Unraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses.

The role of the serine/glycine metabolic pathway (SGP) has recently been demonstrated in tumors; however, the pathological relevance of the SGP in thyroid cancer remains unexplored. Here, we perform metabolomic profiling of 17 tumor-normal pairs; bulk transcriptomics of 263 normal thyroid, 348 papillary, and 21 undifferentiated thyroid cancer samples; and single-cell transcriptomes from 15 cases, showing the impact of mitochondrial one-carbon metabolism in thyroid tumors. High expression of serine hydroxymethyltransferase-2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is associated with low thyroid differentiation scores and poor clinical features. A subpopulation of tumor cells with high mitochondrial one-carbon pathway activity is observed in the single-cell dataset. SHMT2 inhibition significantly compromises mitochondrial respiration and decreases cell proliferation and tumor size in vitro and in vivo. Collectively, our results highlight the importance of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer and suggest that SHMT2 is a potent therapeutic target.

Transcriptomic Analysis of Papillary Thyroid Cancer: A Focus on Immune-Subtyping, Oncogenic Fusion, and Recurrence.

OBJECTIVES: Thyroid cancer is the most common endocrine tumor, with rapidly increasing incidence worldwide. However, its transcriptomic characteristics associated with immunological signatures, driver fusions, and recurrence markers remain unclear. We aimed to investigate the transcriptomic characteristics of advanced papillary thyroid cancer. METHODS: This study included 282 papillary thyroid cancer tumor samples and 155 normal samples from Chungnam National University Hospital and Seoul National University Hospital. Transcriptomic quantification was determined by high-throughput RNA sequencing. We investigated the associations of clinical parameters and molecular signatures using RNA sequencing. We validated predictive biomarkers using the Cancer Genome Atlas database. RESULTS: Through a comparison of differentially expressed genes, gene sets, and pathways in papillary thyroid cancer compared to normal tumor-adjacent tissue, we found increased immune signaling associated with cytokines or T cells and decreased thyroid hormone synthetic pathways. In addition, patients with recurrence presented increased CD8+ T-cell and Th1-cell signatures. Interestingly, we found differentially overexpressed genes related to immune-escape signaling such as CTLA4, IDO1, LAG3, and PDCD1 in advanced papillary thyroid cancer with a low thyroid differentiation score. Fusion analysis showed that the PI3K and mitogen-activated protein kinase (MAPK) signaling pathways were regulated differently according to the RET fusion partner genes (CCDC6 or NCOA4). Finally, we identified HOXD9 as a novel molecular biomarker that predicts the recurrence of thyroid cancer in addition to known risk factors (tumor size, lymph node metastasis, and extrathyroidal extension). CONCLUSION: We identified a high association with immune-escape signaling in the immune-hot group with aggressive clinical characteristics among Korean thyroid cancer patients. Moreover, RET fusion differentially regulated PI3K and MAPK signaling depending on the partner gene of RET, and HOXD9 was found to be a recurrence marker for advanced papillary thyroid cancer.

The blood level of thioredoxin 1 as a supporting biomarker in the detection of breast cancer.

BACKGROUND: There is a long-time unmet need for a means to detect breast cancer (BC) using blood. Although mammography is accepted as the gold standard for screening, a blood-based diagnostic can complement mammography and assist in the accurate detection of BC in the diagnostic process period of early diagnosis. We have previously reported the possible use of thioredoxin 1 (Trx1) in serum as a novel means to detect BC. In the present study, we validated the clinical utility of Trx1 to identify BC by testing sera from biopsy-confirmed cancer patients and women without cancer. METHODS: We have generated monoclonal antibodies against Trx1 and developed an ELISA kit that can quantitate Trx1 in sera. The level of Trx1 was determined in each serum from women without cancer (n = 114), as well as in serum from patients with BC (n = 106) and other types of cancers (n = 74), including cervical, lung, stomach, colorectal, and thyroid cancer. The sera from BC patients were collected and classified by the subjects' age and cancer stage. In addition to the Trx1 levels of BC patients, several pathological and molecular aspects of BC were analyzed. Test results were retrospectively compared to those from mammography. Each test was duplicated, and test results were analyzed by ROC analysis, one-way ANOVA tests, and unpaired t-tests. RESULTS: The mean level of Trx1 from women without cancer was 5.45 ± 4.16 (±SD) ng/ml, that of the other malignant cancer patient group was 2.70 ± 2.01 ng/ml, and that from the BC group was 21.96 ± 6.79 ng/ml. The difference among these values was large enough to distinguish BC sera from non-BC control sera with a sensitivity of 97.17% and specificity of 94.15% (AUC 0.990, p < 0.0001). Most Trx1 levels from BC patients' sera were higher than the cut-off value of 11.4 ng/ml regardless of age, stage, histological grade, type, and specific receptors' expression profile of BC. The level of Trx1 could rescue women from most cases of misread or incomplete mammography diagnoses. CONCLUSION: These results indicated that the blood level of Trx1 could be an effective and accurate means to assist the detection of BC during the early diagnosis period.

