title: Loss of LRIG1 locus increases risk of early and late relapse of stage I/II breast cancer.
abstract: Gains and losses at chromosome 3p12-21 are common in breast tumors and associated with patient outcomes. We hypothesized that the LRIG1 gene at 3p14.1, whose product functions in ErbB-family member degradation, is a critical tumor modifier at this locus. We analyzed 971 stage I/II breast tumors using Affymetrix Oncoscan molecular inversion probe arrays that include 12 probes located within LRIG1. Copy number results were validated against gene expression data available in the public database. By partitioning the LRIG1 probes nearest exon 12/13, we confirm a breakpoint in the gene and show that gains and losses in the subregions differ by tumor and patient characteristics including race/ethnicity. In analyses adjusted for known prognostic factors, loss of LRIG1 was independently associated with risk of any relapse (HR, 1.90; 95% CI, 1.32-2.73), relapse≥5 years (HR, 2.39; 95% CI, 1.31-4.36), and death (HR, 1.55; 95% CI, 1.11-2.16). Analyses of copy number across chromosome 3, as well as expression data from pooled, publicly available datasets, corroborated the hypothesis of an elevated and persistent risk among cases with loss of or low LRIG1. We concluded that loss/low expression of LRIG1 is an independent risk factor for breast cancer metastasis and death in stage I/II patients. Increased hazard in patients with loss/low LRIG1 persists years after diagnosis, suggesting that LRIG1 is acting as a critical suppressor of tumor metastasis and is an early clinical indicator of risk for late recurrences in otherwise low-risk patients.
authors.affiliation: Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden PThompson@azcc.arizona.edu mbondy@bcm.edu.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Thompson
authors.affiliation: Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Ljuslinder
authors.affiliation: Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden.
authors.forename: Spyros
authors.initials: S
authors.lastname: Tsavachidis
authors.affiliation: Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden.
authors.forename: Abenaa
authors.initials: A
authors.lastname: Brewster
authors.affiliation: Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden.
authors.forename: Aysegul
authors.initials: A
authors.lastname: Sahin
authors.affiliation: Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Hedman
authors.affiliation: Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden.
authors.forename: Roger
authors.initials: R
authors.lastname: Henriksson
authors.affiliation: Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden PThompson@azcc.arizona.edu mbondy@bcm.edu.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Bondy
authors.affiliation: Authors' Affiliations: Department of Cellular and Molecular Medicine, The University of Arizona Cancer Center, Tucson, Arizona; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza; Dan L. Duncan Center, Baylor College of Medicine; Departments of Clinical Cancer Prevention and Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Radiation Sciences, Umeå University, Sweden.
authors.forename: Beatrice S
authors.initials: BS
authors.lastname: Melin
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002893:Chromosomes, Human, Pair 3; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging
chemical_list: C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins