Comprehensively Exploring the Mutational Landscape and Patterns of Genomic Evolution in Hypermutated Cancers

Abstract

Tumor heterogeneity results in more than 50% of hypermutated cancers failing to respond to standard immunotherapy. There are numerous challenges in terms of drug resistance, therapeutic strategies, and biomarkers in immunotherapy. In this study, we analyzed primary tumor samples from 533 cancer patients with six different cancer types using deep targeted sequencing and gene expression data from 78 colorectal cancer patients, whereby driver mutations, mutational signatures, tumor-associated neoantigens, and molecular cancer evolution were investigated. Driver mutations, including RET, CBL, and DDR2 gene mutations, were identified in the hypermutated cancers. Most hypermutated endometrial and pancreatic cancer patients carry genetic mutations in EGFR, FBXW7, and PIK3CA that are linked to immunotherapy resistance, while hypermutated head and neck cancer patients carry genetic mutations associated with better treatment responses, such as ATM and BRRCA2 mutations. APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) and DNA repair defects are mutational drivers that are signatures for hypermutated cancer. Cancer driver mutations and other mutational signatures are associated with sensitivity or resistance to immunotherapy, representing potential genetic markers in hypermutated cancers. Using computational prediction, we identified NF1 p.T700I and NOTCH1 p.V2153M as tumor-associated neoantigens, representing potential therapeutic targets for immunotherapy. Sequential mutations were used to predict hypermutated cancers based on genomic evolution. Using a logistic model, we achieved an area under the curve (AUC) = 0.93, accuracy = 0.93, and sensitivity = 0.81 in the testing set. The sequential patterns were distinct among the six cancer types, and the sequential mutation order of MSH2 and the coexisting BRAF genetic mutations influenced the hypermutated phenotype. The TP53~MLH1 and NOTCH1~TET2 sequential mutations impacted colorectal cancer survival (p-value = 0.027 and 0.0001, respectively) by reducing the expression of PTPRCAP (p-value = 1.06 × 10−6) and NOS2 (p-value = 7.57 × 10−7) in immunity. Sequential mutations are significant for hypermutated cancers, which are characterized by mutational heterogeneity. In addition to driver mutations and mutational signatures, sequential mutations in cancer evolution can impact hypermutated cancers. They characterize potential responses or predictive markers for hypermutated cancers. These data can also be used to develop hypermutation-associated drug targets and elucidate the evolutionary biology of cancer survival. In this study, we conducted a comprehensive analysis of mutational patterns, including sequential mutations, and identified useful markers and therapeutic targets in hypermutated cancer patients.

FBXW7 and human tumors: mechanisms of drug resistance and potential therapeutic strategies

“…Shen et al (2022) also found that FBXW7, by promoting eye absent homolog 2 (EYA2) degradation, could reduce the tumor mesenchymal phenotype and enables increased immune cell infiltration, thereby enhancing the response to anti-PD-1 therapy in a mouse tumor model. Mutations in FBXW7 have also been associated with sensitivity or resistance to immunotherapy in endometrial and pancreatic cancers, as analyzed using gene sequencing (Lin et al, 2021). Therefore, screening for FBXW7 status as a biomarker to predict tumor patient response to treatment with immune checkpoint inhibitors (ICBs) or as a target to improve the efficacy of immunotherapy deserves further exploration.…”

Tailored Molecular Imaging of Pheochromocytoma and Paraganglioma: Which Tracer and When

“…With respect to PCC, the most common mutations reported are related to RET proto-oncogene, VHL, SDHx, NF1, and MAX, whereas PGLs with an underlying muta- tion in subunit B of SDH (SDHB) are associated with a higher risk of aggressive behavior and development of metastases [14]. Moreover, the involvement of specific molecular pathways could imply the presence of PPGLs as part of syndromic presentation or even suggest bilateral tumors, the presence of metastatic disease, or pediatric onset.…”

“…Loss-of-function mutations in VHL lead to HIF-2α accumulation, thus promoting angiogenesis, tumor spreading, and metastasis [13]. The second cluster is mainly characterized by RET and NF1 mutations, although HRAS, transmembrane protein 127, MAX, and fibroblast growth factor receptor 1 mutations have been reported [14]. RET encodes a tyrosine kinase receptor and is physiologically involved in RAS/MAPK and PI3K/AKT transduction pathways of proliferation, survival, and angiogenesis; therefore, gain-of-function mutations in RET lead to constitutive activation and consequent deregulation of such pathways determining increased cell survival.…”

“…This is due to the activation of enzymes such as tyrosine hydroxylase, DA ß-hydroxylase, and dopa-decarboxylase and the contemporary reduction of expression of phenylethanolamine N-methyltransferase, which converts NE to E [11]. This is the case in VHL mutations, in which, tumors present only NE hypersecretion, independently of whether the location is adrenal or extra-adrenal, or in PPGLs from patients with SDHB- and SDHD-mutated genes that are characterized by overproduction of DA, either with or without NE, although SDHB-related extra-adrenal abdominal PPGLs could also be biochemically silent [14]. Gene mutations in cluster 2 include MEN2 and NF1 patients whose PPGLs tend to be intra-adrenal and rarely malignant.…”