PIK3CA gene mutations in the helical domain correlate with high tumor mutation burden and poor prognosis in metastatic breast carcinomas with late-line therapies

AbstractGenomic features such as microsatellite instability (MSI) and tumor mutation burden (TMB) are predictive of immune checkpoint inhibitor (ICI) response. However, they do not account for the functional effects of specific driver gene mutations, which may alter the immune microenvironment and influence immunotherapy outcomes. By analyzing a multi-cancer cohort of 1,525 ICI-treated patients, we identified 12 driver genes in 6 cancer types associated with treatment outcomes, including genes involved in oncogenic signaling pathways (NOTCH, WNT, FGFR) and chromatin remodeling. Mutations of PIK3CA, PBRM1, SMARCA4, and KMT2D were associated with worse outcomes across multiple cancer types. In comparison, genes showing cancer-specific associations—such as KEAP1, BRAF, and RNF43—harbored distinct variant types and variants, some of which were individually associated with outcomes. In colorectal cancer, a common RNF43 indel was a putative neoantigen associated with higher immune infiltration and favorable ICI outcomes. Finally, we showed that selected mutations were associated with PD-L1 status and could further stratify patient outcomes beyond MSI or TMB, highlighting their potential as biomarkers for immunotherapy.

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MUC4 mutation correlates with tumor mutation burden and the immune microenvironment in colorectal cancer

10.21203/rs.3.rs-101882/v1 ◽

2020 ◽

Author(s):

Ting Li ◽

Wenjia Hui ◽

Halina Halike ◽

Feng Gao

Keyword(s):

Colorectal Cancer ◽

Immune Response ◽

T Cells ◽

Immune Cells ◽

Gene Mutations ◽

Cancer Genome ◽

Immune Microenvironment ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Mutant Genes

Abstract Background: Immunotherapy is a new strategy for Colorectal cancer (CRC) treatment. Tumor mutation burden (TMB) may act as an emerging biomarker for predicting responses to immunotherapy. Nevertheless, no studies investigate if these gene mutations correlate to TMB and tumor-infiltrating immune cells. Methods: Somatic mutation data for CRC samples were obtained from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) datasets. Then, we investigated the relationship between these mutant genes, TMB and overall survival outcomes. GSEA analysis was performed to explore the underlying mechanism of mutant gene. Finally, we further verified the connection between gene mutations and immune response.Results: We identified 17 common mutant genes shared by both two cohorts. Further analysis found that MUC4 mutation was strongly related to higher TMB and predicted a poorer prognosis. Moreover, functional enrichment analysis of samples with MUC4 mutation revealed that they were involved in regulating the natural killer cell mediated cytotoxicity signaling pathway. Significant changes in the proportion of the immune cells of CD8 T cells, activated NK cells, M1 macrophages and resting memory CD4 T cells were observed using the CIBERSORT algorithm. Conclusions: Our research revealed that MUC4 mutation significantly correlated with increased TMB, a worse prognosis and modulating the immune microenvironment, which may be considered a biomarker to predict the outcome of the immune response in colorectal cancer.

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Co-mutations of KRAS/BRAF and TP53 or the high tumor mutation burden to predict survival in patients with biliary tract carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16650 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16650-e16650

Author(s):

Lingling Guo ◽

Xiaoxia Kou ◽

Panpan Song ◽

Xiaoyu Zhang ◽

Hongjuan Zhang ◽

...

Keyword(s):

Biliary Tract ◽

Poor Prognosis ◽

Clinical Decision Making ◽

Clinical Decision ◽

Biliary Tract Carcinoma ◽

Rank Test ◽

Braf Mutations ◽

Tumor Mutation Burden ◽

Synonymous Mutations ◽

Mutation Burden

e16650 Background: Biliary tract carcinoma (BTC), including cholangiocarcinoma and gallbladder carcinoma, is the second most common type of hepatobiliary cancer. Patients with BTC always show poor prognosis, here we revealed the molecular landscape of BTC in the Chinese population and evaluated the role of different mutations in informing prognosis. Methods: Formalin-Fixed Paraffin-Embedded (FFPE) or freshly-sampled tumor tissues from 59 BTC patients were conducted next-generation sequencing of 620 genes related to oncogenesis. Tumor mutation burden (TMB) value represents the number of non-synonymous mutations per mega base pairs in each sample. Kaplan-Meier survival curves were generated and compared using the log-rank test. Results: Altogether, 59 patients have mutations mainly in TP53, Ras/Raf, PI3K, CDK signaling pathways and SWI/SNF complex. The most frequently mutated gene was TP53(53%), followed by KRAS(23%), ARID1A(17%), ATM(12%), CDKN2A(10%), SMAD4(8%), BRCA2(8%), STK11(7%), BRAF(5%), IDH1(5%) and FGFR3 (3%). Noticeably, only one patient with FGFR2 fusion was detected. The Median TMB of these patients is 2.80 Muts/Mbp (0-36.52 Muts/Mbp). Existing data showed that KRAS/BRAF alterations were associated with a worse overall survival (OS) (median OS 166d vs. 294d, p= 0.063). Further analysis indicated that RAS/BRAF mutations were often co-current with TP53 alternations. And patients with coaltered RAS/BRAF and TP53 demonstrated the worst prognosis (media OS 123d vs. 294d, p= 0.087). In addition, a higher TMB ( > 2.80 Muts/Mb) was also associated with a worse survival (median OS 174d vs. 355d, p= 0.085). Conclusions: We identified KRAS/BRAF, or co-mutations with TP53 and high TMB could predict poor prognosis in BTC patients. These findings will be useful for clinical decision making in patients with refractory biliary tract cancer and for risk stratification of patients in future clinical studies.

