The pan-cancer landscape of prognostic germline variants in 10,582 patients.


BACKGROUND:While clinical factors such as age, grade, stage, and histological subtype provide physicians with information about patient prognosis, genomic data can further improve these predictions. Previous studies have shown that germline variants in known cancer driver genes are predictive of patient outcome, but no study has systematically analyzed multiple cancers in an unbiased way to identify genetic loci that can improve patient outcome predictions made using clinical factors. METHODS:We analyzed sequencing data from the over 10,000 cancer patients available through The Cancer Genome Atlas to identify germline variants associated with patient outcome using multivariate Cox regression models. RESULTS:We identified 79 prognostic germline variants in individual cancers and 112 prognostic germline variants in groups of cancers. The germline variants identified in individual cancers provide additional predictive power about patient outcomes beyond clinical information currently in use and may therefore augment clinical decisions based on expected tumor aggressiveness. Molecularly, at least 12 of the germline variants are likely associated with patient outcome through perturbation of protein structure and at least five through association with gene expression differences. Almost half of these germline variants are in previously reported tumor suppressors, oncogenes or cancer driver genes with the other half pointing to genomic loci that should be further investigated for their roles in cancers. CONCLUSIONS:Germline variants are predictive of outcome in cancer patients and specific germline variants can improve patient outcome predictions beyond predictions made using clinical factors alone. The germline variants also implicate new means by which known oncogenes, tumor suppressor genes, and driver genes are perturbed in cancer and suggest roles in cancer for other genes that have not been extensively studied in oncology. Further studies in other cancer cohorts are necessary to confirm that germline variation is associated with outcome in cancer patients as this is a proof-of-principle study.


Genome Med


Genome medicine


Chatrath A,Przanowska R,Kiran S,Su Z,Saha S,Wilson B,Tsunematsu T,Ahn JH,Lee KY,Paulsen T,Sobierajska E,Kiran M,Tang X,Li T,Kumar P,Ratan A,Dutta A




Has Abstract


2020-02-17 00:00:00












  • Identification of epigenome-wide DNA methylation differences between carriers of APOE ε4 and APOE ε2 alleles.

    abstract:BACKGROUND:The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease, whilst the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Walker RM,Vaher K,Bermingham ML,Morris SW,Bretherick AD,Zeng Y,Rawlik K,Amador C,Campbell A,Haley CS,Hayward C,Porteous DJ,McIntosh AM,Marioni RE,Evans KL

    更新日期:2021-01-04 00:00:00

  • Network-based approaches elucidate differences within APOBEC and clock-like signatures in breast cancer.

    abstract:BACKGROUND:Studies of cancer mutations have typically focused on identifying cancer driving mutations that confer growth advantage to cancer cells. However, cancer genomes accumulate a large number of passenger somatic mutations resulting from various endogenous and exogenous causes, including normal DNA damage and rep...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Kim YA,Wojtowicz D,Sarto Basso R,Sason I,Robinson W,Hochbaum DS,Leiserson MDM,Sharan R,Vadin F,Przytycka TM

    更新日期:2020-05-29 00:00:00

  • Genetic relatedness analysis reveals the cotransmission of genetically related Plasmodium falciparum parasites in Thiès, Senegal.

    abstract:BACKGROUND:As public health interventions drive parasite populations to elimination, genetic epidemiology models that incorporate population genomics can be powerful tools for evaluating the effectiveness of continued intervention. However, current genetic epidemiology models may not accurately simulate the population ...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Wong W,Griggs AD,Daniels RF,Schaffner SF,Ndiaye D,Bei AK,Deme AB,MacInnis B,Volkman SK,Hartl DL,Neafsey DE,Wirth DF

    更新日期:2017-01-24 00:00:00

  • The Human Gene Mutation Database: 2008 update.

    abstract::The Human Gene Mutation Database (HGMD((R))) is a comprehensive core collection of germline mutations in nuclear genes that underlie or are associated with human inherited disease. Here, we summarize the history of the database and its current resources. By December 2008, the database contained over 85,000 different l...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Stenson PD,Mort M,Ball EV,Howells K,Phillips AD,Thomas NS,Cooper DN

    更新日期:2009-01-22 00:00:00

  • Analysis of epigenetic changes in survivors of preterm birth reveals the effect of gestational age and evidence for a long term legacy.

