The molecular mechanisms underlying sex differentiation and gonad development remain elusive in crustaceans. Here, we report the cloning and characterization of a Sry-related high-mobility group family B2 gene (SpSoxB2) from an economic crustacean species, the mud crab Scylla paramamosain. The SpSoxB2 encodes a putative HMG-box protein (317 amino acids) clustered with invertebrate Sox14 homologues in the SoxB2 subgroup, but shared low similarity with SpSox14. SpSoxB2 was expressed in the hepatopancreas, thoracic ganglion, and gonads (relatively higher expression in testis than ovary). In hepatopancreas, SpSoxB2 expression was not significantly affected by sex or gonadal development stages. In testis, it was demonstrated that the SpSoxB2 expression level increased from Stage I to Stage III and then decreased afterwards. During ovarian development, the SpSoxB2 expression level continually increased from Stage I to Stage V. Furthermore, fluorescence in-situ hybridization showed that SpSoxB2 transcripts were present in both somatic and developing germ cells in the gonads. In testis, SpSoxB2 transcripts were strongly localized in spermatocytes and spermatids. In ovary, SpSoxB2 transcripts were detected in follicle cells, oogonia and oocytes, with the strongest signal in follicle cells. Our results demonstrated that the SpSoxB2 gene may play an important role during gonadal development in mud crab.
Abstract Background HER2-low breast cancers were reported to have distinct clinicopathological characteristics from HER2-zero; however, the difference in their genetic features remains unclear. This study investigated the clinical and molecular features of breast tumors according to HER2 status. Methods We analyzed the clinicopathological and genomic data of 523 Chinese women with breast cancer. Genomic data was generated by targeted next-generation sequencing (NGS) of breast tumor samples using a commercial 520 gene panel. The cohort was stratified according to HER2 status as HER2-zero ( n = 90), HER2-low ( n = 231), and HER2-positive ( n = 202) according to their immunohistochemistry and fluorescence in situ hybridization results. Results HER2-low breast tumors were enriched with hormone receptor-positive tumors, and who had lower Ki67 expression levels. Genes were differentially mutated across HER2 subgroups. HER2-low tumors had significantly more mutations involved in PI3K-Akt signaling than HER2-positive ( p < 0.001) and HER2-zero breast tumors ( p < 0.01). HER2-zero tumors had more mutations in checkpoint factors ( p < 0.01), Fanconi anemia ( p < 0.05), and p53 signaling and cell cycle pathway ( p < 0.05) compared to HER2-low breast tumors. Compared with HER2-zero tumors, HER2-low tumors had significantly lower pathological complete response rates after neoadjuvant therapy (15.9% vs. 37.5%, p = 0.042) and proportion of relapsed/progressed patients across follow-up time points ( p = 0.031), but had comparable disease-free survival ( p = 0.271). Conclusion Our results demonstrate the distinct clinical and molecular features and clinical outcomes of HER2-low breast tumors.
Texture is an important factor determining the quality, acceptability of aquatic products to consumers. Swim bladder from croakers is a traditionally important and high-valued aquatic product in Asia. It was generally considered that swim bladder from male croaker has higher texture quality than those from female. Therefore, mono-sex breeding or nutritional regulation represent promising strategies for improving the texture quality and value of swim bladder in the aquaculture industry of croaker. However, no direct evidence has been reported and the molecular basis associated with the sexual difference in the texture properties remains unknown. Here, we investigated the sexual dimorphism in the texture traits of swim bladder of an important marine economic fish, Chu's croaker (Nibea coibor) and its possible molecular mechanism by comparative transcriptome analysis. Results showed that the tested texture parameters (springiness, hardness, chewiness, shear force, etc.) of the swim bladder in male fish (MSB) were significantly higher than those in female (FSB). A total of 143 differentially expressed genes (DEGs) were acquired between sexes. GO and KEGG pathway enrichment analysis indicated that regulation of extracellular matrix component (ECM), ECM-receptor interaction and primary bile acid synthesis pathway may contribute to the sexual difference. Furthermore, 6 validated DEGs (tnc, gjc1, colgalt1, col12a1, cyp27a1, qpct) were demonstrated to be closely correlated with at least four texture traits. In conclusion, for the first time we demonstrated the sexual dimorphism in the texture traits of swim bladder and the result could provide potential molecular targets for regulating the texture quality of swim bladder of the Chu's croaker during aquaculture practice.
