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Grant Details

Grant Number: 4R01CA163353-05 Interpret this number
Primary Investigator: Camp, Nicola
Organization: University Of Utah
Project Title: Shared Genomic Segment Analysis and Tumor Subtyping in High-Risk Brca Pedigrees
Fiscal Year: 2016
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Abstract

DESCRIPTION (provided by applicant): Breast cancer (BrCa) is the most frequently diagnosed cancer in women in the US (prevalence 2.6 million), poses a lifetime risk of 1 in 8, and has a death rate of ~40,000/year. About 10% of BrCa clusters in families (260,000 US women); however, >75% of heritable factors are unknown. The 'missing heritability' is thought to be, in part, due to rare inherited susceptibility variants. Our observations using a unique statewide genealogical and cancer database are consistent with this. Large high-risk pedigrees are accepted to be enriched for rare risk variants and a relevant study design to pursue them. The discovery of rare risk variants is important because they may have immediate relevance for the women carrying them. Furthermore, we hypothesize that more common, low- and moderate-risk variants will also exist in the genes identified. Hence, the identification of novel rare risk variants has the potential to provide immediate clinical impact as well as insight into susceptibility at the population-level and new directions for the field. Two major obstacles hinder rare risk variant discovery: a lack of powerful statistical methods for large pedigrees to identify genomic regions of importance; and genetic heterogeneity -both of which are especially challenging for common diseases, such as BrCa. Recently, we introduced shared genomic segment (SGS) methods which have been shown through simulation and proof-of-principle examples to have good power to identify chromosomal regions harboring rare risk variants in high-risk pedigrees. A regionally-guided strategy allows for efficient, focused sequencing and analysis efforts and strong filtering based on sharing. If, however, compelling regions cannot be identified, whole exome sequencing is a complementary strategy. Whether regional or whole exome, it is important that the cases sequenced in a pedigree share the underlying susceptibility variant/s. Membership in a high-risk pedigree certainly increases the likelihood for homogeneity; however, it is expected that other sources of heterogeneity will exist. We hypothesize that molecular tumor subtyping will be critical to identify more genetically homogeneous BrCa. Breast tumors are known to be heterogeneous in cellular and molecular make-up, and that this molecular heterogeneity can be reduced to four major tumor subtypes that have similar gene expression profiles based on 'intrinsic' gene sets. We will study 25 high-risk intrinsic-characterized BrCa pedigrees to identify rare BrCa risk variants and three follow-up cohorts (3,500 individuals) to identify lower-risk variants. Our massively-parallel sequencing efforts will follow a two-pronged approach, including regionally- guided and whole exome sequencing based on the existence of compelling shared regions. Our follow-up in independent cohorts is imperative for corroboration and to establish a broader understanding of how novel BrCa susceptibility genes more generally influence risk. In summary, we believe our research strategy is well- grounded, highly innovative and a powerful approach to identify new BrCa susceptibility variants.

