Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma

Okosun, Jessica; Bödör, Csaba; Wang, Jun; Araf, Shamzah; Yang, Cheng; Pan, Chenyi; Boller, Sören; Cittaro, Davide; Bożek, Monika; Iqbal, Sameena; Matthews, Janet; Wrench, David; Marzec, Jacek; Tawana, Kiran; Popov, Nikolay; O’Riain, Ciarán; O’Shea, Derville; Carlotti, Emanuela; Davies, Andrew; Lawrie, Charles H.; Matolcsy, András; Calaminici, Maria; Norton, A. J.; Byers, Richard; Mein, Charles A.; Stupka, Elia; Lister, T. Andrew; Lenz, Georg; Montoto, Silvia; Gribben, John G.; Fan, Yuhong; Grosschedl, Rudolf; Chelala, Claude; Fitzgibbon, Jude

doi:10.1038/ng.2856

Cited by 642 publications

(740 citation statements)

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“…Of these, CREBBP mutations were most stable throughout the course of disease, and the most significantly enriched mutations within ancestral EIPs. This is in line with prior observations that these mutations are also shared between the indolent and transformed phases of FL (13,14). In contrast, mutations within KMT2D had variable patterns of representation within diagnosis/relapse tumors from the same patient, and a lower frequency of events within EIPs across patients.…”

Section: Discussionsupporting

confidence: 90%

“…S10G). To ensure this effect was not the result of cosegregation between CREBBP mutations and deletions of the MHC class II locus, we interrogated somatic copy number data from our exome series and additional publicly available high-resolution data (12,13,(22)(23)(24). Although we detected deletions of the MHC class II locus in a subset of patients (SI Appendix, Fig.…”

Section: Frequent Cooccurring Mutations Of Chromatin-modifying Genesmentioning

confidence: 99%

“…This and other evidence therefore suggests that BCL2 translocations are not sufficient for lymphomagenesis and may be harbored in FL precursors, and that secondary genetic alterations are needed to drive clinical disease (4, 9, 10). Next-generation sequencing studies of FL have identified frequent mutation of chromatin-modifying genes (CMGs) (11)(12)(13)(14)(15). These include inactivating mutations of genes that apply activating euchromatin-associated marks [lysine-specific methyltransferase 2D (KTM2D), CREB binding protein (CREBBP), and E1A binding protein p300 (EP300)] and activating mutations within a gene that applies a repressive heterochromatin-associated mark (enhancer of zeste homolog 2, EZH2).…”

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confidence: 99%

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Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

Green

Kihira²,

Liu³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

311

372

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Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation. lymphoma | exome | hierarchy | antigen presentation | CREBBP

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Section: Discussionsupporting

confidence: 90%

Section: Frequent Cooccurring Mutations Of Chromatin-modifying Genesmentioning

confidence: 99%

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confidence: 99%

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Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

Green

Kihira²,

Liu³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

311

372

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“…In follicular lymphoma, mutations in histone H1 genes have been found to affect binding affinities and residence times of affected H1 proteins (31). It was speculated that such mutations would lead to changes in chromatin conformation and altered gene regulation.…”

