Publications by authors named "Paz Polak"

37 Publications

Olaparib for Metastatic Castration-Resistant Prostate Cancer.

N Engl J Med 2020 08;383(9):890

Icahn School of Medicine at Mount Sinai, New York, NY.

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http://dx.doi.org/10.1056/NEJMc2023199DOI Listing
August 2020

A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination-deficient Pancreatic Cancer.

Clin Cancer Res 2020 Oct 14;26(20):5462-5476. Epub 2020 Aug 14.

Rosalind and Morris Goodman Cancer Research Centre of McGill University, Montreal, Quebec, Canada.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) arising in patients with a germline or (g) mutation may be sensitive to platinum and PARP inhibitors (PARPi). However, treatment stratification based on g mutational status alone is associated with heterogeneous responses.

Experimental Design: We performed a seven-arm preclinical trial consisting of 471 mice, representing 12 unique PDAC patient-derived xenografts, of which nine were g mutated. From 179 patients whose PDAC was whole-genome and transcriptome sequenced, we identified 21 cases with homologous recombination deficiency (HRD), and investigated prognostic biomarkers.

Results: We found that biallelic inactivation of / is associated with genomic hallmarks of HRD and required for cisplatin and talazoparib (PARPi) sensitivity. However, HRD genomic hallmarks persisted in xenografts despite the emergence of therapy resistance, indicating the presence of a genomic scar. We identified tumor polyploidy and a low Ki67 index as predictors of poor cisplatin and talazoparib response. In patients with HRD PDAC, tumor polyploidy and a basal-like transcriptomic subtype were independent predictors of shorter survival. To facilitate clinical assignment of transcriptomic subtype, we developed a novel pragmatic two-marker assay (GATA6:KRT17).

Conclusions: In summary, we propose a predictive and prognostic model of g-mutated PDAC on the basis of HRD genomic hallmarks, Ki67 index, tumor ploidy, and transcriptomic subtype.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1439DOI Listing
October 2020

Etiologic Index - A Case-Only Measure of -Associated Cancer Risk.

N Engl J Med 2020 07;383(3):286-288

Icahn School of Medicine at Mount Sinai, New York, NY.

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http://dx.doi.org/10.1056/NEJMc1913988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546370PMC
July 2020

Bilateral Tumors - Inherited or Acquired?

N Engl J Med 2020 Jul;383(3):280-282

From the Department of Human Genetics and the Research Institute of the McGill University Health Centre and Lady Davis Institute, McGill University, Montreal (W.D.F.); and the Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai Hospital, New York (P.P.).

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http://dx.doi.org/10.1056/NEJMcibr2007784DOI Listing
July 2020

Genomic Profiling of Prostate Cancers from Men with African and European Ancestry.

Clin Cancer Res 2020 Sep 10;26(17):4651-4660. Epub 2020 Jul 10.

Division of Hematology/Oncology, Department of Medicine; Helen Diller Family Comprehensive Cancer Center; Bakar Computational Health Sciences Institute; Institute for Human Genetics; San Francisco Veterans Affairs Medical Center; University of California, San Francisco, San Francisco, California.

Purpose: African American (AFR) men have the highest mortality rate from prostate cancer (PCa) compared with men of other racial/ancestral groups. Differences in the spectrum of somatic genome alterations in tumors between AFR men and other populations have not been well-characterized due to a lack of inclusion of significant numbers in genomic studies.

Experimental Design: To identify genomic alterations associated with race, we compared the frequencies of somatic alterations in PCa obtained from four publicly available datasets comprising 250 AFR and 611 European American (EUR) men and a targeted sequencing dataset from a commercial platform of 436 AFR and 3018 EUR men.

Results: Mutations in as well as focal deletions in were more frequent in tumors from AFR men. mutations were associated with increasing Gleason score. amplifications were more frequent in tumors from AFR men with metastatic PCa, whereas deletions in and rearrangements in were less frequent in tumors from AFR men. truncations and amplifications were more frequent in primary PCa from AFR men. Genomic features that could impact clinical decision making were not significantly different between the two groups including tumor mutation burden, MSI status, and genomic alterations in select DNA repair genes, , and in .