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Publications

Predictors of Response Outcomes for Research Recruitment Through a Central Cancer Registry: Evidence From 17 Recruitment Efforts for Population-Based Studies.
Authors: Millar M.M. , Kinney A.Y. , Camp N.J. , Cannon-Albright L.A. , Hashibe M. , Penson D.F. , Kirchhoff A.C. , Neklason D.W. , Gilsenan A.W. , Dieck G.S. , et al. .
Source: American journal of epidemiology, 2019-05-01; 188(5), p. 928-939.
PMID: 30689685
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Re-interpretation of PAM50 gene expression as quantitative tumor dimensions shows utility for clinical trials: application to prognosis and response to paclitaxel in breast cancer.
Authors: Camp N.J. , Madsen M.J. , Herranz J. , Rodríguez-Lescure Á. , Ruiz A. , Martín M. , Bernard P.S. .
Source: Breast cancer research and treatment, 2019 May; 175(1), p. 129-139.
EPub date: 2019-01-23.
PMID: 30673970
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Reparameterization of PAM50 Expression Identifies Novel Breast Tumor Dimensions and Leads to Discovery of a Genome-Wide Significant Breast Cancer Locus at 12q15.
Authors: Madsen M.J. , Knight S. , Sweeney C. , Factor R. , Salama M. , Stijleman I.J. , Rajamanickam V. , Welm B.E. , Arunachalam S. , Jones B. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2018 06; 27(6), p. 644-652.
EPub date: 2018-04-12.
PMID: 29650789
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Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk.
Authors: Waller R.G. , Darlington T.M. , Wei X. , Madsen M.J. , Thomas A. , Curtin K. , Coon H. , Rajamanickam V. , Musinsky J. , Jayabalan D. , et al. .
Source: PLoS genetics, 2018 02; 14(2), p. e1007111.
EPub date: 2018-02-01.
PMID: 29389935
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Panel sequencing of 264 candidate susceptibility genes and segregation analysis in a cohort of non-BRCA1, non-BRCA2 breast cancer families.
Authors: Li J. , Li H. , Makunin I. , kConFab Investigators , Thompson B.A. , Tao K. , Young E.L. , Lopez J. , Camp N.J. , Tavtigian S.V. , et al. .
Source: Breast cancer research and treatment, 2017 Dec; 166(3), p. 937-949.
EPub date: 2017-08-24.
PMID: 28840378
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RNF4-Dependent Oncogene Activation by Protein Stabilization.
Authors: Thomas J.J. , Abed M. , Heuberger J. , Novak R. , Zohar Y. , Beltran Lopez A.P. , Trausch-Azar J.S. , Ilagan M.X.G. , Benhamou D. , Dittmar G. , et al. .
Source: Cell reports, 2016-09-20; 16(12), p. 3388-3400.
PMID: 27653698
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Whole transcriptome profiling of patient-derived xenograft models as a tool to identify both tumor and stromal specific biomarkers.
Authors: Bradford J.R. , Wappett M. , Beran G. , Logie A. , Delpuech O. , Brown H. , Boros J. , Camp N.J. , McEwen R. , Mazzola A.M. , et al. .
Source: Oncotarget, 2016-04-12; 7(15), p. 20773-87.
PMID: 26980748
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Thymic stromal lymphopoietin blocks early stages of breast carcinogenesis.
Authors: Demehri S. , Cunningham T.J. , Manivasagam S. , Ngo K.H. , Moradi Tuchayi S. , Reddy R. , Meyers M.A. , DeNardo D.G. , Yokoyama W.M. .
Source: The Journal of clinical investigation, 2016-04-01; 126(4), p. 1458-70.
EPub date: 2016-02-29.
PMID: 26927668
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Discordant Haplotype Sequencing Identifies Functional Variants at the 2q33 Breast Cancer Risk Locus.
Authors: Camp N.J. , Lin W.Y. , Bigelow A. , Burghel G.J. , Mosbruger T.L. , Parry M.A. , Waller R.G. , Rigas S.H. , Tai P.Y. , Berrett K. , et al. .
Source: Cancer research, 2016-04-01; 76(7), p. 1916-25.
EPub date: 2016-01-21.
PMID: 26795348
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Consensus Analysis of Whole Transcriptome Profiles from Two Breast Cancer Patient Cohorts Reveals Long Non-Coding RNAs Associated with Intrinsic Subtype and the Tumour Microenvironment.
Authors: Bradford J.R. , Cox A. , Bernard P. , Camp N.J. .
Source: PloS one, 2016; 11(9), p. e0163238.
EPub date: 2016-09-29.
PMID: 27685983
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Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.
Authors: Lin W.Y. , Camp N.J. , Ghoussaini M. , Beesley J. , Michailidou K. , Hopper J.L. , Apicella C. , Southey M.C. , Stone J. , Schmidt M.K. , et al. .
Source: Human molecular genetics, 2015-01-01; 24(1), p. 285-98.
EPub date: 2014-08-28.
PMID: 25168388
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Associations of ATR and CHEK1 single nucleotide polymorphisms with breast cancer.
Authors: Lin W.Y. , Brock I.W. , Connley D. , Cramp H. , Tucker R. , Slate J. , Reed M.W. , Balasubramanian S.P. , Cannon-Albright L.A. , Camp N.J. , et al. .
Source: PloS one, 2013; 8(7), p. e68578.
EPub date: 2013-07-03.
PMID: 23844225
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Pairwise shared genomic segment analysis in three Utah high-risk breast cancer pedigrees.
Authors: Cai Z. , Thomas A. , Teerlink C. , Farnham J.M. , Cannon-Albright L.A. , Camp N.J. .
Source: BMC genomics, 2012-11-28; 13, p. 676.
EPub date: 2012-11-28.
PMID: 23190577
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