Erratum to: The current status of cancer survivorship care and a consideration of appropriate care model in Korea.

[This corrects the article on p. 110 in vol. 16.].

Clinical impact of sarcopenia in patients with colon cancer undergoing laparoscopic surgery.

PURPOSE: Previous studies have reported that progressive muscle loss, known as sarcopenia, has a negative impact on colon cancer treatment. However, the majority of studies have analyzed on patients undergoing open resection, and the association of sarcopenia with clinical outcomes is not clear for patients with colon cancer undergoing laparoscopic surgery. Thus, the aim of this study was to evaluate the impact of sarcopenia on clinical outcomes after laparoscopic surgery for colon cancer. METHODS: A total of 423 patients who underwent laparoscopic surgery for colon cancer between November 2010 and October 2014 were included. Body composition was assessed by measuring muscle and fat areas at the third lumbar vertebra (L3) on preoperative computed tomography. The L3 skeletal muscle area was used to calculate the skeletal muscle index and to assess for sarcopenia. RESULTS: Sarcopenia was identified in 54 patients (12.8%). The median time to first flatus (3 days), median time to tolerable soft diet (4 days), and median length of hospital stay (7 days) were not significantly different between patients with and without sarcopenia. However, sarcopenia was an independent risk factor for postoperative complications in the logistic regression multivariate analysis (P = 0.015). Sarcopenia was not associated with overall or disease-free survival. CONCLUSION: Sarcopenia was not negatively associated with functional recovery, hospital stay, and oncologic outcomes in patients with colon cancer who underwent laparoscopic surgery. However, sarcopenia was associated with postoperative complications after laparoscopic surgery for colon cancer.

The current status of cancer survivorship care and a consideration of appropriate care model in Korea.

Purpose: Breast cancer patients with a human epidermal growth factor receptor 2 (HER2) enriched subtype are known to have higher rates of brain metastases (BM) than other patients. This study aimed to evaluate treatment options and survival outcomes. Methods: A total of 115 breast cancer brain metastases (BCBM) patients with nearly complete medical records were retrospectively analyzed. Additionally, 36 patients were HER2 enriched types according to histological subtypes. The BM was found by brain magnetic resonance imaging in patients who had neurologic symptoms or by regular screening. Age, breast tumor size, number of BM, histological subtypes, first treatment of breast cancer, estrogen receptor, and HER2 status, stage, local treatment of BM were analyzed. Median overall survival, 5-year survival were analyzed from the data. Results: The median survival time after BM was 6 months, the mean survival time was 16.3 months, and the 5-year survival after BM was only 8.0%. Factors that significantly affect the survival of BCBM patients include histological subtype, number of BM, use of lapatinib in multivariate analysis. A total of 19 out of 36 HER2 enriched patients were treated with lapatinib or capecitabine. For the treatment of HER2 enriched patients, additional use of blood-brain barrier (BBB) crossing substances, as well as local treatment for BM, significantly improve the survival rate in the Kaplan-Meier method (P=0.001). Conclusion: A combination of local treatment modality for BCBM and the use of substances that cross the BBB for the HER2 enriched patient improved the survival rate.

Combination Assessment of Clinical Complete Response of Patients With Rectal Cancer Following Chemoradiotherapy With Endoscopy and Magnetic Resonance Imaging.

PURPOSE: The response to neoadjuvant chemoradiotherapy (CRT) for rectal cancer can be assessed using digital rectal examination, endoscopy and magnetic resonance imaging (MRI). Precise assessment of clinical complete response (CR) after CRT is essential when deciding between optimizing surgery or organ-preserving treatment. The objectives of this study were to correlate the CR finding in endoscopy and MRI with pathologic CR and to determine the appropriate approach for combining endoscopy and MRI to predict the pathologic CR in patients with rectal cancer after neoadjuvant CRT. METHODS: This retrospective cohort study included 102 patients with rectal cancer who underwent endoscopy and MRI at 2-4 weeks after CRT. We assigned a confidence level (1-4) for the endoscopic and MRI assessments. Accuracy, sensitivity, and specificity were analyzed based on the endoscopy, MRI, and combination method findings. Diagnostic modalities were compared using the likelihood ratios. RESULTS: Of 102 patients, 17 (16.7%) had a CR. The accuracy, sensitivity, and specificity for the prediction CR of endoscopy with biopsy were 85.3%, 52.9%, and 91.8%, while those of MRI were 91.2%, 70.6%, and 95.3%, and those of combined endoscopy and MRI were 89.2%, 52.9%, and 96.5%, respectively. No significant differences were noted in the sensitivity and specificity of any each modality. The prediction rate for CR of the combination method was 92.6% after the posttest probability test. CONCLUSION: Our study demonstrated that combining the interpretation of endoscopy with biopsy and MRI could provide a good prediction rate for CR in patients with rectal cancer after CRT.