusions and nucleotide variants and correlated survival and other clinical features. Results: As expected, KRAS mutations were the most common alteration found (63% of cases); however, the distribution of nucleotide position alterations was more similar to that observed in gastrointestinal tumors than other lung tumors. Within the KRAS-negative cases, we found numerous potentially targetable gene fusions and mutations, including CD74-NRG1, VAMP2-NRG1, TRIM4-BRAF, TPM3-NTRK1, and EML4-ALK gene fusions and ERBB2, BRAF, and PIK3CA mutations. Unexpectedly, we found only two cases with TP53 mutation, which is much lower than observed in lung adenocarcinomas in general. The overall mutation burden was low in histologically confirmed mucinous adenocarcinomas from the public The Cancer Genome Atlas exome data set, regardless of smoking history, suggesting a link between TP53 status and mutation burden in mucinous tumors. There was no significant difference for recurrence-free survival between stage-matched mucinous and nonmucinous adenocarcinomas. It was notable that all recurrence sites were in the lungs for completely resected cases. Conclusions: Our data suggest that mucinous adenocarcinoma is typified by (1) frequent KRAS mutations and a growing list of gene fusions, but rare TP53 mutations, (2) a low mutation burden overall, and (3) a recurrence-free survival similar to stage-matched nonmucinous tumors, with recurrences limited to the lungs.

A Case of ALK-Rearranged Adenocarcinoma with Small Cell Carcinoma-Like Transformation and Resistance to Crizotinib

Histologic changes can be involved in resistance to anticancer drugs. Transformation to small cell lung carcinoma (SCLC) following treatment with EGFR tyrosine kinase inhibitors has been reported in patients with EGFR-mutant lung adenocarcinoma. Herein, we report a case of ALK-rearranged lung adenocarcinoma with SCLC-like histology in a metastatic abdominal nodule that was resistant to crizotinib therapy.

Expression of autophagy related proteins in invasive lobular carcinoma: Comparison to invasive ductal carcinoma

The purpose of this study is to investigate the difference in expression of metabolism-related proteins in invasive lobular carcinoma (ILC) compared to those of the invasive ductal carcinoma (IDC). Tissue microarray was manufactured for 114 cases of ILC and 692 cases of IDC. Immunohistochemical stains were performed as follows: glycolysis (Glut-1, hexokinase II, CAIX, MCT4), glutaminolysis (GLS1, GDH, ASCT2), mitochondria (ATP synthase, SDHA, SDHB), and serine/glycine metabolism (PHGDH, PSAT1, PSPH, SHMT1, GLDC) related proteins. Pleomorphic type (n = 12) of ILC revealed higher expression in hexokinase II, SDHB, and GLDC than classic type (n = 102) (p < 0.05). IDC showed a higher expression of glycolysis (Glut-1, CAIX, MCT4), glutaminolysis (GLS1, ASCT2), and serine/glycine metabolism (PSPH, SHMT1, GLDC) related protein than ILC in tumor cells, whereas ILC revealed higher expression in GDH, SDHA, PHGDH, and PSAT1 than IDC in tumor cells (p < 0.05). In addition, IDC demonstrated a higher expression of metabolism-related proteins than ILC in stromal tissue (p < 0.05). In ILC, tumoral GLDC positivity was correlated with higher nuclear grade (p = 0.026) and higher histologic grade (p = 0.026), and tumoral Glut-1 positivity correlated with higher histologic grade (p = 0.026). Additionally, tumoral PSPH positivity showed a significant correlation to ER negativity and PR negativity (p = 0.026). In conclusion, it reveals different expression patterns of metabolism-related proteins between IDC and ILC

An Unconventional KITENIN/ErbB4-Mediated Downstream Signal of EGF Upregulates c-Jun and the Invasiveness of Colorectal Cancer Cells

Purpose: EGF-stimulated signaling via EGF receptor (EGFR) is important in colorectal tumorigenesis and drug targeting. However, anti-EGFR therapy is not effective in a subset of patients with colorectal cancer, suggesting that unidentified EGF-stimulated pathways might play roles in colorectal cancer. Previously, we identified KAI1 C-terminal interacting tetraspanin (KITENIN) as a metastasis-enhancing gene and found it to be highly expressed in sporadic colorectal cancer tissues. We recently found that EGF further increases KITENIN-induced elevated AP-1 activity. Here we attempted to clarify this novel EGF-stimulated molecular pathway and its roles in colorectal cancer. Experimental Design: We analyzed how EGF modulates the downstream signaling pathway of oncogenic KITENIN in colorectal cancer cells. Biological alterations following EGF treatment were identified in KITENIN-overexpressed colorectal cancer cells with or without alteration of EGFR activity. Results: We identified the KITENIN/ErbB4–Dvl2–c-Jun axis as a novel downstream signal of EGF that is switched on under elevated KITENIN conditions in an EGFR-independent manner. This unconventional EGF signal upregulates c-Jun and enhances invasion and anchorage-independent growth of colorectal cancer cells. In addition, tumor tissues from metastatic patients with colorectal cancer who showed initial poor responses to cetuximab/chemotherapy expressed higher levels of KITENIN than did responders to therapy. Conclusions: Our results highlight the role of an EGFR-independent EGF signal in mediating the invasiveness and tumorigenesis of colorectal cancer cells. This unconventional pathway might be related to the limited clinical efficacy of anti-EGFR agents in a subset of patients with colorectal cancer. Clin Cancer Res; 20(15); 4115–28. ©2014 AACR.