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Abstract 3542: Frequency of homologous recombination-related gene mutations in breast cancer and their correlation with tumor mutation burden

10.1158/1538-7445.am2020-3542 ◽

2020 ◽

Cited By ~ 1

Author(s):

Haitao Lan ◽

Qing Bu ◽

Li Zhuang ◽

Shuang Ren ◽

Xuexin Yan ◽

...

Keyword(s):

Breast Cancer ◽

Homologous Recombination ◽

Gene Mutations ◽

Related Gene ◽

Tumor Mutation Burden ◽

Mutation Burden

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DNA Repair Gene Mutations as Predictors of Immune Checkpoint Inhibitor Response beyond Tumor Mutation Burden

Cell Reports Medicine ◽

10.1016/j.xcrm.2020.100034 ◽

2020 ◽

Vol 1 (3) ◽

pp. 100034 ◽

Cited By ~ 1

Author(s):

David Hsiehchen ◽

Antony Hsieh ◽

Robert M. Samstein ◽

Tianshi Lu ◽

Muhammad S. Beg ◽

...

Keyword(s):

Dna Repair ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Gene Mutations ◽

Repair Gene ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Dna Repair Gene

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The landscape of gene mutations and clinical significance of tumor mutation burden in patients with soft tissue sarcoma who underwent surgical resection and received conventional adjuvant therapy

The International Journal of Biological Markers ◽

10.1177/1724600820925095 ◽

2020 ◽

Vol 35 (3) ◽

pp. 14-22

Author(s):

Li-Bin Xu ◽

Zhen-Guo Zhao ◽

Song-Feng Xu ◽

Xin-Xin Zhang ◽

Ting Liu ◽

...

Keyword(s):

Overall Survival ◽

Survival Analysis ◽

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Adjuvant Therapy ◽

Surgical Resection ◽

Clinical Significance ◽

Gene Mutations ◽

Tumor Mutation Burden ◽

Mutation Burden

Background The aim of this study was to evaluate the landscape of gene mutations and the clinical significance of tumor mutation burden (TMB) in patients with soft tissue sarcoma who underwent surgical resection and received conventional adjuvant therapy. Methods A total of 68 patients with soft tissue sarcoma were included. Postoperative tumor tissue specimens from the patients were collected for DNA extraction. Targeted next-generation sequencing of cancer-relevant genes was performed for the detection of gene mutations and the analysis of TMB. Univariate analysis between TMB status and prognosis was carried out using the Kaplan–Meier survival analysis, and multivariate analysis was adjusted by the Cox regression model. Results No specific genetic mutations associated with soft tissue sarcoma were found. The mutation frequency of TP53, PIK3C2G, NCOR1, and KRAS of the 68 patients with soft tissue sarcoma were observed in 19 cases (27.94%), 15 cases (22.06%), 14 cases (20.59%), and 14 cases (20.59%), respectively. With regard to the analysis of TMB, the overall TMB of the 68 patients with soft tissue sarcoma was relatively low (median: 2.05 per Mb (range: 0∼15.5 per Mb)). Subsequently, TMB status was divided into TMB-Low and TMB-Middle according to the median TMB. Patients with TMB-Low and TMB-Middle were 37 cases (54.41%) and 31 cases (45.59%), respectively. Overall survival analysis indicated that the median overall survival of patients with TMB-Low and TMB-Middle was not reached, and 4.5 years, respectively ( P=0.015). Conclusion This study characterizes the genetic background of patients with STS soft tissue sarcoma. The TMB was of clinical significance for patients with soft tissue sarcoma who underwent surgical resection and received conventional adjuvant therapy.

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Papillary thyroid carcinoma with a high tumor mutation burden has a poor prognosis

International Immunopharmacology ◽

10.1016/j.intimp.2020.107090 ◽

2020 ◽

Vol 89 ◽

pp. 107090

Author(s):

Zhenyu Xie ◽

Xin Li ◽

Yu Lun ◽

Yuzhen He ◽

Song Wu ◽

...

