Molecular characteristics of patients with resectable hepatocellular carcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16140-e16140
Author(s):  
Daobing Zeng ◽  
Menglong Wang ◽  
Jushan Wu ◽  
Dongdong Lin ◽  
Qingliang Guo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Homologous Recombination ◽  
Signaling Pathway ◽  
Parp Inhibitors ◽  
Genetic Alterations ◽  
Immune Checkpoint Blockade ◽  
Molecular Characteristics ◽  
Whole Exome ◽  
Targeted Treatments ◽  
Chinese Cohort

e16140 Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies and leading cause of cancer deaths worldwide. Biomarkers contribute to predict the response of targeted treatments and immunotherapy. Therapy directed toward homologous recombination deficiency (HRD) is now approved in ovarian and breast cancer, but the pattern of HRD is not clear in HCC. The HRD phenotype has been defined as the presence of a non-silent somatic mutation in homologous recombination-related (HRR) genes. Thus, we aimed to analyze the molecular characteristics of resectable HCC, including HRR genes. Methods: Matched tumor/normal DNA from resectable HCC patients (N = 53) were analyzed by whole exome sequencing (WES) or Acornmed panel with 808 cancer-related genes. Results: Overall, 94.3% (50/53) patients exhibited genetic alterations. TP53, ARID1A, PTEN and NBPF1 were the most commonly mutated genes in resectable HCC. In addtion, 35.9% patinets harbored at least one HRR genes mutation. The frequently mutated genes were BRCA2 (4.4%), BRCA1(4.0%), ATM (3.9 %), and RAD50 (3.8%). Interesting, frequency of HRR genes mutation in the Chinese cohort was higher than that in TCGA (35.9 % vs 20.9%). Analysis of carcinogenic pathways shown that ERBB and PI3K-AKT signaling pathway were the common signaling pathway. In resectable HCC, 32.08% (17/53) patients disclosed high TMB (highest 25%). Further analysis found that PTEN mutations were remarkably associated with low TMB (p < 0.05). Conclusions: This study contributes to understand the molecular characteristics of patients with resectable HCC, which will be useful to guide personalized therapy and promote the clinical management in this population. Furthermore, the study suggested that it is feasibility for resectable HCC patients received PARP inhibitors, DNA-damaging chemotherapies, and immune checkpoint blockade therapy.

Analysis of DNA damage repair pathway genes as a predictive biomarker for HAIC in hepatocellular carcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16159-e16159
Author(s):  
Qicong Mai ◽  
Zhiqiang Mo ◽  
Jian He ◽  
Tingting Chen ◽  
Mengli Huang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Damage ◽  
Survival Analysis ◽  
Homologous Recombination ◽  
Mutation Frequency ◽  
Predictive Biomarker ◽  
Wild Type ◽  
Type Group ◽  
Whole Exome ◽  
Chinese Cohort

e16159 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide.Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, fluorouracil, and leucovorin (FOLFOX) is one of the effective treatment for advanced HCC patients. DNA damage repaired (DDR) pathway has been widely researched in many cancers recent years, which was a promising predictive biomarker for the response to platinum-based chemotherapy and Immunotherapy. But the DDR characteristics of different subset pathways in HCC, and its correlation with HAIC efficacy were unknown. Methods: Whole exome sequencing (WES) data of 366 HCC patients was obtained from the Cancer Genome Altas (TCGA). Next generation sequencing (NGS, panel on 381/733-gene) was performed on FFPE tumor samples from 2092 Chinese HCC patients (Chinese cohort). Germ-line or somatic mutations of 32 DDR pathway genes (including Mismatch Repair and Homologous Recombination) were classified as DDR gene mutations. TMB was defined as total number of somatic non-synonymous mutations in coding region. Whole exome sequencing (WES) data and clinical data of 21 HCC advanced patients treated with HAIC were obtained to survival analysis. Results: In total, 59.84% (219/366) of HCC patients in TCGA harboring DDR mutation and 67.38% (1316/2092) in Chinese cohort. In Chinese HCC cohort, the mean TMB level of DDR mutant group was significant higher than wild-type group (mean TMB, mutation vs wild-type = 8.12 vs 6.42 Muts/Mb, P < 0.0001). The top three mutation frequency DDR genes were BRCA2 (17%), ATM (13%) and BARD1 (12%), respectively. The highest mutation frequency DDR subset pathways were Fanconi anemia (FA, 44.14%, 862/2092), homologous recombination repair (HRR, 38.71%, 756/2092) and check point factors (CHP, 17.31%, 338/2092) come in second and third, respectively. Next we compared the TMB level between different DDR subset pathways, the mutant of nucleotide excision repair (NER) pathway harbored the highest medium TMB level (7.26 Muts/Mb). The survival analysis was performed on HCC patients treated with HAIC with FOLFOX. There was no difference in clinical baseline information between DDR mutation group (n = 6) and wild-type group (n = 15). The progression-free survival (PFS) of DDR mutation group were significantly longer than wild-type group (median PFS, mutation vs. wild-type = 8.9 vs. 4.5 months; HR 0.34[95% CI 0.13-0.85]; P = 0.0349), and an extending trend on overall survival (OS) without significant difference (median OS, 15.7 vs 8.9 months; HR 0.37[95% CI 0.13-1.00]; P = 0.0921). Conclusions: The DDR pathways was associated with higher TMB level. Preliminary data from clinical cohorts suggested better treatment outcomes of HAIC with FOLFOX in DDR mutation HCC patients.

scholarly journals Homologous recombination deficiency in breast cancer

2020 ◽  
Vol 13 (4) ◽  
pp. 375-379 ◽  
Author(s):  
Thomas Bartl ◽  
Alex Farr
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Scientific Evidence ◽  
Predictive Marker ◽  
Parp Inhibitors ◽  
Therapeutic Benefit ◽  
Molecular Characteristics ◽  
Mutational Status ◽  
The Individual

SummaryBRCA mutation-related DNA repair deficiencies increase the individual sensitivity to DNA-targeting agents. Therefore, the patient’s BRCA mutational status is evaluated in clinical practice as a predictive marker in response to platinum salts and poly-ADP-ribose polymerase (PARP) inhibitors for breast cancer treatment. A substantial subset of BRCA wild-type breast cancer lesions, however, share both prominent molecular characteristics and clinical behavior patterns with cancer that harbors BRCA mutations, including DNA repair deficiencies. Also referred to as “BRCAness”, this observation is related to aberrations of the homologous recombination (HR) repair pathway, which deprive cancer cells of the ability to adequately mend potentially lethal double-strand breaks and result in a BRCA-like genomic instability. Hence, HR deficiency is a promising target for related therapeutic options and the predictive potential of HR testing for treatment response has been increasingly studied. Several HR deficiency-testing assays have been proposed and prospectively validated for various cancer types; however, preliminary results in early breast cancer are inconsistent. As scientific evidence for a potential therapeutic benefit in breast cancer is scarce, HR testing remains highly experimental and should be limited to the boundaries of clinical studies until results of ongoing phase 3 trials are available.

Landscape of homologous recombination-related (HRR) genes mutations in colon cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15525-e15525
Author(s):  
Tuanjie Zhao ◽  
Chuncheng Ren ◽  
Zhiliang Zhang ◽  
Huanhuan Liu ◽  
Huina Wang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Homologous Recombination ◽  
Clinical Outcomes ◽  
Somatic Mutation ◽  
Immune Checkpoint ◽  
Parp Inhibitors ◽  
Chinese Patients ◽  
Chemotherapy Response ◽  
Molecular Features ◽  
Chinese Cohort

e15525 Background: Homologous recombination deficiency (HRD) might serve as a biomarker of immunotherapy and chemotherapy response. In addtion, HRD is associated with sensitivity to PARP inhibitor (PARPi) therapy. The HRD phenotype has been defined as the presence of a non-silent somatic mutation in homologous recombination-related (HRR) genes. Here, we focused on mutational landscape of HRR genes and the relationship between HRR-related genes and clinical outcomes in colon cancer. Methods: We prospectively sequenced 784 Chinese patients with colon cancer using next-generation sequencing techniques with 808 cancer-related genes. 290 patients with somatic mutation from the TCGA project were included. The 15 HRR genes were selected on clinical evidence of sensitivity to PARP inhibitors and immunotherapy. TCGA datasets were performed to identify the correlations between HRR gene mutations and clinical outcomes. Results: In the Chinese cohort, 11.5% (90/784) patients exhibited deleterious somatic mutation in HRR genes, including ATM (3.3%), BRCA2 (2.4%), CDK12 (2.4%), BRCA1 (1.0%), BRIP1 (1.0%), CHEK2 (0.5%), BARD1 (0.4%), RAD54L (0.4%), PALB2 (0.3%), and RAD51B (0.3%). In TCGA cohort, 28.6% (83/290) patients had at least one deleterious somatic mutation in HRR genes, including ATM (14.8%), BRCA2 (9.0%), CDK12 (7.9%), BRIP1 (3.8%), BRCA1 (3.4%), FANCL (3.1%), CHEK2 (2.4%), PALB2 (2.1%), PPP2R2A (2.1%), RAD54L (2.1%), CHEK1 (1.7%), BARD1 (1.4%), RAD51C (1.4%), RAD51B (1.0%), and RAD51D (0.3%). Overall, the mutational frequency of HRR genes in the Chinese cohort was lower than that in the TCGA cohort (p < 0.001). In the TCGA cohort, colon patients with HRR-mut had significantly higher tumor mutational burden and incidence of microsatellite instability high and enhanced immune activity than patients with HRR-wt. Furthermore, In the MSK-IMPACT cohort treated by immune checkpoint inhibitor, patients with HRR-mut had significantly better OS (p = 0.009) and increased immune activities, such as infiltration of cytotoxic cells (p < 0.05) and exhausted CD8+ T cells (p < 0.01), and increased the IFN-γ scores (p < 0.05) than patients with HRR-wt. Conclusions: Our data suggest that detection of somatic mutations in HRR genes might contribute to identify patients who might benefit from immune checkpoint blockade therapy and PARP inhibitors. In addition, the molecular features of HRR provide new opportunities to predict the tumor response to multiple treatments. Exploring other biomarkers of HRD to predict the response to PARPi and immunotherapeutic in colon cancer is necessary.

scholarly journals High Risk of Hepatocellular Carcinoma Development in Fibrotic Liver: Role of the Hippo-YAP/TAZ Signaling Pathway

2019 ◽  
Vol 20 (3) ◽  
pp. 581 ◽  
Author(s):  
Hyuk Moon ◽  
Kyungjoo Cho ◽  
Sunyeong Shin ◽  
Do Kim ◽  
Kwang-Hyub Han ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Fibrosis ◽  
Liver Cancer ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Genetic Alterations ◽  
Molecular Signaling ◽  
Fibrotic Liver ◽  
Molecular Signaling Pathways ◽  
End Stage

Liver cancer is the fourth leading cause of cancer-related death globally, accounting for approximately 800,000 deaths annually. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, making up about 80% of cases. Liver fibrosis and its end-stage disease, cirrhosis, are major risk factors for HCC. A fibrotic liver typically shows persistent hepatocyte death and compensatory regeneration, chronic inflammation, and an increase in reactive oxygen species, which collaboratively create a tumor-promoting microenvironment via inducing genetic alterations and chromosomal instability, and activating various oncogenic molecular signaling pathways. In this article, we review recent advances in fields of liver fibrosis and carcinogenesis, and consider several molecular signaling pathways that promote hepato-carcinogenesis under the microenvironment of liver fibrosis. In particular, we pay attention to emerging roles of the Hippo-YAP/TAZ signaling pathway in stromal activation, hepatic fibrosis, and liver cancer.

Prevalence of hyperprogressive disease (HPD) mutations and correlations to immune-related biomarkers in a large pan-cancer Chinese cohort.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2649-2649
Author(s):  
Shengli Yang ◽  
Xinyi Liu ◽  
Ting Bei ◽  
Mengli Huang
Keyword(s):  
Immune Checkpoint Blockade ◽  
Molecular Characteristics ◽  
Driver Gene ◽  
Cancer Type ◽  
Wild Type ◽  
Single Nucleotide Variants ◽  
Driver Genes ◽  
Chinese Cohort ◽  
Hyperprogressive Disease ◽  
Pan Cancer

2649 Background: Immune checkpoint blockade (ICI) therapies have demonstrated inspiring clinical efficacy in multiple types of cancer. However, a subset of patients suffered rapid tumor growth after ICI treatment, which is known as hyperprogressive disease (HPD). Although the mechanism of HPD has not been fully elucidated, some genomic alterations, such as CDKN2A/CDKN2B loss and MDM2/MDM4 amplification were reported to occur in tumors with ICI-related HPD. We analyzed the prevalence of these four “HPD mutations” and their association with PD-L1 expression, TMB, and occurrence of driver gene mutations in a large pan-cancer Chinese cohort. Methods: Patients whose tumor tissues were subjected to molecular profiling using targeted next-generation sequencing from January 2017 – November 2020 were included. Single nucleotide variants (SNV), copy number variants (CNV), insertion/deletions (indels) and fusions were called. PD-L1 expression was stratified by CPS 5. Fisher’s exact test were conducted to compare the frequencies of biomarkers and Mann-Whitney U test was used to compare the TMB level between the “HPD mutations” group and their wild-type counterpart. Results: 45,785 patients of 22 types of cancer were queried. Across all 22 cancers, CDKN2A loss and CDKN2B loss were most commonly seen in ESCA (23.3%, 19.8%), while with the lowest frequency in PRAD (0.18%, 0.18%). MDM2 gain and MDM4 gain occurred most frequently in SARC (14.6%) and BRCA (3.3%), respectively, with the lowest frequency in COAD (0.05%, 0.07%). PD-L1 positive (CPS≥5) rates were similar in CDKN2A/B loss, MDM2/4 amp and wild-type groups in the whole cohort (26.1%, 25%, 27.7%). Enrichment of PD-L1 positivity was not observed in HPD-mutant groups in a specific cancer type. Compared with wild-type group, CDKN2A/B loss significantly correlated with higher TMB levels in NSCLC and SARC (p < 0.05) while MDM2/4 amp correlated with lower TMB levels in NSCLC, BTC, and STAD (p < 0.05). In NSCLC, SNV in EGFR, TP53, KEAP1, NFE2L2, STK11, PIK3CA, and SMARCA4 genes were significantly enriched in the CDKN2A/B loss group, while SNV in EGFR, RBM10, AR, KDR genes, and fusion in RET were significantly enriched in MDM2/4 amp group. Conclusions: HPD mutations were significantly associated with TMB level and occurrence of some driver genes, but were not correlated with PD-L1 expression. Our results revealed the immune-related molecular characteristics in tumors with HPD mutations, providing more insights into the exploration for mechanism of HPD.

Potential use of homologous recombination deficiency score as an indicator of therapy selection in leiomyosarcoma patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e23539-e23539
Author(s):  
Yuhong Zhou ◽  
Xi Guo ◽  
He Guo ◽  
Rongyuan Zhuang ◽  
Wenshuai Liu ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Signaling Pathway ◽  
Somatic Mutation ◽  
Stage Iv ◽  
Parp Inhibitors ◽  
P Value ◽  
Rna Seq ◽  
Platinum Based Chemotherapy ◽  
Ppar Signaling

e23539 Background: Leiomyosarcoma (LMS) is one of the most frequent sarcoma subtypes. While surgical resection is the standard treatment of LMS, chemotherapy and radiation have shown additional survival benefit. However, the treatment response is variable and selection of appropriate agents is difficult due to the great heterogeneity of LMS. Matching DNA damaging reagents or PARP inhibitors, to tumors with a general homologous recombination deficit (HRD), can help to deploy these reagents more precisely. We explored the correlation of HRD score with the activation of PARP signaling pathway and retrospectively tested the effect of platinum-based therapy on an LMS patient with high HRD score. Methods: Nineteen LMS samples were subjected to whole exome sequencing and their HRD scores were calculated using a published algorithm. Nine of the LMS samples were also subjected to RNA-seq analysis and undergone GSEA to profile PARP pathway expression. CIBERSORT was employed to profile infiltrating immune cells. Results: The 19 LMS samples are defined as HRD-high (11 samples) or HRD-low (8 samples) if their HRD score is above or equal to, or below the medium respectively. For the 9 samples undergone RNA-seq, 97 genes have differential expression between the two groups (p-value < 0.05, fold change≥ 2). GSEA revealed 23 enriched pathways. Interestingly, PPAR signaling pathway is the most highly enriched one (EnrichmentScore = 0.506, P.adj = 0.005). No other pathogenic germline or somatic mutation in HRD related genes, for example BRCA1/2, is enriched. Additionally, high HRD score is significantly correlated with infiltrating Tregs, monocyte, and M0 macrophages as found in CIBERSORT analysis. To retrospectively test whether HRD score can be used to predict the response to inhibitors of DNA repair pathway, we identified one patient who had received platinum-based combination therapy after failure of first-line chemotherapy. The patient is a 40-year-old female with stage IV LMS and has a high HRD score. She achieved PR with 6-month PFS and remains progression free up to the abstract date, supporting a good correlation between high HRD score and advanced chemotherapy in LMS patients. Conclusions: High HRD score is correlated with activated PPAR pathway and infiltrating Tregs, monocytes and M0 macrophages, and can potentially be used to identify LMS patients with good response to platinum-based chemotherapy even though they have no obvious germline and somatic mutation in genes involved in DNA repair.

scholarly journals Characterisation of PALB2 tumours through whole-exome and whole-transcriptomic analyses

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Pei Sze Ng ◽  
Jia Wern Pan ◽  
Muhammad Mamduh Ahmad Zabidi ◽  
Pathmanathan Rajadurai ◽  
Cheng Har Yip ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Peripheral Blood Lymphocytes ◽  
Molecular Characteristics ◽  
Breast Cancer Patients ◽  
Mutational Status ◽  
Whole Exome ◽  
Increased Risk ◽  
Fresh Frozen ◽  
Somatic Alterations

AbstractRare protein-truncating variants (PTVs) in PALB2 confer increased risk to breast cancer, but relatively few studies have reported the characteristics of tumours with PALB2 PTVs. In this study, we describe molecular characteristics of tumours with either germline or somatic alterations in PALB2. DNA from fresh frozen tumour tissues and matched peripheral blood lymphocytes for 560 breast cancer patients was subjected for whole-exome sequencing (WES), and RNA from tumour tissues was subjected to RNA sequencing (RNA-seq). We found six cases with germline and three with somatic protein-truncating variants in PALB2. The characteristics of tumours in patients with PALB2 PTVs were similar to those with BRCA1 and BRCA2 PTVs, having significantly more somatic alterations, and a high proportion of the mutational signature and genomic scar scores characteristic of deficiencies in homologous recombination (HR), compared to tumours arising in non-carriers. Unlike tumours arising in patients with BRCA1 and BRCA2 PTVs, PALB2 tumours did not have high prevalence of TP53 somatic alterations or an enriched immune microenvironment. In summary, PALB2 tumours show the homologous recombination deficiencies characteristic of BRCA1 and BRCA2 tumours, and highlight the potential clinical relevance of PALB2 mutational status in guiding therapeutic choices.

