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DNA methylation and demethylation regulate the transcription of genes. DNA methylation-associated gene expression of adrenal steroidogenic enzymes may regulate cortisol production in cortisol-producing adenoma (CPA). We aimed to determine the DNA methylation levels of all genes encoding steroidogenic enzymes involved in CPA. Additionally, the aims were to clarify the DNA methylation-associated gene expression and evaluate the difference of CPA genotype from others using DNA methylation data. Twenty-five adrenal CPA and six nonfunctioning adrenocortical adenoma (NFA) samples were analyzed. RNA sequencing and DNA methylation array were performed. The methylation levels at 118 methylation sites of the genes were investigated, and their methylation and mRNA levels were subsequently integrated. Among all the steroidogenic enzyme genes studied, CYP17A1 gene was mainly found to be hypomethylated in CPA compared to that in NFA, and the Benjamini-Hochberg procedure demonstrated that methylation levels at two sites in the CYP17A1 gene body were statistically significant. PRKACA mutant CPAs predominantly exhibited hypomethylation of CYP17A1 gene compared with the GNAS mutant CPAs. Inverse associations between CYP17A1 methylation in three regions of the gene body and its mRNA levels were observed in the NFAs and CPAs. In applying clustering analysis using CYP17A1 methylation and mRNA levels, CPAs with PRKACA mutation were differentiated from NFAs and CPAs with a GNAS mutation. We demonstrated that CPAs exhibited hypomethylation of the CYP17A1 gene body in CPA, especially in the PRKACA mutant CPAs. Methylation of CYP17A1 gene may influence its transcription levels.
Abstract Background: Tumor-infiltrating lymphocytes (TILs) are a useful prognostic factor and predictive biomarker of neoadjuvant chemotherapy treatment response for breast cancer, especially in human epidermal growth factor receptor type 2 (HER2)-positive breast cancer and triple-negative breast cancer (TNBC). However, due to heterogeneity of TIL expression and distribution in the tissues, accurately predicting TIL expression, especially using limited core-needle biopsy specimens, is difficult. Therefore, an accurate and simple preoperative evaluation method is needed. We have reported that the TILs-ultrasonography (US) score determined by characteristic US findings has a predictive performance for lymphocyte-predominant breast cancer (LPBC). This study aimed to investigate whether the TILs-US score with added vascularity assessment has a better predictive performance for LPBC. Methods: This multicenter, retrospective study investigated the validation and scoring of the LPBC characteristic imaging findings and applied it for LPBC and non-LPBC prediction. A total of 100 patients with HER2-positive breast cancer (n = 59) and TNBC (n = 41) treated by curative surgery between January 2014 and December 2021 were evaluated. Stromal lymphocytes in surgical pathological specimens were evaluated; the cutoff value for predicting LPBC was defined as ≥50% stromal TILs. Preoperative US was examined for TIL indicators. The US images with characteristic TILs were scored for LPBC prediction. Univariate and multivariate logistic regression analyses were employed for each potential predictor variable of LPBC. Results: A total of 40 patients with ≥50% stromal TILs were defined as having LPBC. The examined characteristic US findings for predicting LPBC, shape (more lobulated), internal echo level (weaker), posterior echoes (stronger), and vascularity assessment (hypervascularity), were significantly associated with LPBC and used to assign the scoring for predicting LPBC. As previously reported, the TILs-US score ranged from 0–7 points based on three ultrasonic tissue characteristics: shape (round, oval, and polygonal or irregular, 0 points; lobulated, 1 point; and small lobulated, 2 points), internal echo level (high or equal, 0 points; low, 1 point; and extremely low, 2 points), and posterior echoes (shadowing or attenuating, 0 points; no change, 1 point; accentuated, 2 points; and extremely accentuated, 3 points). We further added vascularity assessment (avascular or hypovascular, 0 point; moderately vascular, 1 point; and hypervascular, 2 points) to this scoring system. Based on the receiver operating characteristics (ROC) curves (AUC [Area Under the Curve] 0.77), the score cutoff for predicting LPBC was 4 points for TILs-US score (sensitivity, 0.83; specificity, 0.55; and accuracy, 0.66). Multivariate logistic regression analysis revealed that cT (< T2), estrogen receptor (ER) negativity, and a TILs-US score of ≥4 points were significant LPBC predictors (odds ratio [OR] 3.60; p = 0.028; OR 8.68; p = 0.020; OR 5.99; p = 0.005). Conversely, based on the ROC curves (AUC 0.78), the score cutoff for predicting LPBC was 5 points after adding vascularity assessment (sensitivity, 0.93; specificity, 0.57; and accuracy, 0.71). Multivariate logistic regression analysis revealed that cT (< T2), ER negativity, and a TILs-US score adding vascularity assessment of ≥5 points were significant LPBC predictors (OR 5.12; p = 0.010; OR 10.3; p = 0.019; OR 20.1; p < 0.001). Conclusions: Including the vascularity assessment to the TILs-US score, which can be noninvasively obtained using US, is a more accurate preoperative predictor of LPBC. Vascularity assessment may be an auxiliary factor in predicting LPBC. Univariate and multivariate logistic analysis of significant clinicopathological factors predicting lymphocyte-predominant breast cancer. Citation Format: Yuri Kimura, Norio Masumoto, Sadako Akashi-Tanaka, Kayo Fukui, Midori Noma, Aya Nagata, Takashi Nakamura, Hiroaki Shima, Toshitaka Okuno, Akari Murakami, Yoshiaki Kamei, Shogo Nakano, Koji Arihiro. The TILs-US score adding vascularity assessment based on ultrasonography for predicting tumor-infiltrating lymphocytes in human epidermal growth factor receptor 2-positive and triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-04-10.
Radiofrequency ablation (RFA) is considered a promising alternative to surgical excision for patients with small, unifocal early-stage breast cancer. A significant concern with the application of RFA in patients diagnosed with ductal carcinoma in situ (DCIS) via needle biopsy is the underdiagnosis of invasive cancer. The extent of this underdiagnosis in DCIS patients eligible for RFA has not been clearly defined. This retrospective study assessed lesions diagnosed as DCIS via needle biopsy and eligible for RFA at our institution from April 2009 to March 2024. The eligibility criteria for RFA included a lesion size of ≤ 1.5 cm, unifocality, and clinical node negativity. Underdiagnosis was defined as the presence of invasive cancer in surgical specimens. We evaluated the frequency and risk factors associated with underdiagnosis. During the study period, 606 lesions were diagnosed as DCIS via needle biopsy. Of these, 209 lesions met the criteria for RFA, with underdiagnosis determined in 40 lesions (19.1%). The distribution of pathological T (pT) stages among these lesions was as follows: DCIS in 169 lesions (80.9%), pT1mi in 20 lesions (9.6%), pT1a in 5 lesions (2.4%), pT1b in 9 lesions (4.3%), pT1c in 5 lesions (2.4%), and pT2 in 1 lesion (0.5%). Multivariate logistic regression analysis identified lesion size ≥ 10 mm as a significant risk factor for underdiagnosis (p = 0.016). Adjuvant endocrine therapy and chemotherapy were administered to 26 (65.0%) and 6 (15.0%) of the underdiagnosed lesions, respectively. Our findings highlight the risk of underdiagnosing invasive breast cancer in patients undergoing RFA for needle biopsy-diagnosed DCIS. It is crucial to acknowledge the potential for undertreatment when considering RFA as a treatment option.
