Rare mutations in RINT1 predispose carriers to breast and Lynch Syndrome-spectrum cancers
- Daniel J Park1,
- Kayoko Tao2,
- Florence Le Calvez-Kelm3,
- Tu Nguyen-Dumont1,
- Nivonirina Robinot3,
- Fleur Hammet1,
- Fabrice Odefrey1,
- Helen Tsimiklis1,
- Zhi L Teo1,
- Louise B Thingholm1,
- Erin L Young2,
- Catherine Voegele3,
- Andrew Lonie4,
- Bernard J Pope4,
- Terrell C Roane5,
- Russell Bell6,
- Hao Hu7,
- _ Shankaracharya7,
- Chad D Huff7,
- Jonathan Ellis8,
- Jun Li8,
- Igor V Makunin8,
- Esther M. John9,
- Irene L. Andrulis10,
- Mary Beth Terry11,
- Mary Daly12,
- Saundra S. Buys13,
- Carrie Snyder14,
- Henry T Lynch14,
- Peter Devilee15,
- Graham G. Giles16,
- John L. Hopper17,
- Bing-Jian Feng13,
- Fabienne Lesueur3,
- Sean Tavtigian18,
- Melissa C. Southey1 and
- David E Goldgar13,*
+Author Affiliations
- ↵* Corresponding Author:
David E Goldgar, Huntsman Cancer Institute, University of Utah Health Sciences Center, 30 N. Medical Dr, Salt Lake City, UT, 84132, United States 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). Based on this finding, a population-based case-control mutation-screening study was conducted and identified 29 carriers of rare (MAF < 0.5%), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and 6 in 1,123 frequency-matched controls (OR=3.24, 95%CI 1.29-8.17; p=0.013). RINT1 mutation screening of probands from 798 multiple-case breast cancer families identified 4 additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women in RINT1-mutation carrying families estimated that carriers were at increased risks of Lynch syndrome-spectrum cancers (SIR 3.35, 95% CI 1.7-6.0; P=0.005), particularly for relatives diagnosed with cancer under age 60 years (SIR 10.9, 95%CI 4.7-21; P=0.0003).
- Received February 26, 2014.
- Revision received April 19, 2014.
- Accepted April 28, 2014.
- Copyright © 2014, American Association for Cancer Research.
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