    abstract:BACKGROUND:Preterm birth confers a high risk of adverse long term health outcomes for survivors, yet the underlying molecular mechanisms are unclear. We hypothesized that effects of preterm birth can be mediated through measurable epigenomic changes throughout development. We therefore used a longitudinal birth cohort ...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Cruickshank MN,Oshlack A,Theda C,Davis PG,Martino D,Sheehan P,Dai Y,Saffery R,Doyle LW,Craig JM

    更新日期:2013-10-18 00:00:00

  • Creating a data resource: what will it take to build a medical information commons?

    abstract::National and international public-private partnerships, consortia, and government initiatives are underway to collect and share genomic, personal, and healthcare data on a massive scale. Ideally, these efforts will contribute to the creation of a medical information commons (MIC), a comprehensive data resource that is...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Deverka PA,Majumder MA,Villanueva AG,Anderson M,Bakker AC,Bardill J,Boerwinkle E,Bubela T,Evans BJ,Garrison NA,Gibbs RA,Gentleman R,Glazer D,Goldstein MM,Greely H,Harris C,Knoppers BM,Koenig BA,Kohane IS,La Rosa S,

    更新日期:2017-09-22 00:00:00

  • Differential effects of dietary supplements on metabolomic profile of smokers versus non-smokers.

    abstract:BACKGROUND:Cigarette smoking is well-known to associate with accelerated skin aging as well as cardiovascular disease and lung cancer, in large part due to oxidative stress. Because metabolites are downstream of genetic variation, as well as transcriptional changes and post-translational modifications of proteins, they...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Spitale RC,Cheng MY,Chun KA,Gorell ES,Munoz CA,Kern DG,Wood SM,Knaggs HE,Wulff J,Beebe KD,Chang AL

    更新日期:2012-02-23 00:00:00

  • DawnRank: discovering personalized driver genes in cancer.

    abstract::Large-scale cancer genomic studies have revealed that the genetic heterogeneity of the same type of cancer is greater than previously thought. A key question in cancer genomics is the identification of driver genes. Although existing methods have identified many common drivers, it remains challenging to predict person...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Hou JP,Ma J

    更新日期:2014-07-31 00:00:00

  • Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring.

    abstract:BACKGROUND:The HHIP gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic variant that decreased HHIP transcription. However, little is known about ho...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Lao T,Glass K,Qiu W,Polverino F,Gupta K,Morrow J,Mancini JD,Vuong L,Perrella MA,Hersh CP,Owen CA,Quackenbush J,Yuan GC,Silverman EK,Zhou X

    更新日期:2015-02-14 00:00:00

  • Erratum to: a SNP profiling panel for sample tracking in whole-exome sequencing studies.

    abstract::This is an Erratum to Genome Medicine 2013, 5:89, highlighting an error in Table 1 of the original article. Please see related article:[This corrects the article DOI: 10.1186/gm492.]. ...

    journal_title:Genome medicine

    pub_type: 已发布勘误


    authors: Pengelly RJ,Gibson J,Andreoletti G,Collins A,Mattocks CJ,Ennis S

    更新日期:2015-05-07 00:00:00

  • Biomarker discovery in human cerebrospinal fluid: the need for integrative metabolome and proteome databases.

    abstract::The number of metabolites identified in human cerebrospinal fluid (CSF) has steadily increased over the past 5 years, and in this issue of Genome Medicine David Wishart and colleagues provide a comprehensive update that brings the number of metabolites listed in the CSF metabolome database to 476 compounds. There is n...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Schwarz E,Torrey EF,Guest PC,Bahn S

    更新日期:2012-04-30 00:00:00

  • Novel insights into the HLA class I immunopeptidome and T-cell immunosurveillance.

    abstract::Advances in mass spectrometry have allowed the high-throughput quantitative identification of human leukocyte antigen (HLA) class I ligands, and recent studies have reported on the breadth and diversity of the HLA class I immunopeptidome. These findings have far-reaching implications for immunosurveillance by T cells ...

    journal_title:Genome medicine

    pub_type: 社论,评审


    authors: Melief CJM,Kessler JH

    更新日期:2017-05-24 00:00:00

  • Wnt-regulated lncRNA discovery enhanced by in vivo identification and CRISPRi functional validation.

    abstract:BACKGROUND:Wnt signaling is an evolutionarily conserved developmental pathway that is frequently hyperactivated in cancer. While multiple protein-coding genes regulated by Wnt signaling are known, the functional lncRNAs regulated by Wnt signaling have not been systematically characterized. METHODS:We comprehensively m...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Liu S,Harmston N,Glaser TL,Wong Y,Zhong Z,Madan B,Virshup DM,Petretto E

    更新日期:2020-10-22 00:00:00

  • Defining functional signatures of dysbiosis in periodontitis progression.