Conclusions: Although we identified some novel differences in AFR men compared with other populations, the frequencies of genomic alterations in current therapeutic targets for PCa were similar between AFR and EUR men, suggesting that existing precision medicine approaches could be equally beneficial if applied equitably.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-4112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597977PMC
September 2020

Coronavirus 2019 and People Living With Human Immunodeficiency Virus: Outcomes for Hospitalized Patients in New York City.

Clin Infect Dis 2020 12;71(11):2933-2938

Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: There are limited data regarding the clinical impact of coronavirus disease 2019 (COVID-19) on people living with human immunodeficiency virus (PLWH). In this study, we compared outcomes for PLWH with COVID-19 to a matched comparison group.

Methods: We identified 88 PLWH hospitalized with laboratory-confirmed COVID-19 in our hospital system in New York City between 12 March and 23 April 2020. We collected data on baseline clinical characteristics, laboratory values, HIV status, treatment, and outcomes from this group and matched comparators (1 PLWH to up to 5 patients by age, sex, race/ethnicity, and calendar week of infection). We compared clinical characteristics and outcomes (death, mechanical ventilation, hospital discharge) for these groups, as well as cumulative incidence of death by HIV status.

Results: Patients did not differ significantly by HIV status by age, sex, or race/ethnicity due to the matching algorithm. PLWH hospitalized with COVID-19 had high proportions of HIV virologic control on antiretroviral therapy. PLWH had greater proportions of smoking (P < .001) and comorbid illness than uninfected comparators. There was no difference in COVID-19 severity on admission by HIV status (P = .15). Poor outcomes for hospitalized PLWH were frequent but similar to proportions in comparators; 18% required mechanical ventilation and 21% died during follow-up (compared with 23% and 20%, respectively). There was similar cumulative incidence of death over time by HIV status (P = .94).

Conclusions: We found no differences in adverse outcomes associated with HIV infection for hospitalized COVID-19 patients compared with a demographically similar patient group.
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http://dx.doi.org/10.1093/cid/ciaa880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337691PMC
December 2020

Somatic mutation landscape reveals differential variability of cell-of-origin for primary liver cancer.

Heliyon 2020 Feb 11;6(2):e03350. Epub 2020 Feb 11.

Biomedical Knowledge Engineering Laboratory, Seoul National University, Seoul, 08826, South Korea.

Primary liver tissue cancer types are renowned to display a consistent increase in global disease burden and mortality, thus needing more effective diagnostics and treatments. Yet, integrative research efforts to identify cell-of-origin for these cancers by utilizing human specimen data were poorly established. To this end, we analyzed previously published whole-genome sequencing data for 384 tumor and progenitor tissues along with 423 publicly available normal tissue epigenomic features and single cell RNA-seq data from human livers to assess correlation patterns and extended this information to conduct prediction of the cell-of-origin for primary liver cancer subtypes. Despite mixed histological features, the cell-of-origin for mixed hepatocellular carcinoma/intrahepatic cholangiocarcinoma subtype was predominantly predicted to be hepatocytic origin. Individual sample-level predictions also revealed hepatocytes as one of the major predicted cell-of-origin for intrahepatic cholangiocarcinoma, thus implying trans-differentiation process during cancer progression. Additional analyses on the whole genome sequencing data of hepatic progenitor cells suggest these cells may not be a direct cell-of-origin for liver cancers. These results provide novel insights on the nature and potential contributors of cell-of-origins for primary liver cancers.
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http://dx.doi.org/10.1016/j.heliyon.2020.e03350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016380PMC
February 2020

A deep learning system accurately classifies primary and metastatic cancers using passenger mutation patterns.

Nat Commun 2020 02 5;11(1):728. Epub 2020 Feb 5.

Ontario Institute for Cancer Research, Toronto, ON, M5G0A3, Canada.

