title: Rare mutations in RINT1 predispose carriers to breast and Lynch syndrome-spectrum cancers.
abstract: Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome-sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del), and c.1207G>T (p.D403Y). On the basis of this finding, a population-based case-control mutation-screening study was conducted that identified 29 carriers of rare (minor allele frequency < 0.5%), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and six in 1,123 frequency-matched controls [OR, 3.24; 95% confidence interval (CI), 1.29-8.17; P = 0.013]. RINT1 mutation screening of probands from 798 multiple-case breast cancer families identified four additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women carrying RINT1 mutations estimated that carriers were at increased risk of Lynch syndrome-spectrum cancers [standardized incidence ratio (SIR), 3.35; 95% CI, 1.7-6.0; P = 0.005], particularly for relatives diagnosed with cancer under the age of 60 years (SIR, 10.9; 95% CI, 4.7-21; P = 0.0003).
  
  
  CONCLUSIONS
  The work described in this study adds RINT1 to the growing list of genes in which rare sequence variants are associated with intermediate levels of breast cancer risk. Given that RINT1 is also associated with a spectrum of cancers with mismatch repair defects, these findings have clinical applications and raise interesting biological questions.
authors: Genetic Epidemiology Laboratory, Department of Pathology;
authors: Daniel J
authors: DJ
authors: Park
authors: Oncological Sciences and.
authors: Kayoko
authors: K
authors: Tao
authors: Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon;
authors: Florence
authors: F
authors: Le Calvez-Kelm
authors: Genetic Epidemiology Laboratory, Department of Pathology;
authors: Tu
authors: T
authors: Nguyen-Dumont
authors: Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon;
authors: Nivonirina
authors: N
authors: Robinot
authors: Genetic Epidemiology Laboratory, Department of Pathology;
authors: Fleur
authors: F
authors: Hammet
authors: Genetic Epidemiology Laboratory, Department of Pathology;
authors: Fabrice
authors: F
authors: Odefrey
authors: Genetic Epidemiology Laboratory, Department of Pathology;
authors: Helen
authors: H
authors: Tsimiklis
authors: Genetic Epidemiology Laboratory, Department of Pathology;
authors: Zhi L
authors: ZL
authors: Teo
authors: Genetic Epidemiology Laboratory, Department of Pathology;
authors: Louise B
authors: LB
authors: Thingholm
authors: Oncological Sciences and.
authors: Erin L
authors: EL
authors: Young
authors: Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon;
authors: Catherine
authors: C
authors: Voegele
authors: Victorian Life Sciences Computation Initiative;
authors: Andrew
authors: A
authors: Lonie
authors: Department of Computing and Information Systems; Victorian Life Sciences Computation Initiative;
authors: Bernard J
authors: BJ
authors: Pope
authors: University of Texas at Austin, Austin;
authors: Terrell C
authors: TC
authors: Roane
authors: Oncological Sciences and.
authors: Russell
authors: R
authors: Bell
authors: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas;
authors: Hao
authors: H
authors: Hu
authors: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas;
authors: Shankaracharya
authors: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas;
authors: Chad D
authors: CD
authors: Huff
authors: The QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; Departments of.
authors: Jonathan
authors: J
authors: Ellis
authors: The QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; Departments of.
authors: Jun
authors: J
authors: Li
authors: The QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; Departments of.
authors: Igor V
authors: IV
authors: Makunin
authors: Cancer Prevention Institute of California, Fremont; Department of Health Research and Policy, Stanford Cancer Institute, Stanford, California;
authors: Esther M
authors: EM
authors: John
authors: Department of Molecular Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada;
authors: Irene L
authors: IL
authors: Andrulis
authors: Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York;
authors: Mary B
authors: MB
authors: Terry
authors: Fox Chase Cancer Center, Philadelphia, Pennsylvania;
authors: Mary
authors: M
authors: Daly
authors: Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah;
authors: Saundra S
authors: SS
authors: Buys
authors: Department of Preventive Medicine, Creighton University, Omaha, Nebraska;
authors: Carrie
authors: C
authors: Snyder
authors: Department of Preventive Medicine, Creighton University, Omaha, Nebraska;
authors: Henry T
authors: HT
authors: Lynch
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; and.
authors: Peter
authors: P
authors: Devilee
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne; Centre for Cancer Epidemiology, The Cancer Council Victoria, Carlton, Victoria;
authors: Graham G
authors: GG
authors: Giles
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne; School of Public Health, Seoul National University, Seoul, Korea.
authors: John L
authors: JL
authors: Hopper
authors: Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine; Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah;
authors: Bing-Jian
authors: BJ
authors: Feng
authors: Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon; Genetic Epidemiology of Cancer Team, Institut National de la Santé et de la Recherche Medicale (INSERM), U900, Institut Curie, Mines ParisTech, Paris, France;
authors: Fabienne
authors: F
authors: Lesueur
authors: Oncological Sciences and.
authors: Sean V
authors: SV
authors: Tavtigian
authors: Genetic Epidemiology Laboratory, Department of Pathology; msouthey@unimelb.edu.au david.goldgar@hsc.utah.edu.
authors: Melissa C
authors: MC
authors: Southey
authors: Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine; Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah; msouthey@unimelb.edu.au david.goldgar@hsc.utah.edu.
authors: David E
authors: DE
authors: Goldgar
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: D018797:Cell Cycle Proteins; C422909:RINT1 protein, human