Publications by authors named "Jaegil Kim"

74 Publications

Genetic analysis of dietary intake identifies new loci and functional links with metabolic traits.

Nat Hum Behav 2021 Aug 23. Epub 2021 Aug 23.

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Dietary intake is a major contributor to the global obesity epidemic and represents a complex behavioural phenotype that is partially affected by innate biological differences. Here, we present a multivariate genome-wide association analysis of overall variation in dietary intake to account for the correlation between dietary carbohydrate, fat and protein in 282,271 participants of European ancestry from the UK Biobank (n = 191,157) and Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 91,114), and identify 26 distinct genome-wide significant loci. Dietary intake signals map exclusively to specific brain regions and are enriched for genes expressed in specialized subtypes of GABAergic, dopaminergic and glutamatergic neurons. We identified two main clusters of genetic variants for overall variation in dietary intake that were differently associated with obesity and coronary artery disease. These results enhance the biological understanding of interindividual differences in dietary intake by highlighting neural mechanisms, supporting functional follow-up experiments and possibly providing new avenues for the prevention and treatment of prevalent complex metabolic diseases.
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http://dx.doi.org/10.1038/s41562-021-01182-wDOI Listing
August 2021

Genetic determinants of daytime napping and effects on cardiometabolic health.

Nat Commun 2021 02 10;12(1):900. Epub 2021 Feb 10.

Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Daytime napping is a common, heritable behavior, but its genetic basis and causal relationship with cardiometabolic health remain unclear. Here, we perform a genome-wide association study of self-reported daytime napping in the UK Biobank (n = 452,633) and identify 123 loci of which 61 replicate in the 23andMe research cohort (n = 541,333). Findings include missense variants in established drug targets for sleep disorders (HCRTR1, HCRTR2), genes with roles in arousal (TRPC6, PNOC), and genes suggesting an obesity-hypersomnolence pathway (PNOC, PATJ). Association signals are concordant with accelerometer-measured daytime inactivity duration and 33 loci colocalize with loci for other sleep phenotypes. Cluster analysis identifies three distinct clusters of nap-promoting mechanisms with heterogeneous associations with cardiometabolic outcomes. Mendelian randomization shows potential causal links between more frequent daytime napping and higher blood pressure and waist circumference.
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http://dx.doi.org/10.1038/s41467-020-20585-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876146PMC
February 2021

Subependymal giant cell astrocytomas are characterized by mTORC1 hyperactivation, a very low somatic mutation rate, and a unique gene expression profile.

Mod Pathol 2021 02 13;34(2):264-279. Epub 2020 Oct 13.

Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Subependymal giant-cell astrocytomas (SEGAs) are slow-growing brain tumors that are a hallmark feature seen in 5-10% of patients with Tuberous Sclerosis Complex (TSC). Though histologically benign, they can cause serious neurologic symptoms, leading to death if untreated. SEGAs consistently show biallelic loss of TSC1 or TSC2. Herein, we aimed to define other somatic events beyond TSC1/TSC2 loss and identify potential transcriptional drivers that contribute to SEGA formation. Paired tumor-normal whole-exome sequencing was performed on 21 resected SEGAs from 20 TSC patients. Pathogenic variants in TSC1/TSC2 were identified in 19/21 (90%) SEGAs. Copy neutral loss of heterozygosity (size range: 2.2-46 Mb) was seen in 76% (16/21) of SEGAs (44% chr9q and 56% chr16p). An average of 1.4 other somatic variants (range 0-7) per tumor were identified, unlikely of pathogenic significance. Whole transcriptome RNA-sequencing analyses revealed 190 common differentially expressed genes in SEGA (n = 16, 13 from a prior study) in pairwise comparison to each of: low grade diffuse gliomas (n = 530) and glioblastoma (n = 171) from The Cancer Genome Atlas (TCGA) consortium, ganglioglioma (n = 10), TSC cortical tubers (n = 15), and multiple normal tissues. Among these, homeobox transcription factors (TFs) HMX3, HMX2, VAX1, SIX3; and TFs IRF6 and EOMES were all expressed >12-fold higher in SEGAs (FDR/q-value < 0.05). Immunohistochemistry supported the specificity of IRF6, VAX1, SIX3 for SEGAs in comparison to other tumor entities and normal brain. We conclude that SEGAs have an extremely low somatic mutation rate, suggesting that TSC1/TSC2 loss is sufficient to drive tumor growth. The unique and highly expressed SEGA-specific TFs likely reflect the neuroepithelial cell of origin, and may also contribute to the transcriptional and epigenetic state that enables SEGA growth following two-hit loss of TSC1 or TSC2 and mTORC1 activation.
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http://dx.doi.org/10.1038/s41379-020-00659-9DOI Listing
February 2021

Genomic Predictors of Good Outcome, Recurrence, or Progression in High-Grade T1 Non-Muscle-Invasive Bladder Cancer.

Cancer Res 2020 10 31;80(20):4476-4486. Epub 2020 Aug 31.

Harvard Medical School University, Boston, Massachusetts.

High-grade T1 (HGT1) bladder cancer is the highest risk subtype of non-muscle-invasive bladder cancer with unpredictable outcome and poorly understood risk factors. Here, we examined the association of somatic mutation profiles with nonrecurrent disease (GO, good outcome), recurrence (R), or progression (PD) in a cohort of HGT1 patients. Exome sequencing was performed on 62 HGT1 and 15 matched normal tissue samples. Both tumor only (TO) and paired analyses were performed, focusing on 95 genes known to be mutated in bladder cancer. Somatic mutations, copy-number alterations, mutation load, and mutation signatures were studied. Thirty-three GO, 10 R, 18 PD, and 1 unknown outcome patients were analyzed. Tumor mutational burden (TMB) was similar to muscle-invasive disease and was highest in GO, intermediate in PD, and lowest in R patients ( = 0.017). DNA damage response gene mutations were associated with higher TMB ( < 0.0001) and GO ( = 0.003). ERCC2 and BRCA2 mutations were associated with GO. TP53, ATM, ARID1A, AHR, and SMARCB1 mutations were more frequent in PD. Focal copy-number gain in CCNE1 and CDKN2A deletion was enriched in PD or R ( = 0.047; = 0.06). APOBEC (46%) and COSMIC5 (34%) signatures were most frequent. APOBEC-A and ERCC2 mutant tumors (COSMIC5) were associated with GO ( = 0.047; = 0.0002). pT1b microstaging was associated with a genomic cluster ( = 0.05) with focal amplifications of E2F3/SOX4, PVRL4, CCNE1, and TP53 mutations. Findings were validated using external public datasets. These findings require confirmation but suggest that management of HGT1 bladder cancer may be improved via molecular characterization to predict outcome. SIGNIFICANCE: Detailed genetic analyses of HGT1 bladder tumors identify features that correlate with outcome, e.g., high mutational burden, ERCC2 mutations, and high APOBEC-A/ERCC2 mutation signatures were associated with good outcome.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0977DOI Listing
October 2020

The repertoire of mutational signatures in human cancer.

Nature 2020 02 5;578(7793):94-101. Epub 2020 Feb 5.

Wellcome Sanger Institute, Hinxton, UK.

Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated-but distinct-DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.
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http://dx.doi.org/10.1038/s41586-020-1943-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054213PMC
February 2020

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

Nature 2020 02 5;578(7793):102-111. Epub 2020 Feb 5.

Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.

The discovery of drivers of cancer has traditionally focused on protein-coding genes. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.
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http://dx.doi.org/10.1038/s41586-020-1965-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054214PMC
February 2020

A model combining clinical and genomic factors to predict response to PD-1/PD-L1 blockade in advanced urothelial carcinoma.

Br J Cancer 2020 02 20;122(4):555-563. Epub 2019 Dec 20.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Background: In metastatic urothelial carcinoma (mUC), predictive biomarkers that correlate with response to immune checkpoint inhibitors (ICIs) are lacking. Here, we interrogated genomic and clinical features associated with response to ICIs in mUC.

