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.
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.
e12570 Background: Little is known about the host-tumor interaction in the lymph node basin at a single cell level. This study examines single cell sequences in breast cancer nodal metastasis of a patient with triple negative breast cancer. Methods: The primary breast tumor, sentinel lymph node, an adjacent lymph node with metastatic involvement and a clinically normal-appearing lymph node were collected during operation. Single-cell sequencing was performed on all specimens. Results: 14,016 cells were clustered as 6 cell populations. Cancer cells demonstrated the molecular characteristics of TNBC basal B subtype and highly expressed genes in the MAPK signaling cascade. Tumor associated macrophages regulated antigen processing and presentation and other immune-related pathways to promote tumor invasion. CD8+ and CD4+ T lymphocytes concentrated more in sentinel lymph node and mainly stratified as two transcriptional states. Conclusions: The first single cell report investigates the host-tumor interaction in the lymph node basin of triple-negative breast cancer. Single-cell sequencing analysis suggested that the sentinel lymph node was the initial meeting site of tumor infiltration and immune response, where partial T lymphocytes perform anti-tumor activity while other T cells exhibit an exhaustion state. We proposed a molecular explanation to the well-established clinical principle that the 5-year and 10-year survival outcomes were noninferior between sentinel lymph node dissection (SLND) and axillary lymph node dissection (ALND).
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.
Abstract N6-methyladenosine (m6A) is a common RNA modification on eukaryotic mRNA and several m6a regulatory proteins, which plays a crucial part in breast cancer. But the copy number variations (CNVs) for m6a regulatory proteins and their role in pathogenesis and progression in breast cancer is still unclear. By analyzing the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and the cancer genome atlas (TCGA database), we screened CNVs of ten m6A regulatory genes, including YTHDF3, YTHDF1, FTO, YTHDC1, ALKBH5, METTL3, WTAP, METTL14, YTHDF2, YTHDC2. Among them, YTHDF3 and YTHDF1 amplification had higher alteration rates among ten m6A regulatory genes. YTHDF1 and YTHDF3 amplification resulted in higher mRNA expression (P<0.001). We found that YTHDF1 and YTHDF3 amplification presented a high correlation with worse cinlicopathological characteristics and overall survival (OS) in breast cancer patients. COX regression analysis showed YTHDF1 amplification was an independent risk factor for 10-year OS in breast cancer (HR=1.549, 95% CI: 1.408-1.705, P<0.001, Table). Moreover, GSEA analysis revealed the downstream target of YTHDF1 may be related to MYC signaling regulation and T cell differentiation. In conclusion, we illustrated genetic alteration of m6A regulatory genes in breast cancer patients and found significant relationship between YTHDF1 amplification and worse clinical characteristics, indicating it a potential target for breast cancer treatment in epigenetic modification. Univariate and multivariate Cox proportional hazard analysis for 10-year overall survivalUnivariateUnivariateHR95% CIP valueHR95% CIP valueNode status1.7181.566-1.885<0.0011.5491.408-1.705<0.001Tumor Size1.0161.013-1.019<0.001ER status0.6200.530-0.725<0.0010.5260.440-0.629<0.001PR status0.6120.531-0.707<0.001HER2 status1.7471.445-2.112<0.0011.5171.234-1.866<0.001Age1.0241.018-1.030<0.0011.0331.026-1.039<0.001YTHDF11.8111.419-2.313<0.0011.5491.408-1.705<0.001 Citation Format: Cheukfai Li, Guochun Zhang, Yulei Wang, Bo Chen, Kai Li, Li Cao, Chongyang Ren, Lingzhu Wen, Minghan Jia, Hsiaopei Mok, Jianguo Lai, Weikai Xiao, Xuerui Li, Ning Liao. YTHDF1 amplification associates with clinicopathological featuresand predicts worse survival in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5912.
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.
Purposes: This study was intended to summarize the characteristics and clinical outcome of Liver and Pancreas (LPTx) recipients in the Scientific Registry of Transplant Recipients (SRTR) database vs. the largest series from the First Affiliated Hospital (FAH), Sun Yat-sen University. Methods: The clinical data of 23 patients who underwent LPTx from 2000 to 2016 in the United States and 31 patients who underwent modified LPTx procedure (known as simplified multivisceral transplantation [SMT]) from 2008 to 2017 in our center were reviewed. The indications, surgical techniques, patient and graft survival, and complications were compared between the two groups. Results: All recipients in the FAH group were diagnosed with type 2 diabetes mellitus, while 10 of 23 recipients were diagnosed with type 1 diabetes mellitus in the SRTR group. The 1-, 3-, and 5-year cumulative patient survival rates were 81, 74, and 74% in the FAH group, respectively, and 51, 47, and 37% in the SRTR group, respectively (P = 0.023). No diabetes was observed during follow-up in the FAH group, while the diabetes recurrence rate was 22.2% in the SRTR group (P = 0.03). Conclusion: With multiple techniques modified and indications changed, the SMT procedure yielded a preferable outcome compared to that of the traditional LPTx procedure in records of SRTR. SMT has become a treatment option for patients with end-stage liver disease and concurrent diabetes.
