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Background The homologous recombination (HR) repair pathway for DNA damage, particularly the BRCA1 and BRCA2 genes, has become a target for cancer therapy, with poly ADP-ribose polymerase (PARP) inhibitors showing significant outcomes in treating germline BRCA1/2 (g BRCA1/2 ) mutated breast cancer. Recent studies suggest that some patients with somatic BRCA1/2 (s BRCA1/2 ) mutation or mutations in HR-related genes other than BRCA1/2 may benefit from PARP inhibitors as well, particularly those with PALB2 mutations. The current analysis aims to evaluate the prevalence of genetic alterations specific to BRCA1 , BRCA2 , and PALB2 in a large cohort of Taiwanese breast cancer patients through tumor-targeted sequencing. Methods A total of 924 consecutive assays from 879 Taiwanese breast cancer patients underwent tumor-targeted sequencing (Thermo Fisher Oncomine Comprehensive Assay v3). We evaluated BRCA1 , BRCA2 , and PALB2 mutational profiles, with variants annotated and curated by the ClinVAR, the Oncomine™ Knowledgebase Reporter, and the OncoKB™. We also conducted reflex germline testing using either whole exome sequencing (WES) or whole genome sequencing (WGS), which is ongoing. Results Among the 879 patients analyzed (924 assays), 130 had positive mutations in BRCA1 (3.1%), BRCA2 (8.6%), and PALB2 (5.2%), with a total of 14.8% having genetic alterations. Co-occurrence was noted between BRCA1/BRCA2 , BRCA1/PALB2, and BRCA2/PALB2 mutations. In BRCA1 -mutated samples, only p.K654fs was observed in three patients, while other variants were observed no more than twice. For BRCA2 , p.N372H was the most common (26 patients), followed by p.S2186fs, p.V2466A, and p.X159_splice (5 times each). For PALB2 , p.I887fs was the most common mutation (30 patients). This study identified 176 amino acid changes; 60.2% (106) were not documented in either ClinVAR or the Oncomine™ Knowledgebase Reporter. Using the OncoKB™ for annotation, 171 (97.2%) were found to have clinical implications. For the result of reflex germline testing, three variants ( BRCA1 c.1969_1970del, BRCA1 c.3629_3630del, BRCA2 c.8755-1G > C) were annotated as Pathogenic/Likely pathogenic (P/LP) variants by ClinVar and as likely loss-of-function or likely oncogenic by OncoKB; while one variant ( PALB2 c.448C > T) was not found in ClinVar but was annotated as likely loss-of-function or likely oncogenic by OncoKB. Conclusion Our study depicted the mutational patterns of BRCA1 , BRCA2 , and PALB2 in Taiwanese breast cancer patients through tumor-only sequencing. This highlights the growing importance of BRCA1/2 and PALB2 alterations in breast cancer susceptibility risk and the treatment of index patients. We also emphasized the need to meticulously annotate variants in cancer-driver genes as well as actionable mutations across multiple databases.

Background Breast cancer is one of the leading causes of cancer-related deaths in women, and there is a demand in developing an Asian-based genetic profiling database for breast cancer in improving the treatment response. This study aimed to determine molecular alternations and identify potential therapeutic targets by analyzing the genetic profiling from a cohort of Taiwanese breast cancers using a commercialized next-generation sequencing (NGS) targeted panel. Methods The study population comprised a broad spectrum of breast cancer patients in Taiwan, including Group 1: planned to receive first-line surgery and followed by adjuvant therapy, or early relapse within three years, Group 2: planned to receive first-line neoadjuvant therapy and followed by surgery, and Group 3: de novo stage IV, or stage IV with recurrence beyond three years. Molecular profiles were determined using Thermo Fisher™ Oncomine™ Comprehensive Assay version 3 (TMO comprehensive assay) from Formalin-Fixed Paraffin-Embedded (FFPE) tissues. Level of actionability was evaluated with the ESMO Scale of clinical actionability of molecular targets (ESCAT). Results A total of 380 TMO comprehensive assays were conducted on 372 patients, and we presented targeted sequencing analyses of Tier I: alteration-drug match associated with improved outcome in clinical trials including ERBB2 amplification, BRCA1/2 germline mutation, PIK3CA mutation, and NTRK translocation, and Tier II: antitumor activity associated with the matched alteration-drug but lack of prospective outcome data including PTEN loss, ESR1 mutation, AKT1 mutation, and ERBB2 mutation, and Tier III: matched drug-alteration that led to clinical benefit in another tumor type including MDM2 amplification, and ERBB3 mutation. Among them, 249 (66%) showed at least one actionable alternation based on the ESCAT criteria. The most frequent impacted genes (all variants combined within each sample) were PIK3CA (38%), followed by ERBB2 (23%), ESR1 (10%), AKT1 (6%), and BRCA2 (5%), and the remaining rare variants (less than 5% of assayed cohort) were BRCA1 (3%), MDM2 (2.2%), and ERBB3 (1.1%). Conclusion Targeted sequencing of actionable genes is believed to provide clinical applicability and substantial benefits for Taiwanese breast cancer patients. A valid scale of clinical actionability should be adopted for precision medicine practice under multidisciplinary molecular tumor board.

