Early and multiple origins of metastatic lineages within primary tumors

Many aspects of the evolutionary process of tumorigenesis that are fundamental to cancer biology and targeted treatment have been challenging to reveal, such as the divergence times and genetic clonality of metastatic lineages. To address these challenges, we performed tumor phylogenetics using molecular evolutionary models, reconstructed ancestral states of somatic mutations, and inferred cancer chronograms to yield three conclusions. First, in contrast to a linear model of cancer progression, metastases can originate from divergent lineages within primary tumors. Evolved genetic changes in cancer lineages likely affect only the proclivity toward metastasis. Single genetic changes are unlikely to be necessary or sufficient for metastasis. Second, metastatic lineages can arise early in tumor development, sometimes long before diagnosis. The early genetic divergence of some metastatic lineages directs attention toward research on driver genes that are mutated early in cancer evolution. Last, the temporal order of occurrence of driver mutations can be inferred from phylogenetic analysis of cancer chronograms, guiding development of targeted therapeutics effective against primary tumors and metastases.

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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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Molecular Biology and Evolution of Cancer: From Discovery to Action

Molecular Biology and Evolution ◽

10.1093/molbev/msz242 ◽

2019 ◽

Vol 37 (2) ◽

pp. 320-326 ◽

Cited By ~ 7

Author(s):

Jason A Somarelli ◽

Heather Gardner ◽

Vincent L Cannataro ◽

Ella F Gunady ◽

Amy M Boddy ◽

...

Keyword(s):

Cancer Progression ◽

Cancer Biology ◽

Circulatory System ◽

Evolutionary Process ◽

Deep Understanding ◽

The Body ◽

Ecological Niches ◽

Cell Populations ◽

Cancer Evolution ◽

Metastatic Sites

Abstract Cancer progression is an evolutionary process. During this process, evolving cancer cell populations encounter restrictive ecological niches within the body, such as the primary tumor, circulatory system, and diverse metastatic sites. Efforts to prevent or delay cancer evolution—and progression—require a deep understanding of the underlying molecular evolutionary processes. Herein we discuss a suite of concepts and tools from evolutionary and ecological theory that can inform cancer biology in new and meaningful ways. We also highlight current challenges to applying these concepts, and propose ways in which incorporating these concepts could identify new therapeutic modes and vulnerabilities in cancer.

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Mutational likeliness and entropy help to identify driver mutations and their functional role in cancer

10.1101/354324 ◽

2018 ◽

Author(s):

Giorgio Mattiuz ◽

Salvatore Di Giorgio ◽

Lorenzo Tofani ◽

Antonio Frandi ◽

Francesco Donati ◽

...

Keyword(s):

Cancer Progression ◽

Somatic Mutations ◽

Driver Mutations ◽

Cancer Evolution ◽

Loss Of Function ◽

Driver Genes ◽

Cancer Driver ◽

Cancer Genomes ◽

Passenger Mutations ◽

Mutational Processes

AbstractAlterations in cancer genomes originate from mutational processes taking place throughout oncogenesis and cancer progression. We show that likeliness and entropy are two properties of somatic mutations crucial in cancer evolution, as cancer-driver mutations stand out, with respect to both of these properties, as being distinct from the bulk of passenger mutations. Our analysis can identify novel cancer driver genes and differentiate between gain and loss of function mutations.

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MBCL-08. INTEGRATIVE MOLECULAR ANALYSIS OF PATIENT-MATCHED DIAGNOSTIC AND RELAPSED MEDULLOBLASTOMAS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.484 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii389-iii389

Author(s):

Rahul Kumar ◽

Maximilian Deng ◽

Kyle Smith ◽

Anthony Liu ◽

Girish Dhall ◽

...

Keyword(s):