Methods: Sixty two mUC patients treated with ICI who had targeted tumour sequencing were studied. We examined associations between candidate biomarkers and clinical benefit (CB, any objective reduction in tumour size) versus no clinical benefit (NCB, no change or objective increase in tumour size). Both univariable and multivariable analyses for associations were conducted. A comparator cohort of 39 mUC patients treated with taxanes was analysed by using the same methodology.

Results: Nine clinical and seven genomic factors correlated with clinical outcomes in univariable analysis in the ICI cohort. Among the 16 factors, neutrophil-to-lymphocyte ratio (NLR) ≥5 (OR = 0.12, 95% CI, 0.01-1.15), visceral metastasis (OR = 0.05, 95% CI, 0.01-0.43) and single-nucleotide variant (SNV) count < 10 (OR = 0.04, 95% CI, 0.006-0.27) were identified as independent predictors of NCB to ICI in multivariable analysis (c-statistic = 0.90). None of the 16 variables were associated with clinical benefit in the taxane cohort.

Conclusions: This three-factor model includes genomic (SNV count >9) and clinical (NLR <5, lack of visceral metastasis) variables predictive for benefit to ICI but not taxane therapy for mUC. External validation of these hypothesis-generating results is warranted to enable use in routine clinical care.
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http://dx.doi.org/10.1038/s41416-019-0686-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028947PMC
February 2020

Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion.

Blood Adv 2019 12;3(23):4065-4080

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

Classical Hodgkin lymphoma (cHL) is composed of rare malignant Hodgkin Reed-Sternberg (HRS) cells within an extensive, but ineffective, inflammatory/immune cell infiltrate. HRS cells exhibit near-universal somatic copy gains of chromosome 9p/9p24.1, which increase expression of the programmed cell death protein 1 (PD-1) ligands. To define genetic mechanisms of response and resistance to PD-1 blockade and identify complementary treatment targets, we performed whole-exome sequencing of flow cytometry-sorted HRS cells from 23 excisional biopsies of newly diagnosed cHLs, including 8 Epstein-Barr virus-positive (EBV+) tumors. We identified significantly mutated cancer candidate genes (CCGs) as well as somatic copy number alterations and structural variations and characterized their contribution to disease-defining immune evasion mechanisms and nuclear factor κB (NF-κB), JAK/STAT, and PI3K signaling pathways. EBV- cHLs had a higher prevalence of genetic alterations in the NF-κB and major histocompatibility complex class I antigen presentation pathways. In this young cHL cohort (median age, 26 years), we identified a predominant mutational signature of spontaneous deamination of cytosine- phosphate-guanines ("Aging"), in addition to apolipoprotein B mRNA editing catalytic polypeptide-like, activation-induced cytidine deaminase, and microsatellite instability (MSI)-associated hypermutation. In particular, the mutational burden in EBV- cHLs was among the highest reported, similar to that of carcinogen-induced tumors. Together, the overall high mutational burden, MSI-associated hypermutation, and newly identified genetic alterations represent additional potential bases for the efficacy of PD-1 blockade in cHL. Of note, recurrent cHL alterations, including B2M, TNFAIP3, STAT6, GNA13, and XPO1 mutations and 2p/2p15, 6p21.32, 6q23.3, and 9p/9p24.1 copy number alterations, were also identified in >20% of primary mediastinal B-cell lymphomas, highlighting shared pathogenetic mechanisms in these diseases.
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http://dx.doi.org/10.1182/bloodadvances.2019001012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963251PMC
December 2019

Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade.