Keyword(s):

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Poor Prognosis ◽

Papillary Thyroid ◽

Tumor Mutation Burden ◽

Mutation Burden

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Titin Mutation Is Associated With Tumor Mutation Burden and Promotes Antitumor Immunity in Lung Squamous Cell Carcinoma

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.761758 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xiaona Xie ◽

Yemeng Tang ◽

Jueqi Sheng ◽

Pingping Shu ◽

Xiayan Zhu ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Immune Therapy ◽

Gene Mutations ◽

Lung Squamous Cell Carcinoma ◽

Cancer Genome ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Number Of Patients

Lung squamous cell carcinoma (LUSC) is a leading cause of mobidity and mortality worldwide. Recently, there was a shift in the treatment pattern of immune therapy in LUSC patients; merely a small number of patients with non-small cell lung cancer (NSCLC) at advanced stages respond well to immune checkpoint blockade (ICB) therapy, and tumor mutation burden (TMB) is a valuable independent indicator of response to immune therapy. However, specific gene mutations and their relationship with TMB and tumor-infiltrating immunocytes in LUSC are still unclear. In the present paper, our team analyzed the somatically mutated genes from the ICGC (International Cancer Genome Consortium) and TCGA (The Cancer Genome Atlas) datasets and discovered that 15 frequent gene mutations occurred in both cohorts, including ZFHX4, MUC16, FLG, TP53, LRP1B, TTN, SYNE1, RYR2, CSMD3, USH2A, MUC17, DNAH5, FAM135B, COL11A1, and RYR3. Interestingly, only mutated TTN was related to higher TMB and prognostic outcomes among the 15 mutated genes. Moreover, according to the CIBERSORT algorithm, we revealed that TTN mutation enhanced the antitumor immune response. In conclusion, TTN may have important clinical implications for relevant immune therapy of lung squamous carcinoma.

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Tumor mutation burden in biliary tract cancers with ERBB family or DNA damage repair gene mutations.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15602 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15602-e15602

Author(s):

Yongjie Zhang ◽

Ningjia Shen ◽

Wenlong Yu ◽

Xiaohui Fu ◽

Jia Song ◽

...

Keyword(s):

Dna Damage ◽

Gallbladder Cancer ◽

Cancer Patients ◽

Gene Mutation ◽

Gene Mutations ◽

Tumor Mutation Burden ◽

Biliary Tract Cancers ◽

Clinical Cohort ◽

Damage Repair ◽

Mutation Burden

e15602 Background: Biliary tract cancers (BTCs) are aggressive malignancies associated with resistance to chemotherapy. Though immunotherapy presents a promising results based on several studies, the overall response rate is relative low. Tumor mutation burden (TMB) has been considered as a predictive biomarker of immunotherapy. However, the association between common mutations and TMB in BTCs are still unclear. Methods: We analyzed 76 BTC samples (32 cholangiocarcinoma and 44 gallbladder cancer patients) from the Cancer Genome Altas (TCGA) by whole-exome sequencing and 408 samples (276 cholangiocarcinoma and 132 gallbladder cancer patients) from Chinese clinical cohort by 381-gene targeted sequencing. The association between ERBB family members or DNA damage repair (DDR) genes and TMB was explored, respectively. TMB was defined as total number of somatic non-synonymous mutations in coding region. Results: The mutation frequency of ERBB genes was similar between the TCGA cohort and the clinical cohort (cholangiocarcinoma, 13.6% vs 10.9%; gallbladder cancer, 21.9% vs 17.4%). However, DDR mutation rate from the TCGA data was greater than that from the clinical data without consideration the pathological type (cholangiocarcinoma, 40.9% vs 21.0%; gallbladder cancer, 62.5% vs 29.5%). In cholangiocarcinoma, any ERBB gene mutation was associated with higher TMB level in TCGA cohort (P = 0.0013) and clinical cohort (P = 0.0008). Any DDR gene mutation also significantly contributed to higher TMB in two cohorts (TCGA cohort, P = 0.0001; clinical cohort, P = 0.0139). In gallbladder cancer, the same result was discovered on the significant association between ERBB genes statue and higher TMB in both two data (TCGA cohort, P = 0.0370; clinical cohort, P = 0.0008). On the contrary, higher TMB level was observed in patients carrying any DDR alterations (P = 0.0017) in TCGA cohort, but the association was not found in Chinese cohort (P = 0.2660). Besides, prognosis analysis was performed on patients in TCGA cohort. Cholangiocarcinoma patients harboring any ERBB gene mutation represent significantly poorer overall survival (median, 10.6 vs. 40.1 months; HR, 3.37; P = 0.0186). Conclusions: Chinese BTC patients may exhibit distinct gene mutations. These findings were the supplement of better comprehending BTC genomic characteristics. Further studies are needed to evaluate the efficacy of immunotherapy in BTC patients with ERBB or DDR mutation in Chinese clinical cohort.

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