In cancer, the primary tumour's organ of origin and histopathology are the strongest determinants of its clinical behaviour, but in 3% of cases a patient presents with a metastatic tumour and no obvious primary. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we train a deep learning classifier to predict cancer type based on patterns of somatic passenger mutations detected in whole genome sequencing (WGS) of 2606 tumours representing 24 common cancer types produced by the PCAWG Consortium. Our classifier achieves an accuracy of 91% on held-out tumor samples and 88% and 83% respectively on independent primary and metastatic samples, roughly double the accuracy of trained pathologists when presented with a metastatic tumour without knowledge of the primary. Surprisingly, adding information on driver mutations reduced accuracy. Our results have clinical applicability, underscore how patterns of somatic passenger mutations encode the state of the cell of origin, and can inform future strategies to detect the source of circulating tumour DNA.
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http://dx.doi.org/10.1038/s41467-019-13825-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002586PMC
February 2020

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

Novel POLE pathogenic germline variant in a family with multiple primary tumors results in distinct mutational signatures.

Hum Mutat 2019 01 20;40(1):36-41. Epub 2018 Nov 20.

Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

We describe a family in which four siblings exhibited multiple or classic colonic polyposis with or without colorectal carcinoma (CRC). One female developed three primary tumors, including CRC and carcinomas of the ovary and breast. Whole-exome sequencing of germline DNA from affected and unaffected individuals revealed a novel missense mutation in the exonuclease domain of POLE (c.833C>A; p.Thr278Lys) associated with a highly penetrant, autosomal-dominant inheritance pattern. Functional studies in yeast and demonstration of a high mutational burden in the available tumors confirmed the pathogenicity of the novel variant. Prominent POLE-deficient somatic mutational signatures were seen in the CRCs, but in contrast, a mutational signature typical of concomitant tumoral loss of POLE and mismatch-repair function (POLE-exo /MSI) was noted in the breast cancer. The breast cancer also showed distinctive pathological characteristics that reflect the presence of both the germline POLE variant and the secondary somatic MMR alterations.
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http://dx.doi.org/10.1002/humu.23676DOI Listing
January 2019

Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors.

Nat Genet 2018 09 27;50(9):1271-1281. Epub 2018 Aug 27.

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

Tumor mutational burden correlates with response to immune checkpoint blockade in multiple solid tumors, although in microsatellite-stable tumors this association is of uncertain clinical utility. Here we uniformly analyzed whole-exome sequencing (WES) of 249 tumors and matched normal tissue from patients with clinically annotated outcomes to immune checkpoint therapy, including radiographic response, across multiple cancer types to examine additional tumor genomic features that contribute to selective response. Our analyses identified genomic correlates of response beyond mutational burden, including somatic events in individual driver genes, certain global mutational signatures, and specific HLA-restricted neoantigens. However, these features were often interrelated, highlighting the complexity of identifying genetic driver events that generate an immunoresponsive tumor environment. This study lays a path forward in analyzing large clinical cohorts in an integrated and multifaceted manner to enhance the ability to discover clinically meaningful predictive features of response to immune checkpoint blockade.
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http://dx.doi.org/10.1038/s41588-018-0200-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119118PMC
September 2018

Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hürthle Cell Carcinoma.

Cancer Cell 2018 08;34(2):242-255.e5

Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Thyroid Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Hürthle cell carcinoma of the thyroid (HCC) is a form of thyroid cancer recalcitrant to radioiodine therapy that exhibits an accumulation of mitochondria. We performed whole-exome sequencing on a cohort of primary, recurrent, and metastatic tumors, and identified recurrent mutations in DAXX, TP53, NRAS, NF1, CDKN1A, ARHGAP35, and the TERT promoter. Parallel analysis of mtDNA revealed recurrent homoplasmic mutations in subunits of complex I of the electron transport chain. Analysis of DNA copy-number alterations uncovered widespread loss of chromosomes culminating in near-haploid chromosomal content in a large fraction of HCC, which was maintained during metastatic spread. This work uncovers a distinct molecular origin of HCC compared with other thyroid malignancies.
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http://dx.doi.org/10.1016/j.ccell.2018.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121811PMC
August 2018

Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing.

Cell 2018 07 18;174(2):433-447.e19. Epub 2018 Jun 18.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA. Electronic address:

Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC), but there have been few whole-genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. Unexpectedly, these rearrangements include highly recurrent tandem duplications involving an upstream enhancer of AR in 70%-87% of cases compared with <2% of primary prostate cancers. A subset of cases displayed AR or MYC enhancer duplication in the context of a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC, nominate alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the non-coding mCRPC genome remain to be discovered.
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http://dx.doi.org/10.1016/j.cell.2018.05.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046279PMC
July 2018

Monogenic Diseases of DNA Repair.