Blood 2019 12;134(26):2369-2382

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Primary mediastinal large B-cell lymphomas (PMBLs) are aggressive tumors that typically present as large mediastinal masses in young women. PMBLs share clinical, transcriptional, and molecular features with classical Hodgkin lymphoma (cHL), including constitutive activation of nuclear factor κB (NF-κB), JAK/STAT signaling, and programmed cell death protein 1 (PD-1)-mediated immune evasion. The demonstrated efficacy of PD-1 blockade in relapsed/refractory PMBLs led to recent approval by the US Food and Drug Administration and underscored the importance of characterizing targetable genetic vulnerabilities in this disease. Here, we report a comprehensive analysis of recurrent genetic alterations -somatic mutations, somatic copy number alterations, and structural variants-in a cohort of 37 newly diagnosed PMBLs. We identified a median of 9 genetic drivers per PMBL, including known and newly identified components of the JAK/STAT and NF-κB signaling pathways and frequent B2M alterations that limit major histocompatibility complex class I expression, as in cHL. PMBL also exhibited frequent, newly identified driver mutations in ZNF217 and an additional epigenetic modifier, EZH2. The majority of these alterations were clonal, which supports their role as early drivers. In PMBL, we identified several previously uncharacterized molecular features that may increase sensitivity to PD-1 blockade, including high tumor mutational burden, microsatellite instability, and an apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutational signature. The shared genetic features between PMBL and cHL provide a framework for analyzing the mechanism of action of PD-1 blockade in these related lymphoid malignancies.
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http://dx.doi.org/10.1182/blood.2019002067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933293PMC
December 2019

Scaling computational genomics to millions of individuals with GPUs.

Genome Biol 2019 11 1;20(1):228. Epub 2019 Nov 1.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Current genomics methods are designed to handle tens to thousands of samples but will need to scale to millions to match the pace of data and hypothesis generation in biomedical science. Here, we show that high efficiency at low cost can be achieved by leveraging general-purpose libraries for computing using graphics processing units (GPUs), such as PyTorch and TensorFlow. We demonstrate > 200-fold decreases in runtime and ~ 5-10-fold reductions in cost relative to CPUs. We anticipate that the accessibility of these libraries will lead to a widespread adoption of GPUs in computational genomics.
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http://dx.doi.org/10.1186/s13059-019-1836-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823959PMC
November 2019

Passenger Hotspot Mutations in Cancer.

Cancer Cell 2019 09;36(3):288-301.e14

The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address:

Current statistical models for assessing hotspot significance do not properly account for variation in site-specific mutability, thereby yielding many false-positives. We thus (i) detail a Log-normal-Poisson (LNP) background model that accounts for this variability in a manner consistent with models of mutagenesis; (ii) use it to show that passenger hotspots arise from all common mutational processes; and (iii) apply it to a ∼10,000-patient cohort to nominate driver hotspots with far fewer false-positives compared with conventional methods. Overall, we show that many cancer hotspot mutations recurring at the same genomic site across multiple tumors are actually passenger events, recurring at inherently mutable genomic sites under no positive selection.
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http://dx.doi.org/10.1016/j.ccell.2019.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371346PMC
September 2019

RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues.

Science 2019 Jun;364(6444)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

How somatic mutations accumulate in normal cells is poorly understood. A comprehensive analysis of RNA sequencing data from ~6700 samples across 29 normal tissues revealed multiple somatic variants, demonstrating that macroscopic clones can be found in many normal tissues. We found that sun-exposed skin, esophagus, and lung have a higher mutation burden than other tested tissues, which suggests that environmental factors can promote somatic mosaicism. Mutation burden was associated with both age and tissue-specific cell proliferation rate, highlighting that mutations accumulate over both time and number of cell divisions. Finally, normal tissues were found to harbor mutations in known cancer genes and hotspots. This study provides a broad view of macroscopic clonal expansion in human tissues, thus serving as a foundation for associating clonal expansion with environmental factors, aging, and risk of disease.
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http://dx.doi.org/10.1126/science.aaw0726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350423PMC
June 2019

Next-generation characterization of the Cancer Cell Line Encyclopedia.

Nature 2019 05 8;569(7757):503-508. Epub 2019 May 8.

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from individuals of various lineages and ethnicities. Integration of these data with functional characterizations such as drug-sensitivity, short hairpin RNA knockdown and CRISPR-Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers. Together, this dataset and an accompanying public data portal provide a resource for the acceleration of cancer research using model cancer cell lines.
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http://dx.doi.org/10.1038/s41586-019-1186-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697103PMC
May 2019

The Cancer Genome Atlas Expression Subtypes Stratify Response to Checkpoint Inhibition in Advanced Urothelial Cancer and Identify a Subset of Patients with High Survival Probability.

