Low immunogenicity of common cancer hot spot mutations resulting in false immunogenic selection signals

Cancer is driven by somatic mutations that result in a cellular fitness advantage. This selective advantage is expected to be counterbalanced by the immune system when these driver mutations simultaneously lead to the generation of neoantigens, novel peptides that are presented at the cancer cell membrane via HLA molecules from the MHC complex. The presentability of these peptides is determined by a patient’s MHC genotype and it has been suggested that this results in MHC genotype-specific restrictions of the oncogenic mutational landscape. Here, we generated a set of virtual patients, each with an identical and prototypical MHC genotype, and show that the earlier reported HLA affinity differences between observed and unobserved mutations are unrelated to MHC genotype variation. We demonstrate how these differences are secondary to high frequencies of 13 hot spot driver mutations in 6 different genes. Several oncogenic mechanisms were identified that lower the peptides’ HLA affinity, including phospho-mimicking substitutions in BRAF, destabilizing tyrosine mutations in TP53 and glycine-rich mutational contexts in the GTP-binding KRAS domain. In line with our earlier findings, our results emphasize that HLA affinity predictions are easily misinterpreted when studying immunogenic selection processes.

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Genetic Architectures and Cell-of-Origin in Glioblastoma

Frontiers in Oncology ◽

10.3389/fonc.2020.615400 ◽

2021 ◽

Vol 10 ◽

Author(s):

Hyun Jung Kim ◽

Jung Won Park ◽

Jeong Ho Lee

Keyword(s):

Brain Cancer ◽

Somatic Mutations ◽

Driver Mutations ◽

Fundamental Issue ◽

Cell Of Origin ◽

Cellular Origin ◽

Common Cancer ◽

The Central Nervous System ◽

Glial Precursor ◽

Novel Therapeutic

An aggressive primary brain cancer, glioblastoma (GBM) is the most common cancer of the central nervous system in adults. However, an inability to identify its cell-of-origin has been a fundamental issue hindering further understanding of the nature and pathogenesis of GBM, as well as the development of novel therapeutic targets. Researchers have hypothesized that GBM arises from an accumulation of somatic mutations in neural stem cells (NSCs) and glial precursor cells that confer selective growth advantages, resulting in uncontrolled proliferation. In this review, we outline genomic perspectives on IDH-wildtype and IDH-mutant GBMs pathogenesis and the cell-of-origin harboring GBM driver mutations proposed by various GBM animal models. Additionally, we discuss the distinct neurodevelopmental programs observed in either IDH-wildtype or IDH-mutant GBMs. Further research into the cellular origin and lineage hierarchy of GBM will help with understanding the evolution of GBMs and with developing effective targets for treating GBM cancer cells.

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The adaptive potential of non-heritable somatic mutations

10.1101/2021.04.30.442123 ◽

2021 ◽

Author(s):

Paco Majic ◽

Yagmur E Erten ◽

Joshua L Payne

Keyword(s):

Somatic Mutation ◽

Adaptive Evolution ◽

Somatic Mutations ◽

Fitness Landscape ◽

Selective Advantage ◽

Adaptive Potential ◽

Fitness Advantage ◽

Organismal Fitness ◽

Proof Of Principle ◽

Evolving Populations

Non-heritable somatic mutations are typically associated with deleterious effects such as in cancer and senescence, so their role in adaptive evolution has received little attention. However, most somatic mutations are harmless and some even confer a fitness advantage to the organism carrying them. We hypothesized that heritable, germline genotypes that are likely to express an advantageous phenotype via non-heritable somatic mutation will have a selective advantage over other germline genotypes, and this advantage will channel evolving populations toward more fit germline genotypes, thus promoting adaptation. We tested this hypothesis by simulating evolving populations of developing organisms with an impermeable germline-soma separation navigating a minimal fitness landscape. The simulations revealed the conditions under which non-heritable somatic mutations promote adaptation. Specifically, this can occur when the somatic mutation supply is high, when only very few cells with the advantageous somatic mutation are required to increase organismal fitness, and when the somatic mutation also confers a selective advantage to cells with that mutation. We therefore provide proof-of-principle that non-heritable somatic mutations can promote adaptive evolution via a process we call somatic genotypic exploration. We discuss the biological plausibility of this phenomenon, as well as its evolutionary implications.

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Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2012-2703 ◽

2013 ◽

Vol 98 (2) ◽

pp. E364-E369 ◽

Cited By ~ 120

Author(s):

Nishant Agrawal ◽

Yuchen Jiao ◽

Mark Sausen ◽

Rebecca Leary ◽

Chetan Bettegowda ◽

...