N Engl J Med 2018 02;378(5):491

McGill University, Montreal, QC, Canada

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http://dx.doi.org/10.1056/NEJMc1716072DOI Listing
February 2018

Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations.

J Hepatol 2018 05 31;68(5):959-969. Epub 2018 Jan 31.

Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan. Electronic address:

Background & Aims: Biliary tract cancers (BTCs) are clinically and pathologically heterogeneous and respond poorly to treatment. Genomic profiling can offer a clearer understanding of their carcinogenesis, classification and treatment strategy. We performed large-scale genome sequencing analyses on BTCs to investigate their somatic and germline driver events and characterize their genomic landscape.

Methods: We analyzed 412 BTC samples from Japanese and Italian populations, 107 by whole-exome sequencing (WES), 39 by whole-genome sequencing (WGS), and a further 266 samples by targeted sequencing. The subtypes were 136 intrahepatic cholangiocarcinomas (ICCs), 101 distal cholangiocarcinomas (DCCs), 109 peri-hilar type cholangiocarcinomas (PHCs), and 66 gallbladder or cystic duct cancers (GBCs/CDCs). We identified somatic alterations and searched for driver genes in BTCs, finding pathogenic germline variants of cancer-predisposing genes. We predicted cell-of-origin for BTCs by combining somatic mutation patterns and epigenetic features.

Results: We identified 32 significantly and commonly mutated genes including TP53, KRAS, SMAD4, NF1, ARID1A, PBRM1, and ATR, some of which negatively affected patient prognosis. A novel deletion of MUC17 at 7q22.1 affected patient prognosis. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes such as BRCA1, BRCA2, RAD51D, MLH1, or MSH2 were detected in 11% (16/146) of BTC patients.

Conclusions: BTCs have distinct genetic features including somatic events and germline predisposition. These findings could be useful to establish treatment and diagnostic strategies for BTCs based on genetic information.

Lay Summary: We here analyzed genomic features of 412 BTC samples from Japanese and Italian populations. A total of 32 significantly and commonly mutated genes were identified, some of which negatively affected patient prognosis, including a novel deletion of MUC17 at 7q22.1. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes were detected in 11% of patients with BTC. BTCs have distinct genetic features including somatic events and germline predisposition.
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http://dx.doi.org/10.1016/j.jhep.2018.01.009DOI Listing
May 2018

Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors.

Nat Commun 2017 11 6;8(1):1324. Epub 2017 Nov 6.

Eli and Edythe L. Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, 02142, MA, USA.

Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing.
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http://dx.doi.org/10.1038/s41467-017-00965-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673918PMC
November 2017

Analysis of somatic microsatellite indels identifies driver events in human tumors.

Nat Biotechnol 2017 Oct 11;35(10):951-959. Epub 2017 Sep 11.

Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts, USA.

Microsatellites (MSs) are tracts of variable-length repeats of short DNA motifs that exhibit high rates of mutation in the form of insertions or deletions (indels) of the repeated motif. Despite their prevalence, the contribution of somatic MS indels to cancer has been largely unexplored, owing to difficulties in detecting them in short-read sequencing data. Here we present two tools: MSMuTect, for accurate detection of somatic MS indels, and MSMutSig, for identification of genes containing MS indels at a higher frequency than expected by chance. Applying MSMuTect to whole-exome data from 6,747 human tumors representing 20 tumor types, we identified >1,000 previously undescribed MS indels in cancer genes. Additionally, we demonstrate that the number and pattern of MS indels can accurately distinguish microsatellite-stable tumors from tumors with microsatellite instability, thus potentially improving classification of clinically relevant subgroups. Finally, we identified seven MS indel driver hotspots: four in known cancer genes (ACVR2A, RNF43, JAK1, and MSH3) and three in genes not previously implicated as cancer drivers (ESRP1, PRDM2, and DOCK3).
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http://dx.doi.org/10.1038/nbt.3966DOI Listing
October 2017

A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer.