Section: Discussionmentioning

confidence: 99%

Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial–mesenchymal transition

Zhao

Bellone

Lopez

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

186

175

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Carcinosarcomas (CSs) of the uterus and ovary are highly aggressive neoplasms containing both carcinomatous and sarcomatous elements. We analyzed the mutational landscape of 68 uterine and ovarian CSs by whole-exome sequencing. We also performed multiregion whole-exome sequencing comprising two carcinoma and sarcoma samples from six tumors to resolve their evolutionary histories. The results demonstrated that carcinomatous and sarcomatous elements derive from a common precursor having mutations typical of carcinomas. In addition to mutations in cancer genes previously identified in uterine and ovarian carcinomas such as TP53, PIK3CA, PPP2R1A, KRAS, PTEN, CHD4, and BCOR, we found an excess of mutations in genes encoding histone H2A and H2B, as well as significant amplification of the segment of chromosome 6p harboring the histone gene cluster containing these genes. We also found frequent deletions of the genes TP53 and MBD3 (a member with CHD4 of the nucleosome remodeling deacetylase complex) and frequent amplification of chromosome segments containing the genes PIK3CA, TERT, and MYC. Stable transgenic expression of H2A and H2B in a uterine serous carcinoma cell line demonstrated that mutant, but not wild-type, histones increased expression of markers of epithelial-mesenchymal transition (EMT) as well as tumor migratory and invasive properties, suggesting a role in sarcomatous transformation. Comparison of the phylogenetic relationships of carcinomatous and sarcomatous elements of the same tumors demonstrated separate lineages leading to these two components. These findings define the genetic landscape of CSs and suggest therapeutic targets for these highly aggressive neoplasms.uterine carcinosarcoma | ovarian carcinosarcoma | exome sequencing C arcinosarcomas (CSs) of the female genital tract, also known as mixed malignant Müllerian tumors, are rare but highly aggressive tumors characterized by a biphasic histology. These cancers most commonly arise in the uterus, followed by the ovaries, fallopian tubes, and vagina (1-3). The diagnosis of CS requires the presence of both sarcomatous and carcinomatous components. Although the pathogenesis of CSs remains under debate, an increasing body of evidence supports the origin of both elements from a common epithelial cell that undergoes sarcomatous dedifferentiation, rather than two independent progenitors (2-5).The overall 5-y survival is only 30 ± 9% for all stages, and the recurrence rate after surgery is extremely high (50-80%) (3-5). The uncertain origin and poor prognosis of uterine and ovarian CSs motivate determination of the molecular basis of CS aggressive behavior in the hope of developing novel and effective treatment modalities. ResultsThe Genetic Landscape of CS. A total of 68 patients with stage I-IV uterine (n = 44) and ovarian (n = 24) CSs were studied. Their clinical and histological features are presented in SI Appendix, Table S1. Upon surgical removal of tumors, primary cell lines were prepared (five tumors) or tumors were frozen (63 tumors). Among t...

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“…As the resolution of cancer evolutionary analyses improves, the number of examples of parallel evolution increases, including but not limited to events involving EGFR in glioblastoma (Francis et al, 2014;Kim et al, 2015), TP53 and ATRX in glioma , activation of the MAPK pathway in multiple myeloma (Bolli et al, 2014;Melchor et al, 2014), NOTCH1 and GNPTAB recurrent mutations in esophageal adenocarcinoma (Murugaesu et al, 2015), SMO mutations in medulloblastoma (Morrissy et al, 2016), distinct AR amplification events in prostate cancer (Gundem et al, 2015), KMTD2D and CREBBP mutations in follicular lymphoma (Okosun et al, 2014) and PTEN and TP53 mutations, FGFR2 amplifications and RUNX1 deletions in primary breast cancer (Yates et al, 2015), as well as distinct CCNE1 amplifications in ovarian cancers (McPherson et al, 2016). In clear cell renal carcinoma, an early clonal event is 3p loss of heterozygosity, which appears to prime the tumor for second hits in SETD2, PBRM1 and BAP1 (all of which are encoded on chromosome 3p) later in tumor evolution (Gerlinger et al, 2014a).…”

Section: Contingency and Convergencementioning

confidence: 99%

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

McGranahan

Swanton

2017

Cell

2,030

1,694

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Intratumor heterogeneity, which fosters tumor evolution, is a key challenge in cancer medicine. Here we review data and technologies that have revealed intra-tumor heterogeneity across cancer types, and the dynamics, constraints and contingencies inherent to tumor evolution. We emphasize the importance of macro-evolutionary leaps, often involving large-scale chromosomal alterations, in driving tumor evolution and metastasis, and consider the role of the tumor microenvironment in engendering heterogeneity and drug-resistance. We suggest that bold approaches to drug development, harnessing the adaptive properties of the immunemicroenvironment whilst limiting those of the tumor, combined with advances in clinical trial-design, will improve patient outcome.

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Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma

Cited by 642 publications

References 58 publications

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial–mesenchymal transition

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

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