Eur Urol 2019 06 7;75(6):961-964. Epub 2019 Mar 7.

Scott Department of Urology and the Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. Electronic address:

Analysis of the IMvigor 210 trials involving patients with platinum-refractory or cisplatin-ineligible urothelial carcinoma who were treated with the PD-L1 inhibitor atezolizumab identified a resistance signature as an immune biomarker. Transcriptome profiling of 368 tumor samples from this trial revealed that the "genomically unstable" Lund subtype classification was associated with the best response. We developed and applied a novel single-patient subtype classifier based on The Cancer Genome Atlas 2017 expression-based molecular subtypes. We identified 11 patients with a neuronal subtype, with a 100% response rate in eight confirmed cases (2 complete response, 6 partial response), and 72% overall, including 3/11 patients with an unconfirmed response. The survival probability was extraordinarily high for the neuronal subtype, which represents a high-risk cohort with advanced disease, and may be secondary to low levels of TGFβ expression and high mutation/neoantigen burden. PATIENT SUMMARY: We describe a methodology for genomic classification of an individual patient's bladder cancer tumor and have identified a subtype that is associated with a high response rate to immunotherapy. This is an important step forward in identifying the right treatment for the right patient, which is the goal of personalized precision medicine.
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http://dx.doi.org/10.1016/j.eururo.2019.02.017DOI Listing
June 2019

Mutational Analysis of 472 Urothelial Carcinoma Across Grades and Anatomic Sites.

Clin Cancer Res 2019 04 28;25(8):2458-2470. Epub 2018 Dec 28.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: The purpose of this study is to characterize the mutational landscape across the spectrum of urothelial carcinoma (UC) to identify mutational features and potential therapeutic targets.

Experimental Design: Using targeted exome sequencing ( = 237 genes), we analyzed the mutation spectra of 82 low-grade nonmuscle-invasive bladder cancers (LG-NMIBC), 126 high-grade (HG) NMIBC, 199 muscle-invasive bladder cancers (MIBC), 10 LG-upper tract urothelial cancers (LG-UTUC), and 55 HG-UTUC.

Results: and mutations were significantly more common in LG-NMIBC (72% and 44%, respectively) versus other bladder subtypes. alterations were also enriched in LG-UTUC versus HG-UTUC tumors (80% vs. 16%). In contrast, and mutations were significantly more frequent in all 3 HG urothelial carcinoma subtypes than in LG-NIMBC (45%-58% vs. 4%; 9%-22% vs. 0; respectively). Among LG-NMIBC tumors, mutations were more common in women than in men (71% vs. 38%). HG-NMIBC and MIBC had higher tumor mutational burden (TMB) than LG-NMIBC ( = 0.001 and < 0.01, respectively). DNA-damage repair (DDR) alterations were associated with a higher TMB in HG-NMIBC and MIBC tumors, and these two tumor types were also enriched for an APOBEC mutational signature compared with LG-NMIBC and HG-UTUC. Alterations in , and correlated with worse overall survival in HG-UTUC and occurred concurrently.

Conclusions: Our analysis suggests that a fraction of MIBCs likely arise from precursor lesions other than LG-NMIBC. mutations are twice as common in women with LG-NIMBC than those in men. DDR gene mutations and APOBEC mutagenesis drive mutations in HG-NMIBC and MIBC. UTUC has a distinct mutation profile from bladder cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3147DOI Listing
April 2019

Quantification of somatic mutation flow across individual cell division events by lineage sequencing.