Nat Genet 2017 Oct 21;49(10):1476-1486. Epub 2017 Aug 21.

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

Biallelic inactivation of BRCA1 or BRCA2 is associated with a pattern of genome-wide mutations known as signature 3. By analyzing ∼1,000 breast cancer samples, we confirmed this association and established that germline nonsense and frameshift variants in PALB2, but not in ATM or CHEK2, can also give rise to the same signature. We were able to accurately classify missense BRCA1 or BRCA2 variants known to impair homologous recombination (HR) on the basis of this signature. Finally, we show that epigenetic silencing of RAD51C and BRCA1 by promoter methylation is strongly associated with signature 3 and, in our data set, was highly enriched in basal-like breast cancers in young individuals of African descent.
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http://dx.doi.org/10.1038/ng.3934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376751PMC
October 2017

Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors.

Nat Genet 2016 06 25;48(6):600-606. Epub 2016 Apr 25.

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

Alterations in DNA repair pathways are common in tumors and can result in characteristic mutational signatures; however, a specific mutational signature associated with somatic alterations in the nucleotide- excision repair (NER) pathway has not yet been identified. Here we examine the mutational processes operating in urothelial cancer, a tumor type in which the core NER gene ERCC2 is significantly mutated. Analysis of three independent urothelial tumor cohorts demonstrates a strong association between somatic ERCC2 mutations and the activity of a mutational signature characterized by a broad spectrum of base changes. In addition, we note an association between the activity of this signature and smoking that is independent of ERCC2 mutation status, providing genomic evidence of tobacco-related mutagenesis in urothelial cancer. Together, these analyses identify an NER-related mutational signature and highlight the related roles of DNA damage and subsequent DNA repair in shaping tumor mutational landscape.
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http://dx.doi.org/10.1038/ng.3557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936490PMC
June 2016

Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair.

Cell 2016 Jan 21;164(3):538-49. Epub 2016 Jan 21.

Massachusetts General Hospital Cancer Center and Department of Pathology, 55 Fruit Street, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. Electronic address:

Mutational processes constantly shape the somatic genome, leading to immunity, aging, cancer, and other diseases. When cancer is the outcome, we are afforded a glimpse into these processes by the clonal expansion of the malignant cell. Here, we characterize a less explored layer of the mutational landscape of cancer: mutational asymmetries between the two DNA strands. Analyzing whole-genome sequences of 590 tumors from 14 different cancer types, we reveal widespread asymmetries across mutagenic processes, with transcriptional ("T-class") asymmetry dominating UV-, smoking-, and liver-cancer-associated mutations and replicative ("R-class") asymmetry dominating POLE-, APOBEC-, and MSI-associated mutations. We report a striking phenomenon of transcription-coupled damage (TCD) on the non-transcribed DNA strand and provide evidence that APOBEC mutagenesis occurs on the lagging-strand template during DNA replication. As more genomes are sequenced, studying and classifying their asymmetries will illuminate the underlying biological mechanisms of DNA damage and repair.
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http://dx.doi.org/10.1016/j.cell.2015.12.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753048PMC
January 2016

APOBEC-Induced Cancer Mutations Are Uniquely Enriched in Early-Replicating, Gene-Dense, and Active Chromatin Regions.

Cell Rep 2015 Nov 29;13(6):1103-1109. Epub 2015 Oct 29.

Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

An antiviral component of the human innate immune system-the APOBEC cytidine deaminases-was recently identified as a prominent source of mutations in cancers. Here, we investigated the distribution of APOBEC-induced mutations across the genomes of 119 breast and 24 lung cancer samples. While the rate of most mutations is known to be elevated in late-replicating regions that are characterized by reduced chromatin accessibility and low gene density, we observed a marked enrichment of APOBEC mutations in early-replicating regions. This unusual mutagenesis profile may be associated with a higher propensity to form single-strand DNA substrates for APOBEC enzymes in early-replicating regions and should be accounted for in statistical analyses of cancer genome mutation catalogs aimed at understanding the mechanisms of carcinogenesis as well as highlighting genes that are significantly mutated in cancer.
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http://dx.doi.org/10.1016/j.celrep.2015.09.077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644490PMC
November 2015

Comprehensive assessment of cancer missense mutation clustering in protein structures.