    abstract::Periodontitis is a common inflammatory disease that leads to tooth loss and has been linked to cardiovascular disease and diabetes mellitus. The periodontal microbiome is highly diverse, and metatranscriptomic studies have indicated that the genes that are expressed by the microbiota are more relevant than the microbi...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Wang GP

    更新日期:2015-04-27 00:00:00

  • Pharmacogenomics of adverse drug reactions.

    abstract::Considerable progress has been made in identifying genetic risk factors for idiosyncratic adverse drug reactions in the past 30 years. These reactions can affect various tissues and organs, including liver, skin, muscle and heart, in a drug-dependent manner. Using both candidate gene and genome-wide association studie...

    journal_title:Genome medicine

    pub_type: 杂志文章,评审


    authors: Daly AK

    更新日期:2013-01-29 00:00:00

  • CRISPR-SONIC: targeted somatic oncogene knock-in enables rapid in vivo cancer modeling.

    abstract::CRISPR/Cas9 has revolutionized cancer mouse models. Although loss-of-function genetics by CRISPR/Cas9 is well-established, generating gain-of-function alleles in somatic cancer models is still challenging because of the low efficiency of gene knock-in. Here we developed CRISPR-based Somatic Oncogene kNock-In for Cance...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Mou H,Ozata DM,Smith JL,Sheel A,Kwan SY,Hough S,Kucukural A,Kennedy Z,Cao Y,Xue W

    更新日期:2019-04-16 00:00:00

  • Precision cancer mouse models through genome editing with CRISPR-Cas9.

    abstract::The cancer genome is highly complex, with hundreds of point mutations, translocations, and chromosome gains and losses per tumor. To understand the effects of these alterations, precise models are needed. Traditional approaches to the construction of mouse models are time-consuming and laborious, requiring manipulatio...

    journal_title:Genome medicine

    pub_type: 杂志文章,评审


    authors: Mou H,Kennedy Z,Anderson DG,Yin H,Xue W

    更新日期:2015-06-09 00:00:00

  • Consensus: a framework for evaluation of uncertain gene variants in laboratory test reporting.

    abstract::Accurate interpretation of gene testing is a key component in customizing patient therapy. Where confirming evidence for a gene variant is lacking, computational prediction may be employed. A standardized framework, however, does not yet exist for quantitative evaluation of disease association for uncertain or novel g...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Crockett DK,Ridge PG,Wilson AR,Lyon E,Williams MS,Narus SP,Facelli JC,Mitchell JA

    更新日期:2012-05-28 00:00:00

  • Moving pathogen genomics out of the lab and into the clinic: what will it take?

    abstract::Pathogen genomic analysis is a potentially transformative new approach to the clinical and public-health management of infectious diseases. Health systems investing in this technology will need to build infrastructure and develop policies that ensure genomic information can be generated, shared and acted upon in a tim...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Luheshi LM,Raza S,Peacock SJ

    更新日期:2015-12-30 00:00:00

  • Pancreatic cancer genomics: insights and opportunities for clinical translation.

    abstract::Pancreatic cancer is a highly lethal tumor type for which there are few viable therapeutic options. It is also caused by the accumulation of mutations in a variety of genes. These genetic alterations can be grouped into those that accumulate during pancreatic intraepithelial neoplasia (precursor lesions) and thus are ...

    journal_title:Genome medicine

    pub_type: 杂志文章,评审


    authors: Makohon-Moore A,Brosnan JA,Iacobuzio-Donahue CA

    更新日期:2013-03-28 00:00:00

  • Ultradeep analysis of tumor heterogeneity in regions of somatic hypermutation.

    abstract::Tumor heterogeneity is of growing importance in the treatment of cancers. Mutational hot spots are prime locations for determining number and proportions of low variant allele frequency (VAF) tumor subclones by next generation sequencing. Low VAF detection is complicated by poor mapping efficiency in regions with high...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Spence JM,Spence JP,Abumoussa A,Burack WR

    更新日期:2015-03-12 00:00:00

  • Huntington's disease: the case for genetic modifiers.

    abstract::For almost three decades, Huntington's disease has been a prototype for the application of genetic strategies to human disease. HD, the Huntington's disease gene, was the first autosomal defect mapped using only DNA markers, a finding in 1983 that helped to spur similar studies in many other disorders and contributed ...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Gusella JF,MacDonald ME

    更新日期:2009-08-21 00:00:00

  • NARD: whole-genome reference panel of 1779 Northeast Asians improves imputation accuracy of rare and low-frequency variants.