Molecular Analysis ◽

Copy Number ◽

Driver Mutations ◽

P Value ◽

Next Generation ◽

Driver Genes ◽

Methylation Array ◽

Primary Tumors ◽

Group 4 ◽

Group 3

Abstract INTRODUCTION The next generation of clinical trials for relapsed medulloblastoma demands a thorough understanding of the clinical behavior of relapsed tumors as well as the molecular relationship to their diagnostic counterparts. METHODS A multi-institutional molecular cohort of patient-matched (n=126 patients) diagnostic MBs and relapses/subsequent malignancies was profiled by DNA methylation array. Entity, subgroup classification, and genome-wide copy-number aberrations were assigned while parallel next-generation (whole-exome or targeted panel) sequencing on the majority of the cohort facilitated inference of somatic driver mutations. RESULTS Comprised of WNT (2%), SHH (41%), Group 3 (18%), Group 4 (39%), primary tumors retained subgroup affiliation at relapse with the notable exception of 10% of cases. The majority (8/13) of discrepant classifications were determined to be secondary glioblastomas. Additionally, rare (n=3) subgroup-switching events of Group 4 primary tumors to Group 3 relapses were identified coincident with MYC/MYCN pathway alterations. Amongst truly relapsing MBs, copy-number analyses suggest somatic clonal divergence between primary MBs and their respective relapses with Group 3 (55% of alterations shared) and Group 4 tumors (63% alterations shared) sharing a larger proportion of cytogenetic alterations compared to SHH tumors (42% alterations shared; Chi-square p-value < 0.001). Subgroup- and gene-specific patterns of conservation and divergence amongst putative driver genes were also observed. CONCLUSION Integrated molecular analysis of relapsed MB discloses potential mechanisms underlying treatment failure and disease recurrence while motivating rational implementation of relapse-specific therapies. The degree of genetic divergence between primary and relapsed MBs varied by subgroup but suggested considerably higher conservation than prior estimates.

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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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Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

10.1101/825240 ◽

2019 ◽

Cited By ~ 1

Author(s):

Zheng Hu ◽

Zan Li ◽

Zhicheng Ma ◽

Christina Curtis

Keyword(s):

Clonal Evolution ◽

Tumor Development ◽

Distant Metastases ◽

Driver Mutations ◽

Sequencing Data ◽

Primary Tumors ◽

Lung Cancer Patients ◽

Systemic Spread ◽

Cancer Spread ◽

Early Tumor

AbstractMetastasis is the primary cause of cancer-related deaths, but the natural history, clonal evolution and impact of treatment are poorly understood. We analyzed exome sequencing data from 457 paired primary tumor and metastatic samples from 136 breast, colorectal and lung cancer patients, including untreated (n=99) and treated (n=100) metastatic tumors. Treated metastases often harbored private ‘driver’ mutations whereas untreated metastases did not, suggesting that treatment promotes clonal evolution. Polyclonal seeding was common in untreated lymph node metastases (n=17/29, 59%) and distant metastases (n=20/70, 29%), but less frequent in treated distant metastases (n=9/94, 10%). The low number of metastasis-private clonal mutations is consistent with early metastatic seeding, which we estimated commonly occurred 2-4 years prior to diagnosis across these cancers. Further, these data suggest that the natural course of metastasis is selectively relaxed relative to early tumor development and that metastasis-private mutations are not drivers of cancer spread but instead associated with drug resistance.

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Mutational analysis of driver genes with tumor suppressive and oncogenic roles in gastric cancer

PeerJ ◽

10.7717/peerj.3585 ◽

2017 ◽

Vol 5 ◽

pp. e3585 ◽

Cited By ~ 2

Author(s):

Tianfang Wang ◽

Yining Liu ◽

Min Zhao

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Complex Disease ◽

Mutational Analysis ◽

Driver Mutations ◽

Driver Genes ◽

Protein Coding ◽

Mirna Genes ◽

Genetic Mechanisms ◽

New Treatment

Gastric cancer (GC) is a complex disease with heterogeneous genetic mechanisms. Genomic mutational profiling of gastric cancer not only expands our knowledge about cancer progression at a fundamental genetic level, but also could provide guidance on new treatment decisions, currently based on tumor histology. The fact that precise medicine-based treatment is successful in a subset of tumors indicates the need for better identification of clinically related molecular tumor phenotypes, especially with regard to those driver mutations on tumor suppressor genes (TSGs) and oncogenes (ONGs). We surveyed 313 TSGs and 160 ONGs associated with 48 protein coding and 19 miRNA genes with both TSG and ONG roles. Using public cancer mutational profiles, we confirmed the dual roles of CDKN1A and CDKN1B. In addition to the widely recognized alterations, we identified another 82 frequently mutated genes in public gastric cancer cohort. In summary, these driver mutation profiles of individual GC will form the basis of personalized treatment of gastric cancer, leading to substantial therapeutic improvements.

