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Cancer Discov. 2014 Jul;4(7):804-15. doi: 10.1158/2159-8290.CD-14-0212. Epub 2014 May 2.

Rare mutations in RINT1 predispose carriers to breast and Lynch syndrome-spectrum cancers.

Author information

1
Genetic Epidemiology Laboratory, Department of Pathology;
2
Oncological Sciences and.
3
Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon;
4
Victorian Life Sciences Computation Initiative;
5
Department of Computing and Information Systems; Victorian Life Sciences Computation Initiative;
6
University of Texas at Austin, Austin;
7
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas;
8
The QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; Departments of.
9
Cancer Prevention Institute of California, Fremont; Department of Health Research and Policy, Stanford Cancer Institute, Stanford, California;
10
Department of Molecular Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada;
11
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York;
12
Fox Chase Cancer Center, Philadelphia, Pennsylvania;
13
Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah;
14
Department of Preventive Medicine, Creighton University, Omaha, Nebraska;
15
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; and.
16
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;
17
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.
18
Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine; Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah;
19
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;
20
Genetic Epidemiology Laboratory, Department of Pathology; msouthey@unimelb.edu.au david.goldgar@hsc.utah.edu.
21
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.

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).

SIGNIFICANCE:

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.

PMID:
25050558
PMCID:
PMC4234633
DOI:
10.1158/2159-8290.CD-14-0212
[Indexed for MEDLINE]
Free PMC Article

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