Abstract Background: The data on the prevalence of cancer-related germline mutations and the phenotypes associated with some rare mutations in Chinese breast cancer patients are limited. In this study, the mutation profile of a large cohort of unselected Chinese breast cancer patients were elucidated to determine the prevalence of likely pathogenic or pathogenic (LP/P) germline mutations and their association with clinicopathologic features as well as somatic mutations.Methods: To elucidate the genomic and somatic mutation profile of 524 Chinese breast cancer patients with various stages unselected for predisposing factors, targeted sequencing was performed using a panel consisting of 520 cancer-related genes including 62 cancer susceptibility genes for germline profile. To analyze the somatic mutation profile of the germline mutation carriers, the patients were divided into three groups according to germline mutations: BRCA1/2 (Germline-BRCA1/2), non-BRCA1/2 (Germline-others) and germline wild-type (gWT) groups.Results: A total of 58 patients (11.1%) carried 76 LP/P germline variants in 15 cancer predisposition genes. Germline BRCA1/2 mutations were detected in 29 (5.53%) patients; with 11 (2.10%) BRCA1 carriers and 18 (3.44%) BRCA2 carriers. In addition, LP/P germline mutations were detected in other genes including MUTYH (n=4), PALB2 (n=4), ATM (n=3), BRIP1 (n=3), CDH1 (n=3), RAD51C (n=3), CHEK2 (n=2), FANCA (n=2), PMS2 (n=2), TP53 (n=2), FANCI (n=1), FANCL (n=1) and PTEN (n=1). At least one VUS was identified in 490 (93.5%) patients. Young age (P=0.011), premenopausal status (P=0.013), and breast/ovarian cancer family history (P=0.001) were correlated with germline mutations. Furthermore, patients with Germline-BRCA1/2 had significantly more missense mutations (P=0.02) and less copy number amplification (P=0.04) than patients carrying Germline-others. Meanwhile, mutation types were comparable between Germline-others and gWT patients (P>0.05). Furthermore, the somatic mutation rates for AKT1, CCND1, FGFR1 and PIK3CA varied among the three groups. No mutations in AKT1 and CCND1 were detected in the Germline-BRCA1/2 group. FGFR1 mutations were detected in 24% of the Germline-others group, while the Germline-BRCA1/2 and gWT groups had 10% and 9%, respectively. Moreover, PIK3CA mutations was significantly fewer in the Germline-BRCA1/2 group than Germline-Others (P=0.02) and gWT patients (P=0.002).Conclusions: Our study is the largest germline mutation study in unselected breast cancer patients in Southern China interrogating all breast or ovarian cancer-related genes listed in the US genetic guidelines. The inclusion of the 15 most common cancer susceptibility genes in cancer predisposition screening is important in the Chinese population for selecting the subset of breast cancer patients to receive multigene panel testing. Furthermore, our study also revealed the distinct somatic mutations profiles in germline mutation carriers, which contributes for a better understanding of the tumor characteristics of patients with LP/P germline mutations. Citation Format: Ning Liao, Bo Chen, Guochun Zhang, Chongyang Ren, Yulei Wang, Liping Guo, Li Cao, Lingzhu Wen, Kai Li, Minghan Jia, Cheukfai Li, Hsiaopei Mok, Guangnan Wei, Jiali Lin, Zhou Zhang, Ting Hou, Analyn Lizaso, Jing Liu. Comprehensive analysis of the prevalence of germline mutations and their association with somatic mutations in Chinese unselected breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-03-05.