Abstract Background: Overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer (BC) is associated with lower survival and higher risk of disease recurrence. A new subtype of HER2-low BC which has been proposed from several studies demonstrates that HER2-low patients have distinct somatically genetic alterations and clinical outcomes. We have previously reported that HER2-low BC had distinct clinical and somatic mutational feature compared with HER2-zero and HER2-high tumors. We have therefore extended studies by comparing germline mutation expression among these HER2 subgroups. Methods: 530 Chinese women with BC were enrolled in a prospective protocol between May 2021 to March 2023 at Guangdong Provincial People's Hospital. Genomics data was generated from a gene panel that surveys 102 tumor mutations. Germline variants were classified into pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB) and benign (B) groups according to the ACMG/AMP Standards and Guidelines. The cohort was divided into three groups based on HER2 status as HER2-zero (n = 107), HER2-low (n = 259), and HER2-high (n = 127) according to immunohistochemistry and/or fluorescence in situ hybridization results. Results: The most common mutated genes were ATM, FANCD2, ATR, BRACA2, RECQL4 and APC. A total of 71 pathogenic or likely pathogenic (P/LP) mutations were identified in 25 cancer susceptibility genes from 64 patients (12.16%). The most frequent mutated P/LP genes are BRCA2, BRCA1, PALB2, PMS2, MUTYH and PTEN in the HER2-low group; BRCA2, BRCA1 and PALB2 in the HER2-zero cohort; Interestingly, among the nine HER2-high patients, we detected unique P/LP genes in each sample including MRE11, FANCM, ATM, FLCN, NTRK1, TP53, BRCA1, CHEKE2 and FANCA. In addition to P/LP mutations, 751 variants of uncertain significance (VUS) in 95 cancer susceptibility genes were also detected in 361 patients (68.11%). The most frequent mutated VUS mutations occurred genes are FANCD2, ATM, RECQL4, RAD54B and ATR in HER2-low group; ATM, FANCA, POLE, MSH2 and FANCD2 in HER2-zero cohort; and ATM, BRCA2, RECQL4, POLE, FANCI and FANCM for HER2-high patients. Most of mutated genes were homologous recombination repair (HRR) or DNA damage repair (DDR) pathway related genes. Several genes were differentially altered across HER2 subgroups, including the mutation frequency of the BMPR1A (p=0.0344), MSH2 (p=0.0103), and RAD51C (p=0.0336) genes that were significantly higher in HER2-zero group. It’s worth noting that RAD51C was only mutated in HER2-zero subgroup. BMPR1A and MSH2 were also mutated in HER2-low patients. Differentially mutated genes in specific HER2 subgroups may contribute to better research and choice of future therapeutic approaches. In 115 patients who received neoadjuvant therapy and 84 of them were evaluable for pathological response data, HER2-low patients had lower pathological complete response (pCR) rates than HER2-zero and HER2-high subgroups (p=0.0008). In particular, DDR pathway gene ERCC1 have significantly higher mutation frequency in pCR patients (p=0.0115). Conclusion: HER2-low BC patients have distinct germline mutational signatures and differential clinical outcomes under neoadjuvant systemic therapy. These results have provided additional evidence that HER2-low patients comprise a fourth subtype of BC that needs to be accounted for separately in terms of clinical treatment and outcome reporting. Keywords: breast cancer, germline mutations, human epidermal growth factor receptor 2 (HER2), HER2-low, targeted therapy, next-generation sequencing Table 1. List of most frequent mutated genes in HER2-zero, HER2-low and HER2-high groups Citation Format: Ning Liao, Weiqi Zhang, Liangqiu Liu, Wendy Wu, Siqi Wang, Li Cao, Jianguo Lai, Xueying Zhang, Airong Yang, Yulei Wang, Cheukfai Li, Guochun Zhang, Chongyang Ren, Lingzhu Wen. Unique molecular signatures of germline mutations in low expression of human epidermal growth factor receptor 2 (HER2) breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-08-09.
Checkpoint inhibitor therapy has become increasingly important and has been endorsed as a treatment regimen in breast cancer. But benefits were limited to a small proportion of patients. We aimed to develop an improved signature on the basis of immune genes for detection of potential benefit from immunotherapy. Gene expression data of patients with breast cancer initially extracted from The Cancer Genome Atlas were analyzed. Ten genes were selected from the interaction of differentially expressed genes as well as immune-related genes to develop a survival signature. We compared the high-risk and low-risk groups by gene set enrichment analysis, immune infiltration, checkpoint molecule expression and immunophenoscore. Ten genes were extracted from interactions of differentially expressed and immune-related genes. The immune risk score was determined on the basis of the Cox regression coefficient of hub genes and validated with the GSE96058 dataset. Immune cell infiltrates, including CD8 + T cells, plasma cells, follicular helper T cells, CD4 + memory T cells, M1 macrophages, regulatory T cells and resting NK cells, were more highly infiltrated in the high-risk group as compared to the low-risk group. Checkpoint molecules, including CTLA-4, PD-L1, TIM-3, VISTA, ICOS, PD-1, and PD-L2, were expressed at markedly lower levels in the high-risk group as compared to the low-risk group. Immunophenoscores, as a surrogate of response to immune checkpoint therapy, was observed significant lower in the high-risk group. The 10-gene prognostic signature could identify patients’ survival and was correlated with the biomarkers of immune checkpoint inhibitor therapy, which may guide precise therapeutic decisions in clinical practice.
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