Rare mutations in RINT1 predispose carriers to breast and lynch syndrome-Spectrum cancers

Daniel J. Park, Kayoko Tao, Florence Le Calvez-Kelm, Tu Nguyen-Dumont, Nivonirina Robinot, Fleur Hammet, Fabrice Odefrey, Helen Tsimiklis, Zhi L. Teo, Louise B. Thingholm, Erin L. Young, Catherine Voegele, Andrew Lonie, Bernard J. Pope, Terrell C. Roane, Russell Bell, Hao Hu, Shankaracharya, Chad D. Huff, Jonathan EllisJun Li, Igor V. Makunin, Esther M. John, Irene L. Andrulis, Mary B. Terry, Mary Daly, Saundra S. Buys, Carrie Snyder, Henry T. Lynch, Peter Devilee, Graham G. Giles, John L. Hopper, Bing Jian Feng, Fabienne Lesueur, Sean V. Tavtigian, Melissa C. Southey, David E. Goldgar

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


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% confi- dence interval (CI), 1.29-8.17; P = 0.013]. RINT1 mutation screening of probands from 798 multiplecase 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).

Original languageEnglish (US)
Pages (from-to)804-815
Number of pages12
JournalCancer Discovery
Issue number7
StatePublished - Jul 2014

All Science Journal Classification (ASJC) codes

  • Oncology


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