Proc Natl Acad Sci U S A 2015 Oct 21;112(40):E5486-95. Epub 2015 Sep 21.

Department of Pathology and Cancer Center, Massachusetts General Hospital, Boston, MA 02114; Harvard Medical School, Boston, MA 02115; Broad Institute of MIT and Harvard, Cambridge, MA 02142;

Large-scale tumor sequencing projects enabled the identification of many new cancer gene candidates through computational approaches. Here, we describe a general method to detect cancer genes based on significant 3D clustering of mutations relative to the structure of the encoded protein products. The approach can also be used to search for proteins with an enrichment of mutations at binding interfaces with a protein, nucleic acid, or small molecule partner. We applied this approach to systematically analyze the PanCancer compendium of somatic mutations from 4,742 tumors relative to all known 3D structures of human proteins in the Protein Data Bank. We detected significant 3D clustering of missense mutations in several previously known oncoproteins including HRAS, EGFR, and PIK3CA. Although clustering of missense mutations is often regarded as a hallmark of oncoproteins, we observed that a number of tumor suppressors, including FBXW7, VHL, and STK11, also showed such clustering. Beside these known cases, we also identified significant 3D clustering of missense mutations in NUF2, which encodes a component of the kinetochore, that could affect chromosome segregation and lead to aneuploidy. Analysis of interaction interfaces revealed enrichment of mutations in the interfaces between FBXW7-CCNE1, HRAS-RASA1, CUL4B-CAND1, OGT-HCFC1, PPP2R1A-PPP2R5C/PPP2R2A, DICER1-Mg2+, MAX-DNA, SRSF2-RNA, and others. Together, our results indicate that systematic consideration of 3D structure can assist in the identification of cancer genes and in the understanding of the functional role of their mutations.
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http://dx.doi.org/10.1073/pnas.1516373112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603469PMC
October 2015

Genome-wide patterns and properties of de novo mutations in humans.

Nat Genet 2015 Jul 18;47(7):822-826. Epub 2015 May 18.

Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Mutations create variation in the population, fuel evolution and cause genetic diseases. Current knowledge about de novo mutations is incomplete and mostly indirect. Here we analyze 11,020 de novo mutations from the whole genomes of 250 families. We show that de novo mutations in the offspring of older fathers are not only more numerous but also occur more frequently in early-replicating, genic regions. Functional regions exhibit higher mutation rates due to CpG dinucleotides and show signatures of transcription-coupled repair, whereas mutation clusters with a unique signature point to a new mutational mechanism. Mutation and recombination rates independently associate with nucleotide diversity, and regional variation in human-chimpanzee divergence is only partly explained by heterogeneity in mutation rate. Finally, we provide a genome-wide mutation rate map for medical and population genetics applications. Our results provide new insights and refine long-standing hypotheses about human mutagenesis.
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http://dx.doi.org/10.1038/ng.3292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485564PMC
July 2015

Cell-of-origin chromatin organization shapes the mutational landscape of cancer.

Nature 2015 Feb;518(7539):360-364

Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115.

Cancer is a disease potentiated by mutations in somatic cells. Cancer mutations are not distributed uniformly along the human genome. Instead, different human genomic regions vary by up to fivefold in the local density of cancer somatic mutations, posing a fundamental problem for statistical methods used in cancer genomics. Epigenomic organization has been proposed as a major determinant of the cancer mutational landscape. However, both somatic mutagenesis and epigenomic features are highly cell-type-specific. We investigated the distribution of mutations in multiple independent samples of diverse cancer types and compared them to cell-type-specific epigenomic features. Here we show that chromatin accessibility and modification, together with replication timing, explain up to 86% of the variance in mutation rates along cancer genomes. The best predictors of local somatic mutation density are epigenomic features derived from the most likely cell type of origin of the corresponding malignancy. Moreover, we find that cell-of-origin chromatin features are much stronger determinants of cancer mutation profiles than chromatin features of matched cancer cell lines. Furthermore, we show that the cell type of origin of a cancer can be accurately determined based on the distribution of mutations along its genome. Thus, the DNA sequence of a cancer genome encompasses a wealth of information about the identity and epigenomic features of its cell of origin.
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http://dx.doi.org/10.1038/nature14221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405175PMC
February 2015

Integrative analysis of 111 reference human epigenomes.