Keyword(s):

Thyroid Cancer ◽

Somatic Mutations ◽

Medullary Thyroid Cancer ◽

Driver Mutations ◽

High Confidence ◽

Kras Mutations ◽

Protein Coding ◽

Medullary Thyroid ◽

Oncogenic Mutations ◽

Independent Cohort

Abstract Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.

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Clonal approaches to understanding the impact of mutations on hematologic disease development

Blood ◽

10.1182/blood-2018-11-835405 ◽

2019 ◽

Vol 133 (13) ◽

pp. 1436-1445 ◽

Cited By ~ 6

Author(s):

Jyoti Nangalia ◽

Emily Mitchell ◽

Anthony R. Green

Keyword(s):

Somatic Mutations ◽

Clonal Selection ◽

Single Cells ◽

Driver Mutations ◽

Great Promise ◽

Tumor Evolution ◽

Disease Development ◽

Hematopoietic Tissue ◽

The Impact

Abstract Interrogation of hematopoietic tissue at the clonal level has a rich history spanning over 50 years, and has provided critical insights into both normal and malignant hematopoiesis. Characterization of chromosomes identified some of the first genetic links to cancer with the discovery of chromosomal translocations in association with many hematological neoplasms. The unique accessibility of hematopoietic tissue and the ability to clonally expand hematopoietic progenitors in vitro has provided fundamental insights into the cellular hierarchy of normal hematopoiesis, as well as the functional impact of driver mutations in disease. Transplantation assays in murine models have enabled cellular assessment of the functional consequences of somatic mutations in vivo. Most recently, next-generation sequencing–based assays have shown great promise in allowing multi-“omic” characterization of single cells. Here, we review how clonal approaches have advanced our understanding of disease development, focusing on the acquisition of somatic mutations, clonal selection, driver mutation cooperation, and tumor evolution.

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PATH-40. SPORADIC NF2 WILD-TYPE MULTIPLE MENINGIOMAS HARBOR DISTINCT DRIVER MUTATIONS

Neuro-Oncology ◽

10.1093/neuonc/noab196.492 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi124-vi124

Author(s):

Insa Prilop ◽

Thomas Pinzer ◽

Daniel Cahill ◽

Priscilla Brastianos ◽

Gabriele Schackert ◽

...

Keyword(s):

Hot Spot ◽

Low Frequency ◽

Neurofibromatosis Type ◽

Driver Mutations ◽

Wild Type ◽

Driver Genes ◽

Who Grade ◽

Genetic Changes ◽

Histologic Subtype ◽

Multiple Meningiomas

Abstract OBJECTIVE Multiple meningiomas (MM) are rare and present a unique management challenge. While the mutational landscape of single meningiomas has been extensively studied, understanding the molecular pathogenesis of sporadic MM remains incomplete. The objective of this study is to elucidate the genetic features of sporadic MM. METHODS We identified nine patients with MM (n=19) defined as ≥2 spatially separated synchronous or metachronous meningiomas. We profiled genetic changes in these tumors using next-generation sequencing (NGS) assay that covers a large number of targetable and frequently mutated genes in meningiomas including AKT1, KLF4, NF2, PIK3CA/PIK3R1, POLR2A, SMARCB1, SMO, SUFU, TRAF7, and the TERT promoter. RESULTS Most of MM were WHO grade 1 (n= 16, 84.2%). Within individual patients, no driver mutation was shared between separate tumors. All but two cases harbored different hot spot mutations in known meningioma-driver genes like TRAF7 (n= 5), PIK3CA (n= 4), AKT1 (n= 3), POLR2A (n=1) and SMO (n= 1). Moreover, individual tumors differed in histologic subtype in 8/9 patients. The low frequency of NF2 mutations in our series stands in contrast to previous studies that included hereditary cases arising in the setting of neurofibromatosis type 2 (NF2). CONCLUSIONS Our findings provide evidence for genomic inter-tumor heterogeneity and an independent molecular origin of sporadic NF2 wild-type MM. Furthermore, these findings suggest that genetic characterization of each lesion is warranted in sporadic MM.

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Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1814027116 ◽

2018 ◽

Vol 116 (2) ◽

pp. 619-624 ◽

Cited By ~ 11

Author(s):

Charles Li ◽

Elena Bonazzoli ◽

Stefania Bellone ◽

Jungmin Choi ◽

Weilai Dong ◽

...