BackgroundThe aim of this study was to investigate the role of IL-17A in the cancer microenvironment and the recurrence of triple negative breast cancer (TNBC).MethodsUsing human TNBC cell lines, the role of IL17-A was investigated by knocked down of IL-17A (ΔIL-17A) and by administration of IL-17A into the culture medium. Cell proliferation assays, migration assays, as well as Western blot analysis and real-time PCR, were used to evaluate IL-17A-related signaling. Three types of 4T1 cells were implanted into BALB/c mice, namely wild type (WT), ΔIL-17A, and WT + neutralizing IL-17 antibody (WT + Ab) cells. Tumor weight, necrosis area, and the number of circulating tumor cells (CTCs) were measured. Immunohistochemistry and Western blotting were used to analyze expression of CD34, CD8, and TGF-β1 as well as anoikis resistance. The Kaplan–Meier’s method was used to correlate IL-17A expression and patient outcome, including disease-free survival (DFS) and overall survival (OS).ResultsOur results demonstrated that IL-17A was able to stimulate the migratory activity, but not the growth rate, of MDA-MB-231/468 cells. In vivo, for the ΔIL-17A group, there was an increase in necrosis area, a decrease in tumor CD34 expression and a reduction in the number of CTCs. Furthermore, in WT + Ab group, there was a decreased in tumor expression of CD34, fewer CD8 ( +) cells, and fewer CTCs, but an increase in expression of TGF-β1 expression. Both of the above were compared to the WT group. Knockdown of IL-17A also decreased anoikis resistance in human TNBC and the murine 4T1 cell lines. Kaplan–Meier analysis disclosed a negative correlation between tumor expression of IL-17A and OS in TNBC patients.ConclusionWe conclude that IL-17A promotes migratory and angiogenic activity in tumors, enhances anoikis resistance, and modulates the immune landscape of the tumor microenvironment such changes favor cancer metastasis.

Avocados may suffer from short-term waterlogging stress when exposed to high temperatures and heavy rainfall during the summer in Taiwan. We compared the waterlogging responses of own-rooted and grafted seedlings of two Taiwan cultivars, ‘Black-Beauty’ and ‘Hung-Hsin-Yuan’, by stomatal conductance (gs) and chlorophyll fluorescence parameters. Four-day waterlogging and four-day post-waterlogging recovery periods were investigated. Both gs and Fv/Fm of own-rooted seedlings of two cultivars were significant reductions in response to short-term waterlogging. The grafted seedlings on the same cultivar rootstock were evaluated by gs and Fv/Fm during the growth and the growth cessation periods, respectively. The combined responses of gs and Fv/Fm under short-term waterlogging showed that ‘Black-Beauty’ was sensitive to stress because of decreased gs after waterlogging or decreased Fv/Fm after the two-day recovery period. ‘Hung-Hsin-Yuan’ showed more tolerance to waterlogging stress, especially during the growth cessation. This indicates that the vegetative dormancy may affect the evaluation of the stress response of avocados. Our results revealed that gs and Fv/Fm can be effective indicators in the four-day waterlogging of avocado, and the growth status of avocado seedlings should be considered during stress-tolerant variety selection.