Nature 2015 Feb;518(7539):317-30

1] Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, Massachusetts 02139, USA. [2] The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.
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http://dx.doi.org/10.1038/nature14248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530010PMC
February 2015

Genetic variation in human DNA replication timing.

Cell 2014 Nov 13;159(5):1015-1026. Epub 2014 Nov 13.

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

Genomic DNA replicates in a choreographed temporal order that impacts the distribution of mutations along the genome. We show here that DNA replication timing is shaped by genetic polymorphisms that act in cis upon megabase-scale DNA segments. In genome sequences from proliferating cells, read depth along chromosomes reflected DNA replication activity in those cells. We used this relationship to analyze variation in replication timing among 161 individuals sequenced by the 1000 Genomes Project. Genome-wide association of replication timing with genetic variation identified 16 loci at which inherited alleles associate with replication timing. We call these "replication timing quantitative trait loci" (rtQTLs). rtQTLs involved the differential use of replication origins, exhibited allele-specific effects on replication timing, and associated with gene expression variation at megabase scales. Our results show replication timing to be shaped by genetic polymorphism and identify a means by which inherited polymorphism regulates the mutability of nearby sequences.
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http://dx.doi.org/10.1016/j.cell.2014.10.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359889PMC
November 2014

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge.

Authors:
Catherine A Brownstein Alan H Beggs Nils Homer Barry Merriman Timothy W Yu Katherine C Flannery Elizabeth T DeChene Meghan C Towne Sarah K Savage Emily N Price Ingrid A Holm Lovelace J Luquette Elaine Lyon Joseph Majzoub Peter Neupert David McCallie Peter Szolovits Huntington F Willard Nancy J Mendelsohn Renee Temme Richard S Finkel Sabrina W Yum Livija Medne Shamil R Sunyaev Ivan Adzhubey Christopher A Cassa Paul I W de Bakker Hatice Duzkale Piotr Dworzyński William Fairbrother Laurent Francioli Birgit H Funke Monica A Giovanni Robert E Handsaker Kasper Lage Matthew S Lebo Monkol Lek Ignaty Leshchiner Daniel G MacArthur Heather M McLaughlin Michael F Murray Tune H Pers Paz P Polak Soumya Raychaudhuri Heidi L Rehm Rachel Soemedi Nathan O Stitziel Sara Vestecka Jochen Supper Claudia Gugenmus Bernward Klocke Alexander Hahn Max Schubach Mortiz Menzel Saskia Biskup Peter Freisinger Mario Deng Martin Braun Sven Perner Richard J H Smith Janeen L Andorf Jian Huang Kelli Ryckman Val C Sheffield Edwin M Stone Thomas Bair E Ann Black-Ziegelbein Terry A Braun Benjamin Darbro Adam P DeLuca Diana L Kolbe Todd E Scheetz Aiden E Shearer Rama Sompallae Kai Wang Alexander G Bassuk Erik Edens Katherine Mathews Steven A Moore Oleg A Shchelochkov Pamela Trapane Aaron Bossler Colleen A Campbell Jonathan W Heusel Anne Kwitek Tara Maga Karin Panzer Thomas Wassink Douglas Van Daele Hela Azaiez Kevin Booth Nic Meyer Michael M Segal Marc S Williams Gerard Tromp Peter White Donald Corsmeier Sara Fitzgerald-Butt Gail Herman Devon Lamb-Thrush Kim L McBride David Newsom Christopher R Pierson Alexander T Rakowsky Aleš Maver Luca Lovrečić Anja Palandačić Borut Peterlin Ali Torkamani Anna Wedell Mikael Huss Andrey Alexeyenko Jessica M Lindvall Måns Magnusson Daniel Nilsson Henrik Stranneheim Fulya Taylan Christian Gilissen Alexander Hoischen Bregje van Bon Helger Yntema Marcel Nelen Weidong Zhang Jason Sager Lu Zhang Kathryn Blair Deniz Kural Michael Cariaso Greg G Lennon Asif Javed Saloni Agrawal Pauline C Ng Komal S Sandhu Shuba Krishna Vamsi Veeramachaneni Ofer Isakov Eran Halperin Eitan Friedman Noam Shomron Gustavo Glusman Jared C Roach Juan Caballero Hannah C Cox Denise Mauldin Seth A Ament Lee Rowen Daniel R Richards F Anthony San Lucas Manuel L Gonzalez-Garay C Thomas Caskey Yu Bai Ying Huang Fang Fang Yan Zhang Zhengyuan Wang Jorge Barrera Juan M Garcia-Lobo Domingo González-Lamuño Javier Llorca Maria C Rodriguez Ignacio Varela Martin G Reese Francisco M De La Vega Edward Kiruluta Michele Cargill Reece K Hart Jon M Sorenson Gholson J Lyon David A Stevenson Bruce E Bray Barry M Moore Karen Eilbeck Mark Yandell Hongyu Zhao Lin Hou Xiaowei Chen Xiting Yan Mengjie Chen Cong Li Can Yang Murat Gunel Peining Li Yong Kong Austin C Alexander Zayed I Albertyn Kym M Boycott Dennis E Bulman Paul M K Gordon A Micheil Innes Bartha M Knoppers Jacek Majewski Christian R Marshall Jillian S Parboosingh Sarah L Sawyer Mark E Samuels Jeremy Schwartzentruber Isaac S Kohane David M Margulies