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Identifying metastasis-initiating miRNA-target regulations of colorectal cancer from expressional changes in primary tumors

Scientific Reports ◽

10.1038/s41598-020-71868-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Jongmin Lee ◽

Hye Kyung Hong ◽

Sheng-Bin Peng ◽

Tae Won Kim ◽

Woo Yong Lee ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Cancer Progression ◽

Cancer Biology ◽

Mirna Target ◽

Target Genes ◽

Expression Profiles ◽

Statistical Significance ◽

Primary Tumors ◽

Significant Difference

Abstract Colorectal cancer (CRC) is prevalent with high mortality, with liver metastasis contributing as a major factor that worsens the survival of patients. The roles of miRNAs in CRC have been elucidated, subsequent to recent studies that suggest the involvement of miRNAs in cancer biology. In this study, we compare the miRNA and gene expression profiles of primary tumors between two groups of patients (with and without liver metastasis) to identify the metastasis-initiating microRNA-target gene regulations. Analysis from 33 patients with metastasis and 14 patients without metastasis revealed that 17 miRNAs and their 198 predicted target genes are differentially expressed, where the target genes showed association with cancer progression and metastasis with statistical significance. In order to evaluate the clinical implications of the findings, we classified CRC patients of independent data into two groups based on the identified miRNA-target regulations, where one group was closer to primary tumors with metastasis than the other group. The comparison of survival showed statistically significant difference, thereby implying the roles of the identified miRNA-target regulations in cancer progression and metastasis. The identification of metastasis-initiating miRNA-target regulations in this study will lead to better understanding of the roles of miRNAs in CRC progression.

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Mutant Allele Imbalance in Cancer

Annual Review of Cancer Biology ◽

10.1146/annurev-cancerbio-051320-124252 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Craig M. Bielski ◽

Barry S. Taylor

Keyword(s):

Cancer Biology ◽

Mutant Allele ◽

Tumor Biology ◽

Cellular Level ◽

Driver Mutations ◽

Annual Review ◽

Publication Date ◽

Cancer Evolution ◽

Allele Imbalance ◽

And Function

The search for somatic mutations that drive the initiation and progression of human tumors has dominated recent cancer research. While much emphasis has been placed on characterizing the prevalence and function of driver mutations, comparatively less is known about their serial genetic evolution. Indeed, study of this phenomenon has largely focused on tumor-suppressor genes recessive at the cellular level or mechanisms of resistance in tumors with mutant oncogenes targeted by therapy. There is, however, a growing appreciation that despite a decades-old presumption of heterozygosity, changes in mutant oncogene zygosity are common and drive dosage and stoichiometry changes that lead to selective growth advantages. Here, we review the recent progress in understanding mutant allele imbalance and its implications for tumor biology, cancer evolution, and response to anticancer therapy. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Biological mechanisms linked to inflammation in cancer: Discovery of tumor microenvironment-related biomarkers and their clinical application in solid tumors

The International Journal of Biological Markers ◽

10.1177/1724600820906155 ◽

2020 ◽

Vol 35 (1_suppl) ◽

pp. 8-11 ◽

Cited By ~ 3

Author(s):

Paola Nisticò ◽

Gennaro Ciliberto

Keyword(s):

Tumor Microenvironment ◽

Tumor Cells ◽

Cancer Progression ◽

Cancer Biology ◽

Tumor Development ◽

Short Paper ◽

Great Relevance ◽

Cellular Components ◽

The Relationship

Our view of cancer biology radically shifted from a “cancer-cell-centric” vision to a view of cancer as an organ disease. The concept that genetic and/or epigenetic alterations, at the basis of cancerogenesis, are the main if not the exclusive drivers of cancer development and the principal targets of therapy, has now evolved to include the tumor microenvironment in which tumor cells can grow, proliferate, survive, and metastasize only within a favorable environment. The interplay between cancer cells and the non-cellular and cellular components of the tumor microenvironment plays a fundamental role in tumor development and evolution both at the primary site and at the level of metastasis. The shape of the tumor cells and tumor mass is the resultant of several contrasting forces either pro-tumoral or anti-tumoral which have at the level of the tumor microenvironment their battle field. This crucial role of tumor microenvironment composition in cancer progression also dictates whether immunotherapy with immune checkpoint inhibitor antibodies is going to be efficacious. Hence, tumor microenvironment deconvolution has become of great relevance in order to identify biomarkers predictive of efficacy of immunotherapy. In this short paper we will briefly review the relationship between inflammation and cancer, and will summarize in 10 short points the key concepts learned so far and the open challenges to be solved.

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