Mary B. Daly, Fabrice Odefrey, John L. Hopper, Andrew Lonie, Sean V. Tavtigian, Erin L. Young, Jun Li, Igor V. Makunin, Kayoko Tao, Hao Hu, Fleur Hammet, Graham G. Giles, Terrell C Roane, Jonathan Ellis, Russell Bell, Irene L. Andrulis, Nivonirina Robinot, Melissa C. Southey, Catherine Voegele, Carrie Snyder, Louise B. Thingholm, David E. Goldgar, Mary Beth Terry, Esther M. John, Daniel J. Park, Tu Nguyen-Dumont, Zhi Ling Teo, Shankaracharya, Henry T. Lynch, Bing Jian Feng, Saundra S. Buys, Fabienne Lesueur, Peter Devilee, Florence Le Calvez-Kelm, Helen Tsimiklis, Bernard J. Pope, and Chad D. Huff
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. Cancer Discov; 4(7); 804–15. ©2014 AACR. See related commentary by Ngeow and Eng, p. 762 This article is highlighted in the In This Issue feature, p. 745