Genome Biol 2014 Mar 25;15(3):R53. Epub 2014 Mar 25.

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance.

Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization.

Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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http://dx.doi.org/10.1186/gb-2014-15-3-r53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073084PMC
March 2014

Reduced local mutation density in regulatory DNA of cancer genomes is linked to DNA repair.

Nat Biotechnol 2014 Jan 15;32(1):71-5. Epub 2013 Dec 15.

1] Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA. [3] The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

Carcinogenesis and neoplastic progression are mediated by the accumulation of somatic mutations. Here we report that the local density of somatic mutations in cancer genomes is highly reduced specifically in accessible regulatory DNA defined by DNase I hypersensitive sites. This reduction is independent of any known factors influencing somatic mutation density and is observed in diverse cancer types, suggesting a general mechanism. By analyzing individual cancer genomes, we show that the reduced local mutation density within regulatory DNA is linked to intact global genome repair machinery, with nearly complete abrogation of the hypomutation phenomenon in individual cancers that possess mutations in components of the nucleotide excision repair system. Together, our results connect chromatin structure, gene regulation and cancer-associated somatic mutation.
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http://dx.doi.org/10.1038/nbt.2778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116484PMC
January 2014

Mutational heterogeneity in cancer and the search for new cancer-associated genes.

Nature 2013 Jul 16;499(7457):214-218. Epub 2013 Jun 16.

The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.

Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.
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http://dx.doi.org/10.1038/nature12213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919509PMC
July 2013

Differential relationship of DNA replication timing to different forms of human mutation and variation.

Am J Hum Genet 2012 Dec 21;91(6):1033-40. Epub 2012 Nov 21.

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

Human genetic variation is distributed nonrandomly across the genome, though the principles governing its distribution are only partially known. DNA replication creates opportunities for mutation, and the timing of DNA replication correlates with the density of SNPs across the human genome. To enable deeper investigation of how DNA replication timing relates to human mutation and variation, we generated a high-resolution map of the human genome's replication timing program and analyzed its relationship to point mutations, copy number variations, and the meiotic recombination hotspots utilized by males and females. DNA replication timing associated with point mutations far more strongly than predicted from earlier analyses and showed a stronger relationship to transversion than transition mutations. Structural mutations arising from recombination-based mechanisms and recombination hotspots used more extensively by females were enriched in early-replicating parts of the genome, though these relationships appeared to relate more strongly to the genomic distribution of causative sequence features. These results indicate differential and sex-specific relationship of DNA replication timing to different forms of mutation and recombination.
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http://dx.doi.org/10.1016/j.ajhg.2012.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516607PMC
December 2012