Keyword(s):

Ovarian Cancer ◽

Somatic Mutations ◽

Driver Mutations ◽

Cancer Evolution ◽

Metastatic Tumors ◽

Driver Genes ◽

Primary Tumors ◽

Mutational Landscape ◽

Recurrent Tumors ◽

Bet Inhibitors

Ovarian cancer remains the most lethal gynecologic malignancy. We analyzed the mutational landscape of 64 primary, 41 metastatic, and 17 recurrent fresh-frozen tumors from 77 patients along with matched normal DNA, by whole-exome sequencing (WES). We also sequenced 13 pairs of synchronous bilateral ovarian cancer (SBOC) to evaluate the evolutionary history. Lastly, to search for therapeutic targets, we evaluated the activity of the Bromodomain and Extra-Terminal motif (BET) inhibitor GS-626510 on primary tumors and xenografts harboring c-MYC amplifications. In line with previous studies, the large majority of germline and somatic mutations were found in BRCA1/2 (21%) and TP53 (86%) genes, respectively. Among mutations in known cancer driver genes, 77% were transmitted from primary tumors to metastatic tumors, and 80% from primary to recurrent tumors, indicating that driver mutations are commonly retained during ovarian cancer evolution. Importantly, the number, mutation spectra, and signatures in matched primary–metastatic tumors were extremely similar, suggesting transcoelomic metastases as an early dissemination process using preexisting metastatic ability rather than an evolution model. Similarly, comparison of SBOC showed extensive sharing of somatic mutations, unequivocally indicating a common ancestry in all cases. Among the 17 patients with matched tumors, four patients gained PIK3CA amplifications and two patients gained c-MYC amplifications in the recurrent tumors, with no loss of amplification or gain of deletions. Primary cell lines and xenografts derived from chemotherapy-resistant tumors demonstrated sensitivity to JQ1 and GS-626510 (P = 0.01), suggesting that oral BET inhibitors represent a class of personalized therapeutics in patients harboring recurrent/chemotherapy-resistant disease.

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Algorithmic Methods to Infer the Evolutionary Trajectories in Cancer Progression

10.1101/027359 ◽

2015 ◽

Cited By ~ 3

Author(s):

Giulio Caravagna ◽

Alex Graudenzi ◽

DANIELE RAMAZZOTTI ◽

Rebeca Sanz-Pamplona ◽

Luca De Sano ◽

...

Keyword(s):

Cancer Progression ◽

Current Knowledge ◽

Population Level ◽

Selective Advantage ◽

Explanatory Models ◽

Driver Mutations ◽

Cross Sectional ◽

Progression Model ◽

Colorectal Cancer Progression ◽

Ngs Data

The genomic evolution inherent to cancer relates directly to a renewed focus on the voluminous next generation sequencing (NGS) data, and machine learning for the inference of explanatory models of how the (epi)genomic events are choreographed in cancer initiation and development. However, despite the increasing availability of multiple additional -omics data, this quest has been frustrated by various theoretical and technical hurdles, mostly stemming from the dramatic heterogeneity of the disease. In this paper, we build on our recent works on "selective advantage" relation among driver mutations in cancer progression and investigate its applicability to the modeling problem at the population level. Here, we introduce PiCnIc (Pipeline for Cancer Inference), a versatile, modular and customizable pipeline to extract ensemble-level progression models from cross-sectional sequenced cancer genomes. The pipeline has many translational implications as it combines state-of-the-art techniques for sample stratification, driver selection, identification of fitness-equivalent exclusive alterations and progression model inference. We demonstrate PiCnIc's ability to reproduce much of the current knowledge on colorectal cancer progression, as well as to suggest novel experimentally verifiable hypotheses.

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Nucleotide excision repair is impaired by binding of transcription factors to DNA

10.1101/028886 ◽

2015 ◽

Author(s):

Radhakrishnan Sabarinathan ◽

Loris Mularoni ◽

Jordi Deu-Pons ◽

Abel Gonzalez-Perez ◽

Nuria Lopez-Bigas

Keyword(s):

Nucleotide Excision Repair ◽

Mutation Rate ◽

Binding Sites ◽

Somatic Mutations ◽

Excision Repair ◽

Replication Timing ◽

Driver Mutations ◽

Cancer Driver ◽

Nucleotide Excision ◽

Active Transcription

Somatic mutations are the driving force of cancer genome evolution. The rate of somatic mutations appears in great variability across the genome due to chromatin organization, DNA accessibility and replication timing. However, other variables that may influence the mutation rate locally, such as DNA-binding proteins, are unknown. Here we demonstrate that the rate of somatic mutations in melanoma tumors is highly increased at active Transcription Factor binding sites (TFBS) and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Therefore, our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of mutations at their binding sites. This finding has important implications in our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.