Genome Res 2018 12 20;28(12):1901-1918. Epub 2018 Nov 20.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

Mutation data reveal the dynamic equilibrium between DNA damage and repair processes in cells and are indispensable to the understanding of age-related diseases, tumor evolution, and the acquisition of drug resistance. However, available genome-wide methods have a limited ability to resolve rare somatic variants and the relationships between these variants. Here, we present lineage sequencing, a new genome sequencing approach that enables somatic event reconstruction by providing quality somatic mutation call sets with resolution as high as the single-cell level in subject lineages. Lineage sequencing entails sampling single cells from a population and sequencing subclonal sample sets derived from these cells such that knowledge of relationships among the cells can be used to jointly call variants across the sample set. This approach integrates data from multiple sequence libraries to support each variant and precisely assigns mutations to lineage segments. We applied lineage sequencing to a human colon cancer cell line with a DNA polymerase epsilon () proofreading deficiency (HT115) and a human retinal epithelial cell line immortalized by constitutive telomerase expression (RPE1). Cells were cultured under continuous observation to link observed single-cell phenotypes with single-cell mutation data. The high sensitivity, specificity, and resolution of the data provide a unique opportunity for quantitative analysis of variation in mutation rate, spectrum, and correlations among variants. Our data show that mutations arrive with nonuniform probability across sublineages and that DNA lesion dynamics may cause strong correlations between certain mutations.
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http://dx.doi.org/10.1101/gr.238543.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280753PMC
December 2018

Type 2 diabetes genetic loci informed by multi-trait associations point to disease mechanisms and subtypes: A soft clustering analysis.

PLoS Med 2018 09 21;15(9):e1002654. Epub 2018 Sep 21.

Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America.

Background: Type 2 diabetes (T2D) is a heterogeneous disease for which (1) disease-causing pathways are incompletely understood and (2) subclassification may improve patient management. Unlike other biomarkers, germline genetic markers do not change with disease progression or treatment. In this paper, we test whether a germline genetic approach informed by physiology can be used to deconstruct T2D heterogeneity. First, we aimed to categorize genetic loci into groups representing likely disease mechanistic pathways. Second, we asked whether the novel clusters of genetic loci we identified have any broad clinical consequence, as assessed in four separate subsets of individuals with T2D.

Methods And Findings: In an effort to identify mechanistic pathways driven by established T2D genetic loci, we applied Bayesian nonnegative matrix factorization (bNMF) clustering to genome-wide association study (GWAS) results for 94 independent T2D genetic variants and 47 diabetes-related traits. We identified five robust clusters of T2D loci and traits, each with distinct tissue-specific enhancer enrichment based on analysis of epigenomic data from 28 cell types. Two clusters contained variant-trait associations indicative of reduced beta cell function, differing from each other by high versus low proinsulin levels. The three other clusters displayed features of insulin resistance: obesity mediated (high body mass index [BMI] and waist circumference [WC]), "lipodystrophy-like" fat distribution (low BMI, adiponectin, and high-density lipoprotein [HDL] cholesterol, and high triglycerides), and disrupted liver lipid metabolism (low triglycerides). Increased cluster genetic risk scores were associated with distinct clinical outcomes, including increased blood pressure, coronary artery disease (CAD), and stroke. We evaluated the potential for clinical impact of these clusters in four studies containing individuals with T2D (Metabolic Syndrome in Men Study [METSIM], N = 487; Ashkenazi, N = 509; Partners Biobank, N = 2,065; UK Biobank [UKBB], N = 14,813). Individuals with T2D in the top genetic risk score decile for each cluster reproducibly exhibited the predicted cluster-associated phenotypes, with approximately 30% of all individuals assigned to just one cluster top decile. Limitations of this study include that the genetic variants used in the cluster analysis were restricted to those associated with T2D in populations of European ancestry.

Conclusion: Our approach identifies salient T2D genetically anchored and physiologically informed pathways, and supports the use of genetics to deconstruct T2D heterogeneity. Classification of patients by these genetic pathways may offer a step toward genetically informed T2D patient management.
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http://dx.doi.org/10.1371/journal.pmed.1002654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150463PMC
September 2018

Mutational processes shape the landscape of TP53 mutations in human cancer.

Nat Genet 2018 10 17;50(10):1381-1387. Epub 2018 Sep 17.

Dana-Farber Cancer Institute, Boston, MA, USA.