Genetic alterations of Wnt signaling pathway-associated genes in hepatocellular carcinoma

2007 ◽  
Vol 23 (1) ◽  
pp. 110-118 ◽  
Author(s):  
Young-Dae Kim ◽  
Chang-Hwan Park ◽  
Hyun-Soo Kim ◽  
Sung-Kyu Choi ◽  
Jong-Sun Rew ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Genetic Alterations

Frequency of homologous recombination deficiency gene mutations in melanoma and its relevance to the immunotherapeutic response.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15073-e15073
Author(s):  
Huanhuan Liu ◽  
Yanrui Zhang ◽  
Feng Ding ◽  
Yun Zhang ◽  
Xiayuan Liang ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Somatic Mutation ◽  
Gene Mutations ◽  
Tumor Infiltrating Lymphocytes ◽  
Bioinformatic Analysis ◽  
Immune Checkpoint Blockade ◽  
Homologous Recombination Deficiency ◽  
Molecular Features ◽  
Chinese Cohort ◽  
Melanoma Patients

e15073 Background: Homologous recombination deficiency (HRD) can regulate the tumor immune microenvironment based on increasing tumor-infiltrating lymphocytes and therefore might serve as a biomarker of immunotherapeutic response. The HRD phenotype has been defined as the presence of a non-silent somatic mutation in homologous recombination-related (HRR) genes. Here, we focused on frequency of HRR genes mutation and the relationship between HRR genes mutation and clinical immunotherapy responses in melanoma. Methods: We prospectively sequenced 130 Chinese melanoma patients using next-generation sequencing techniques with Acornmed panel with 808 cancer-related genes. 208 patients with WES data from the TCGA project were included. Correlations between HRR gene mutations and clinical outcomes were identified via bioinformatic analysis using TCGA datasets. Results: In the Chinese cohort, 40% (52/130) patients exhibited genomic alterations in HRR genes. The frequently mutated genes were ATM (14%), BRCA2 (13%), CHEK2 (6%), PALB2 (6%), BRIP1 (4.6%), BARD1 (3%), BRCA1 (2%), CDK12 (2%), CHEK1 (1%), FANCL (1%), and RAD54L (1%). In TCGA cohort, 26% (53/208) patients had at least one somatic mutation in an HRR gene. The frequently mutated genes were BRCA2 (9%), BRCA1 (7%), ATM (6%), BRIP1 (4%), PALB2 (4%), BRAD1 (1%), CHEK2 (1%), PPP2R2A (1%), RAD51B (1%), RAD51C (1%), RAD54L (1%), CHEK1 (1%), and RAD51D. Chinese melanoma patients had higher frequently mutated HRR genes compared to that in TCGA patients (40% vs 26%, p=0.005). In addition, compared with TCGA cohort, the Chinese cohort had higher frequency for ATM (14% vs 6%, p=0.019) and CHEK2 (6% vs 2%, p=0.006). The TCGA cohort had a higher frequency of BRCA1 mutations than the Chinese cohort, although the difference was not statistically significant. Unfortunately, we did not find a significant correlation between HRR mutation and immune cells. Interestingly, in the TCGA cohort, patients with HRR-mut had significantly better OS than patients with HRR-wt (log-rank p=0.027). Conclusions: Our data suggest that detection of somatic mutations in HRR genes might contribute to identify patients who might benefit from immune checkpoint blockade therapy. In addition, the molecular features of HRD provide new opportunities to predict the tumor response to multiple treatments.[Table: see text]

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