In hospitals, the deterioration of a patient's condition leading to death is often preceded by physiological abnormalities in the hours to days beforehand. Several risk‐scoring systems have been developed to identify patients at risk of major adverse events; however, such systems often exhibit low sensitivity and specificity. To identify the risk factors associated with in‐hospital cardiac arrest (IHCA), we conducted a retrospective cohort study at a tertiary medical center in Taiwan. Four machine learning algorithms were employed to identify the factors most predictive of IHCA. The support vector machine model was discovered to be the most effective at predicting IHCA. The ten most critical physiological parameters at 8 h prior to the event were pulse rate, age, white blood cell count, lymphocyte count, body temperature, body mass index, systolic and diastolic blood pressure, platelet count, and use of central nervous system‐active medication. Using these parameters, we can enhance early warning and rapid response systems in our hospital, potentially reducing the incidence of IHCA in clinical practice.

PurposeDeleterious germline BRCA1/2 mutations are among the most highly pathogenic variants in hereditary breast and ovarian cancer syndrome. Recently, genes implicated in homologous recombination repair (HRR) pathways have been investigated extensively. Defective HRR genes may indicate potential clinical benefits from PARP (poly ADP ribose polymerase) inhibitors beyond BRCA1/2 mutations. MethodsWe evaluated the prevalence of BRCA1/2 mutations as well as alterations in HRR genes with targeted sequencing. A total of 648 consecutive breast cancer samples were assayed, and HRR genes were evaluated for prevalence in breast cancer tissues. ResultsAmong 648 breast cancers, there were 17 truncating and 2 missense mutations in BRCA1 and 45 truncating and 1 missense mutation in BRCA2, impacting 3% and 5% of the study population (collectively altered in 6%) with cooccurrence of BRCA1/2 in 7 breast cancers. On the other hand, HRR genes were altered in 122 (19%) breast cancers, while TBB (Talazoparib Beyond BRCA) trial-interrogated genes (excluding BRCA1/2) were mutated in 107 (17%) patients. Beyond BRCA1/2, the most prevalent HRR mutant genes came from ARID1A (7%), PALB2 (7%), and PTEN (6%). Collectively, 164 (25%) of the 648 Taiwanese breast cancer samples harbored at least one mutation among HRR genes. ConclusionsThe prevalence of BRCA1/2 mutations was far below one tenth, while the prevalence of HRR mutations was much higher and approached one-fourth among Taiwanese breast cancers. Further opportunities to take advantage of defective HRR genes for breast cancer treatment should be sought for the realization of precision medicine.

The aim of this study was to elucidate molecular profiling in HER2-low tumors based on a promising dataset. A total of 615 consecutive HER2-negative breast cancer samples were assayed. The genomic mutations in the two groups with different HER2 expression levels (HER2-0 vs. HER2-low) were compared. The mutation types obtained via next-generation targeted sequencing were correlated with the clinicopathological features of the patients with HER2-0 and HER2-low breast cancer. The results showed that there was a significantly higher percentage of receptor-positive (ER/PR) tumors and more low-level Ki-67 tumors, but a lower incidence of stage I/II tumors in the HER2-low group compared to the HER2-0 group. There was a significantly higher frequency of 17.62% (65/369) for PIK3CA_SNA in the HER2-low group than in the HER2-0 group, which had a frequency of only 9.35% (23/246) (p = 0.006). When the called gene alterations in the triple-negative breast cancer (TNBC) group were compared with those in the luminal-like breast cancer group, there was a significantly high frequency of 28.17% (140/497) for ERBB2_SNA in a luminal-like group than in the TNBC group(16.95% (20/118)).We conclude that the early detection of PIK3CA mutations is likely to be important and might help therapeutic decision making in patients with HER2-low tumors.