Unlike most tumor suppressor genes, the most common genetic alterations in tumor protein p53 (TP53) are missense mutations. Mutant p53 protein is often abundantly expressed in cancers and specific allelic variants exhibit dominant-negative or gain-of-function activities in experimental models. To gain a systematic view of p53 function, we interrogated loss-of-function screens conducted in hundreds of human cancer cell lines and performed TP53 saturation mutagenesis screens in an isogenic pair of TP53 wild-type and null cell lines. We found that loss or dominant-negative inhibition of wild-type p53 function reliably enhanced cellular fitness. By integrating these data with the Catalog of Somatic Mutations in Cancer (COSMIC) mutational signatures database, we developed a statistical model that describes the TP53 mutational spectrum as a function of the baseline probability of acquiring each mutation and the fitness advantage conferred by attenuation of p53 activity. Collectively, these observations show that widely-acting and tissue-specific mutational processes combine with phenotypic selection to dictate the frequencies of recurrent TP53 mutations.
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http://dx.doi.org/10.1038/s41588-018-0204-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168352PMC
October 2018

Sequential Response to Inhibition With Subsequent Exceptional Response to Atezolizumab in a Patient With Fusion-Positive Metastatic Urothelial Carcinoma.

JCO Precis Oncol 2018 24;2. Epub 2018 Jul 24.

and , Brigham and Women's Hospital, Harvard Medical School; , , , and , Dana Farber Cancer Institute; and , The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA.

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http://dx.doi.org/10.1200/PO.18.00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885951PMC
July 2018

Author Correction: Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.

Nat Med 2018 Aug;24(8):1290-1291

Mayo Clinic, Rochester, MN, USA.

In the version of this article originally published, an asterisk was omitted from Fig. 1a. The asterisk has been added to the figure. Additionally, a "NOTCH2" label was erroneously included in Fig. 4a. The label has been removed. The errors have been corrected in the PDF and HTML versions of this article.
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http://dx.doi.org/10.1038/s41591-018-0097-4DOI Listing
August 2018

Publisher Correction: Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.

Nat Med 2018 Aug;24(8):1292

Mayo Clinic, Rochester, MN, USA.

In the version of this article originally published, some text above the "Tri-nucleotide sequence motifs" label in Fig. 2a appeared incorrectly. The text was garbled and should have appeared as nucleotide codes.Additionally, the labels on the bars in Fig. 2c were not italicized in the original publication. These are gene symbols, and they should have been italicized.The colored labels above the graphs in Fig. 4b were also erroneously not italicized. These labels represent gene names and loci, and they should have been italicized.
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http://dx.doi.org/10.1038/s41591-018-0098-3DOI Listing
August 2018

Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine.

Cancer Discov 2018 09 14;8(9):1096-1111. Epub 2018 Jun 14.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC. Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. .
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http://dx.doi.org/10.1158/2159-8290.CD-18-0275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192263PMC
September 2018

Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma.

Cancer Res 2018 07 3;78(13):3421-3431. Epub 2018 May 3.

Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.

Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. was the most frequently altered gene (83% of dogs have either mutations or SCNA in ), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase , has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species. Canine osteosarcoma genomics identify SETD2 as a possible oncogenic driver of osteosarcoma, and findings establish the canine model as a useful comparative model for the corresponding human disease. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-3558DOI Listing
July 2018

Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.

Nat Med 2018 05 30;24(5):679-690. Epub 2018 Apr 30.

Mayo Clinic, Rochester, MN, USA.

Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.
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http://dx.doi.org/10.1038/s41591-018-0016-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613387PMC
May 2018

Comprehensive Characterization of Cancer Driver Genes and Mutations.

Cell 2018 04;173(2):371-385.e18

Computational and Systems Biology, Genome Institute of Singapore, Singapore, 138672.

Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%-85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors.
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http://dx.doi.org/10.1016/j.cell.2018.02.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029450PMC
April 2018

Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics.

Cell 2018 04;173(2):305-320.e10

Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA.

The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing.
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http://dx.doi.org/10.1016/j.cell.2018.03.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916814PMC
April 2018

Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas.

Cancer Cell 2018 04 2;33(4):721-735.e8. Epub 2018 Apr 2.

Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA. Electronic address:

We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.
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http://dx.doi.org/10.1016/j.ccell.2018.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966039PMC
April 2018
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