553 Background: HER2 expression or amplification qualify patients to receive targeted therapeutics against HER2; however, traditional methods of quantifying HER2 amplification using fluorescence in situ hybridization (FISH) do not include a reliable definition for low level amplification. With the promising response rate of patients with low HER2 amplified-metastatic breast cancer to subsequent-line trastuzumab deruxtecan (DS-8201a) therapy, there is a need to improve the existing criteria to accurately identify patients with low HER2. In our study, we investigate whether HER2 amplification quantified by NGS could provide a method to stratify patients into subgroups. Methods: A total of 774 patients diagnosed with breast cancer from Guangdong Provincial People's Hospital (GDPH) who underwent targeted NGS using 520 or 33 cancer-related genes and had their HER2 status evaluated with either FISH or IHC were included in this study. HER2 status were defined as per 2018 ASCO/ACP guidelines. Results: Our results demonstrate that NGS could quantify HER2 amplification with high sensitivity and specificity, with area under the curve of 0.990 [95%CI: 0.982-0.999]. The receiver operating curve indicated an optimal cut-off of 2.62 copy number (CN) for identifying IHC/FISH HER2-negative status with 97.8% specificity. Meanwhile, the cut-off of ≥ 3.62 CN identified patients with IHC/FISH HER2-positive status with 99.8% specificity. Among the 774 patients, 65.8% (n = 509) had HER2 CN of ≤ 2.62 and were classified as HER2 non-amplified, while 25.8% (n = 199) had HER2 CN of ≥ 3.62, classified as HER2-amplified. The remaining 66 patients (8.5%) had HER2 CN between 2.62 and 3.62, and were the patients with heterogeneous IHC/FISH results, classified using NGS as HER2 low-amplified. Patients with low-amplified (49.0% vs. 38.8%, P < 0.001) and amplified (50.3% vs. 38.8%, P < 0.001) HER2 had significantly more number of copy number amplifications in other gene, including CDK12, RARA, and SPOP (P < 0.001, P < 0.001) than patients with HER2 non-amplified, indicating distinct mutation profile. Conclusions: Our results demonstrate that NGS could provide a more accurate stratification of patients based on their HER2 amplification levels. Patients with low levels of HER2 amplification has a distinct mutation profile, suggesting that NGS could serve as a robust tool to identify patients with HER2 amplification, whether high or low, who could benefit treatment with targeted agents designed against heterogeneous HER2 expression.
Background: The complexity of breast cancer at the clinical, morphological and genomic levels has been extensively studied in the western population. However, the mutational genomic profiles in Chinese breast cancer patients have not been explored in any detail. Methods: We performed targeted sequencing using a panel consisting of 33 breast cancer-related genes to investigate the genomic landscape of 304 consecutive treatment-naïve Chinese breast cancer patients at Guangdong Provincial People's Hospital (GDPH), and further compared the results to those in 453 of Caucasian breast cancer patients from The Cancer Genome Atlas (TCGA). Results: The most frequently mutated gene was TP53 (45%), followed by PIK3CA (44%), GATA3 (18%), MAP3K1 (10%), whereas the copy-number amplifications were frequently observed in genes of ERBB2 (24%), MYC (23%), FGFR1 (13%) and CCND1 (10%). Among the 8 most frequently mutated or amplified genes, at least one driver was identifiable in 87.5% (n=267) of our GDPH cohort, revealing the significant contribution of these known driver genes in the development of Chinese breast cancer. Compared to TCGA data, the median age at diagnosis in our cohort was significantly younger (48 vs. 58 years; P<0.001), while the distribution of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) statuses were similar. The largest difference occurred in HR+/HER2- subtype, where 8 of the 10 driver genes compared had statistically significant differences in their frequency, while there were differences in 2 of 10 driver genes among the TNBC and HR+/HER2+ group, but none in the HR-/HER2+ patients in our cohort compared to the TCGA data. Collectively, the most significant genomic difference was a significantly higher prevalence for TP53 and AKT1 in Chinese patients. Additionally, more than half of TP53-mutation HR+/HER2- Chinese patients (~60%) are likely to harbor more severe mutations in TP53, such as nonsense, indels, and splicing mutations. Conclusions: We elucidated the mutational landscape of cancer genes in Chinese breast cancer and further identified significant genomic differences between Asian and Caucasian patients. These results should improve our understanding of pathogenesis and/or metastatic behavior of breast cancer across races/ethnicities, including a better selection of targeted therapies.