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Discovering the drivers of clonal hematopoiesis

10.1101/2020.10.22.350140 ◽

2020 ◽

Cited By ~ 1

Author(s):

Oriol Pich ◽

Iker Reyes-Salazar ◽

Abel Gonzalez-Perez ◽

Nuria Lopez-Bigas

Keyword(s):

Positive Selection ◽

Molecular Mechanisms ◽

Somatic Mutations ◽

Cancer Genomics ◽

Variant Calling ◽

Selective Advantage ◽

Cancer Genes ◽

Driver Genes ◽

Hematopoietic Stem ◽

Clonal Hematopoiesis

AbstractMutations in genes that confer a selective advantage to hematopoietic stem cells (HSCs) in certain conditions drive clonal hematopoiesis (CH). While some CH drivers have been identified experimentally or through epidemiological studies, the compendium of all genes able to drive CH upon mutations in HSCs is far from complete. We propose that identifying signals of positive selection in blood somatic mutations may be an effective way to identify CH driver genes, similarly as done to identify cancer genes. Using a reverse somatic variant calling approach, we repurposed whole-genome and whole-exome blood/tumor paired samples of more than 12,000 donors from two large cancer genomics cohorts to identify blood somatic mutations. The application of IntOGen, a robust driver discovery pipeline, to blood somatic mutations across both cohorts, and more than 24,000 targeted sequenced samples yielded a list of close to 70 genes with signals of positive selection in CH, available at http://www.intogen.org/ch. This approach recovers all known CH genes, and discovers novel candidates. Generating this compendium is an essential step to understand the molecular mechanisms of CH and to accurately detect individuals with CH to ascertain their risk to develop related diseases.

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Additive effects of variants of unknown significance in replication repair-associated DNA polymerase genes on mutational burden and prognosis across diverse cancers

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002336 ◽

2021 ◽

Vol 9 (9) ◽

pp. e002336

Author(s):

Jieer Ying ◽

Lin Yang ◽

Jiani C Yin ◽

Guojie Xia ◽

Minyan Xing ◽

...

Keyword(s):

Hot Spot ◽

The Cancer Genome Atlas ◽

Driver Mutations ◽

Cancer Type ◽

Additive Effects ◽

Variants Of Unknown Significance ◽

Mutational Burden ◽

Pathway Gene ◽

Exonuclease Domain ◽

Unknown Significance

BackgroundDefects in replication repair-associated DNA polymerases often manifest an ultra-high tumor mutational burden (TMB), which is associated with higher probabilities of response to immunotherapies. The functional and clinical implications of different polymerase variants remain unclear.MethodsTargeted next-generation sequencing using a 425-cancer gene panel, which covers all exonic regions of three polymerase genes (POLE, POLD1, and POLH), was conducted in a cohort of 12,266 patients across 16 different tumor types from January 2017 to January 2019. Prognostication of POL variant-positive patients was performed using a cohort of 4679 patients from the The Cancer Genome Atlas (TCGA) datasets.ResultsThe overall prevalence of somatic and germline polymerase variants was 4.2% (95% CI 3.8% to 4.5%) and 0.7% (95% CI 0.5% to 0.8%), respectively, with highest frequencies in endometrial, urinary, prostate, and colorectal cancers (CRCs). While most germline polymerase variants showed no clear functional consequences, we identified a candidate p.T466A affecting the exonuclease domain of POLE, which might be underlying the early onset in a case with childhood CRC. Low frequencies of known hot-spot somatic mutations in POLE were detected and were associated with younger age, the male sex, and microsatellite stability. In both the panel and TCGA cohorts, POLE drivers exhibited high frequencies of alterations in genes in the DNA damage and repair (DDR) pathways, including BRCA2, ATM, MSH6, and ATR. Variants of unknown significance (VUS) of different polymerase domains showed variable penetrance with those in the exonuclease domain of POLE and POLD1 displaying high TMB. VUS in POL genes exhibited an additive effect as carriers of multiple VUS had exponentially increased TMB and prolonged overall survival. Similar to cases with driver mutations, the TMB-high POL VUS samples showed DDR pathway involvement and polymerase hypermutation signatures. Combinatorial analysis of POL and DDR pathway status further supported the potential additive effects of POL VUS and DDR pathway genes and revealed distinct prognostic subclasses that were independent of cancer type and TMB.ConclusionsOur results demonstrate the pathogenicity and additive prognostic value of POL VUS and DDR pathway gene alterations and suggest that genetic testing may be warranted in patients with diverse solid tumors.

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