The Clinicopathologic Features of Molecular Apocrine Breast Cancer

Background To elucidate the clinicopathologic features and their implications on the immunohistochemistry in cases of molecular apocrine breast cancer (MABC). Methods Immunohistochemical (IHC) staining for estrogen receptor (ER), human epidermal growth factor receptor 2 (HER-2), cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR), androgen receptor (AR), gamma-glutamyltrasferase 1 (GGT1) and Ki-67 was performed on tissue microarray breast cancer samples from 204 patients. Phenotypes of breast cancer were divided based on the IHC status of ER, AR and GGT1 into the following: luminal type, ER positive and AR and/or GGT1 positive; basal type, ER, AR, and GGT1 negative; non-basal type, ER positive and AR and GGT1 negative; and MABC type, ER negative and AR and/or GGT1 positive. Results In our series of patients (n=204), there were 26 cases of MABC. Besides, there were 18, 60, and 100 cases of luminal type, basal type and non-basal type, respectively. The MABC demonstrated apocrine histology and a higher prevalence of HER-2 positivity than other phenotypes. With the basal type, the MABC manifested a more frequent expression of CK5/6 and EGFR and a higher Ki-67 index than other phenotypes (p<0.001). There were no significant differences in patient prognosis between the phenotypes of breast cancer. Conclusions MABC are distinguishable from other phenotypes based on the apocrine histology and a higher expression rate of HER-2.

MicroRNA alteration and putative target genes in high-grade prostatic intraepithelial neoplasia and prostate cancer: STAT3 and ZEB1 are upregulated during prostate carcinogenesis

We aimed to identify alteration of cancer‐related miRNAs in HGPIN and PCa, and to investigate the clinical implications of HGPIN as a precancerous lesion of PCa.

Rosai-Dorfman Disease in the breast with increased IgG4 expressing plasma cells: a case report.

Rosai-Dorfman disease (RDD) can present in any anatomic site, but breast involvement is rarely reported. Recently, a relationship between RDD and IgG4-related sclerosing disease has been suggested. Here we report another case of RDD with overlapping features of IgG4-related sclerosing disease occurring in a right breast of a 62-year-old female. On microscopic examination, the mass demonstrated a characteristic zonal pattern of proliferation of large polygonal histiocytes and lymphoplasma cells with stromal fibrosis. Emperipolesis was observed in histiocytes with abundant cytoplasm, which showed immunoreactivity for S-100 protein and CD68; the diagnosis of RDD was made. Sheets of plasma cells in the fibrotic stroma demonstrated positive reactions for IgG and IgG4. The mean count of IgG4-positive plasma cells was 100.2/high power field, and the ratio of IgG4/IgG was 56.7%. Additional findings of stromal fibrosis and obliteration of preexisting breast lobules suggested overlapping features with IgG4-related sclerosing disease.

Adipocyte biology in breast cancer: From silent bystander to active facilitator

Adipocytes account for the largest proportion among the cells that comprise breast tissue; therefore, they are considered to be a critical cell type in the tumor microenvironment of breast cancer. In breast cancer, adipocytes are not only found adjacent to cancer cells, but they also play an active role in the entire process of cancer development, progression, metastasis, and treatment response. Factors including the secretion of adipokines such as leptin and adiponectin, as well as autotaxin, interleukin 6, tumor necrosis factor alpha, and hepatic growth factor, metabolic remodeling that supports the growth of breast cancer by transfer of fatty acids to increase mitochondrial β-oxidation, extracellular matrix remodeling and endotrophin production from type IV collagen, and cancer-associated fibroblast phenotype changes have all been implicated in this comprehensive process. Moreover, adipocytes may act as obstacles to therapy, as they are involved in mechanisms of resistance against various breast cancer treatments. Adipose tissues may also be a reservoir for dormant tumor cells during postsurgical autologous fat grafting. Thus, adipocytes, and the processes and pathways in which they are involved, could be effective therapeutic targets for breast cancer. In this review, we focus on the current understanding of adipocyte biology as it affects breast cancer.