    abstract::Here, we present the Northeast Asian Reference Database (NARD), including whole-genome sequencing data of 1779 individuals from Korea, Mongolia, Japan, China, and Hong Kong. NARD provides the genetic diversity of Korean (n = 850) and Mongolian (n = 384) ancestries that were not present in the 1000 Genomes Project Phas...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Yoo SK,Kim CU,Kim HL,Kim S,Shin JY,Kim N,Yang JSW,Lo KW,Cho B,Matsuda F,Schuster SC,Kim C,Kim JI,Seo JS

    更新日期:2019-10-22 00:00:00

  • Optimizing the treatment of BRAF mutant melanoma.

    abstract::Selective inhibitors of the kinases BRAF and MEK for the treatment of patients with otherwise refractory BRAF mutant melanoma have demonstrated impressive efficacy, and combination treatment with these agents may prove to be even more effective. However, these drugs are not curative, mainly because of the relatively r...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Settleman J

    更新日期:2014-04-28 00:00:00

  • Moderate- to low-risk variant alleles of cutaneous malignancies and nevi: lessons from genome-wide association studies.

    abstract::Cutaneous malignancies, especially malignant melanoma, exhibit great genetic heterogeneity. As a result, some individuals and families have particularly increased risk due to genetic predisposition to the disease. The susceptibility alleles range from rarely occurring, heritable, high-risk variants to ubiquitously occ...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Udayakumar D,Tsao H

    更新日期:2009-10-27 00:00:00

  • Best practices for bioinformatic characterization of neoantigens for clinical utility.

    abstract::Neoantigens are newly formed peptides created from somatic mutations that are capable of inducing tumor-specific T cell recognition. Recently, researchers and clinicians have leveraged next generation sequencing technologies to identify neoantigens and to create personalized immunotherapies for cancer treatment. To cr...

    journal_title:Genome medicine

    pub_type: 杂志文章,评审


    authors: Richters MM,Xia H,Campbell KM,Gillanders WE,Griffith OL,Griffith M

    更新日期:2019-08-28 00:00:00

  • Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma.

    abstract:BACKGROUND:Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin caused by either the integration of Merkel cell polyomavirus (MCPyV) and expression of viral T antigens or by ultraviolet-induced damage to the tumor genome from excessive sunlight exposure. An increasing number of deep s...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Starrett GJ,Thakuria M,Chen T,Marcelus C,Cheng J,Nomburg J,Thorner AR,Slevin MK,Powers W,Burns RT,Perry C,Piris A,Kuo FC,Rabinowits G,Giobbie-Hurder A,MacConaill LE,DeCaprio JA

    更新日期:2020-03-18 00:00:00

  • The three-body problem of therapy with induced pluripotent stem cells.

    abstract::Regenerative medicine has a three-body problem: alignment of the dynamics of the genome, stem cell and patient. Focusing on the rare inherited fragile skin disorder epidermolysis bullosa, three recent innovative studies have used induced pluripotent stem cells and gene correction, revertant mosaicism or genome editing...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Tolar J,McGrath JA

    更新日期:2015-02-20 00:00:00

  • The balance of expression of PTPN22 splice forms is significantly different in rheumatoid arthritis patients compared with controls.

    abstract:BACKGROUND:The R620W variant in protein tyrosine phosphatase non-receptor 22 (PTPN22) is associated with rheumatoid arthritis (RA). The PTPN22 gene has alternatively spliced transcripts and at least two of the splice forms have been confirmed to encode different PTPN22 (LYP) proteins, but detailed information regarding...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Ronninger M,Guo Y,Shchetynsky K,Hill A,Khademi M,Olsson T,Reddy PS,Seddighzadeh M,Clark JD,Lin LL,O'Toole M,Padyukov L

    更新日期:2012-01-20 00:00:00

  • Allele-specific expression in the human heart and its application to postoperative atrial fibrillation and myocardial ischemia.

    abstract:BACKGROUND:Allele-specific expression (ASE) is differential expression of each of the two chromosomal alleles of an autosomal gene. We assessed ASE patterns in the human left atrium (LA, n = 62) and paired samples from the left ventricle (LV, n = 76) before and after ischemia, and tested the utility of differential ASE...

    journal_title:Genome medicine

    pub_type: 杂志文章


    authors: Sigurdsson MI,Saddic L,Heydarpour M,Chang TW,Shekar P,Aranki S,Couper GS,Shernan SK,Seidman JG,Body SC,Muehlschlegel JD

    更新日期:2016-12-06 00:00:00