Citrus depressa Hayata is the native and widespread citrus species in Taiwan. The notable character is that C. depressa has a distinct aroma different from local citrus. The ex situ germplasm of scions from different collection regions has variant leaf shapes and different odor characteristics. Establishing volatile biomarkers for classifying the local C. depressa is beneficial to commercial development. Volatile organic compounds (VOCs) of fresh leaves from seven C. depressa accessions which were collected from different locations in Taiwan were extracted by headspace solid-phase microextraction and analyzed by GC-MS. The volatile compositions from each season showed the diversity, and linalool, of which the average relative content is 52.7%, was the most volatile component in any season. The other main VOCs of leaves of C. depressa were γ-terpinene, limonene, β-ocimene, and α-terpineol. The result of linear discriminant analysis by VOC markers shows that there are two main different types which are (1) accessions from the central and the east of Taiwan and (2) accessions which are closer to C. depressa in Okinawa, Japan. Five major VOC-related synthase genes were selected and the gene expression was used to classify the varieties. The clustering result is the same with VOC-based discrimination. Our results reveal leaf volatile profiling is capable of being the discrimination markers, and the possibility for constructing molecular markers is directly related to characteristics from secondary metabolites phenotyping.

Citrus depressa Hayata is a small-fruit citrus species; it is indigenous to Kagoshima, Okinawa, and Taiwan. The metabolites and volatile organic compounds (VOCs) that affect the flavor of its fruits have not been investigated based on geographical origin. In the present study, we investigated the metabolite and VOC profiles of 18 C. depressa cultivation lines from these regions. Multivariate analysis revealed differences in the metabolites of C. depressa based on its cultivation origins; variations in sugar, sugar alcohol, and amino acid contents were also observed. Fruits from Kagoshima and Okinawa had higher galactinol, trehalose, xylose, glucose, and sucrose intensities than fruits from Taiwan (log2-fold change; 2.65–3.44, 1.68–2.13, 1.37–2.01, 1.33–1.57, and 1.07–1.43, respectively), whereas the Taiwanese lines contained higher leucine, isoleucine, serine, and alanine. In contrast to the Taiwanese Nantou line, other cultivation lines had comparable total VOC contents, and the VOCs of all lines were dominated by limonene, γ-terpinene, and p-cymene. Accordingly, the highest VOC intensities were recorded in the Nantou line, which was followed by Shikunin sweet (Kagoshima) and Taoyuan (Taiwan) (log10 normalize concentration; 5.11, 3.08, and 3.01, respectively). Moreover, multivariate analysis plots elucidated the difference in the VOCs of Ishikunibu (Okinawa), Shikunin sweet, and Taoyuan and between those of most Kagoshima and Okinawa cultivation lines. These results suggest that both the cultivation line and origin influence the metabolites and VOCs of C. depressa, thus possibly affecting its flavor quality; the data provide a valuable insight for utilizing C. depressa of different cultivation lines and origins to produce foods and beverages.

Citrus depressa Hayata is a citrus cultivar grown in Japan and Taiwan. To assess the differences in genetic characteristics and volatile organic components (VOCs) in the leaves and edible parts of the fruits of 23 C. depressa accessions from different geographic origins, the tissues were analyzed using cleaved amplified polymorphic sequence markers and gas chromatography-mass spectrometry. A phylogenetic cluster analysis demonstrated that Kagoshima accessions had a close genetic relationship with one another, with Okinawan “Izumi kugani-like” being the most distinct accession. The predominant volatiles in the leaves were γ-terpinene, p-cymene, limonene, and linalool. Multivariate analysis and volcano plots revealed distinct volatiles in the leaves of each cultivation region: piperitone and citronellal (Kagoshima); 5,9,9-trimethyl-spiro[3.5]non-5-en-1-one (Okinawa); and hexanal (Taiwan). Furthermore, the edible parts of Taiwanese fruits contained abundant amounts of monoterpenes, including linalool and 1,8-cineole. In contrast, Kagoshima and Okinawa accessions were rich in aldehydes and esters, respectively. In conclusion, the genetic and volatile profiles of 23 C. depressa accessions of different origins could be distinguished, and multivariate analysis suggested that C. depressa contains diverse VOCs depending on where it is cultivated. These findings demonstrate the exclusivity of C. depressa resources in each region, which could assist farmers and agro-industries in promoting food products derived from C. depressa fruits.