The data on the phenotypes associated with some rare germline mutations in Chinese breast cancer patients are limited.The difference in somatic mutation profiles in breast cancer patients with germline BRCA and non-BRCA mutations remains unexplored.We interrogated the germline and somatic mutational profile of 524 Chinese breast cancer patients with various stages unselected for predisposing factors using a panel consisting of 520 cancer-related genes including 62 cancer susceptibility genes.We divided the patients into three groups according to germline mutations: Germline-BRCA1/2, Germline-others (non-BRCA) and Others (non-carriers).A total of 58 patients (11.1%) carried 76 likely pathogenic or pathogenic (LP/P) germline variants in 15 cancer predisposition genes.Germline BRCA1/2 mutations were detected from 29 (5.53%) patients; with 11 (2.10%)BRCA1 carriers and 18 (3.44%)BRCA2 carriers.In addition, LP/P germline mutations were detected in other genes including MUTYH (n=4), PALB2 (n=4), ATM (n=3), BRIP1 (n=3), CDH1 (n=3), RAD51C (n=3), CHEK2 (n=2), FANCA (n=2), PMS2 (n=2), TP53 (n=2), FANCI (n=1), FANCL (n=1) and PTEN (n=1).At least one variant of uncertain significance (VUS) was identified in 490 (93.5%) patients.Young age (P=0.011),premenopausal status (P=0.013), and breast/ovarian cancer family history (P=0.001) were correlated with germline mutations.Germline-BRCA1/2 group was detected with more missense (P=0.02) and less copy-number amplification (P=0.04)than Germline-others group.Meanwhile, Germline-others group and Others group are very similar (P>0.05).The mutation rates of AKT1, CCND1, FGFR1, and PIK3CA were different among the three groups.By investigating all breast and ovarian cancerrelated genes listed in the US genetic guidelines, we identified 15 cancer susceptibility genes frequently mutated in the germline of our population and must be included in cancer predisposition screening.Our study contributed a better understanding of the tumor characteristics of patients with LP/P germline mutations.
Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have become integral elements within the current landscape of breast cancer treatment modalities; however, they are associated with interstitial lung disease (ILD), which is rare but potentially fatal. Notably, only a few studies have compared the difference in ILD incidence between PD-1 and PD-L1 inhibitors. Therefore, this study aimed to assess the discrepancies regarding ILD risk between the two immune checkpoint inhibitors. We also reported three cases of ILD after PD-1 inhibitor treatment. We comprehensively searched PubMed, EMBASE, and the Cochrane Library to identify clinical trials that investigated PD-1/PD-L1 inhibitor treatment for patients with breast cancer. Pooled overall estimates of incidence and risk ratio (RR) were calculated with a 95% confidence interval (CI), and a mirror group analysis was performed using eligible studies. This meta-analysis included 29 studies with 4,639 patients who received PD-1/PD-L1 inhibitor treatment. A higher ILD incidence was observed among 2,508 patients treated with PD-1 inhibitors than among 2,131 patients treated with PD-L1 inhibitors (0.05 vs. 0.02). The mirror group analysis further revealed a higher ILD event risk in patients treated with PD-1 inhibitors than in those treated with PD-L1 inhibitors (RR = 2.34, 95% CI, 1.13–4.82, P = 0.02). Our findings suggest a greater risk of ILD with PD-1 inhibitors than with PD-L1 inhibitors. These findings are instrumental for clinicians in treatment deliberations, and the adoption of more structured diagnostic approaches and management protocols is necessary to mitigate the risk of ILD.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)