Rare mutations in RINT1 predispose carriers to early-onset breast cancer. D. J. Park1, K. Tao2, F. Le Calvez-Kelm3, T. Nguyen-Dumont1, N. Robinot3, F. Hammet1, F. Odefrey1, H. Tsimiklis1, Z. L. Teo1, L. B. Thingholm1, C. Voegele3, A. Lonie4, B. J. Pope4, E. M. John5,6, I. L. Andrulis7, M. B. Terry8, M. Daly9, S. Buys10, G. G. Giles11, J. L. Hopper12, D. E. Goldgar13, F. Lesueur3, S. V. Tavtigian2, M. C. Southey1, Breast Cancer Family Registry, kConFab 1) Genetic Epidemiology Laboratory, The University of Melbourne, Victoria 3010, Australia; 2) Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; 3) Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, 69372 Lyon, France; 4) Victorian Life Sciences Computation Initiative, Carlton, Victoria 3010, Australia; 5) Cancer Prevention Institute of California, Fremont, CA 94538, USA; 6) Department of Health Research and Policy, Stanford Cancer Center Institute, Stanford, CA 94305, USA; 7) Department of Molecular Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; 8) Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA; 9) Fox Chase Cancer Center, Philadelphia, PA 19111, USA; 10) Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; 11) Centre for Cancer Epidemiology, The Cancer Council Victoria, Carlton, Victoria 3052, Australia; 12) Centre for Molecular, Environmental, Genetic, and Analytical Epidemiology, School of Population Health, The University of Melbourne, Victoria 3010, Australia; 13) Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.

   Whole-exome sequencing analysis of germline DNA from 93 people from 49 early-onset, multiple-case breast cancer families identified three mutations in RINT1 (NM_021930), each occurring in a separate family, and not present in the public sequencing databases: p.Q115X, p.M378del and p.D403Y. The latter two variants occurred at protein positions that are evolutionarily conserved. In the family harbouring p.Q115X, the mutation was carried by all of the four women who were affected with unilateral breast cancer and by a male relative affected by bladder and lung cancers.
   RINT1 was originally identified as a RAD50-interacting protein. It has since been demonstrated that RINT1 functions as a tumour suppressor that maintains Golgi dynamics and centrosome integrity. In addition, overexpression of truncated RINT1 has been shown to result in a defective radiation-induced G2/M checkpoint. Mice carrying only one functional copy of Rint1 spontaneously develop a variety of tumours including mammary adenocarcinomas at a combined rate of 81% (Lin et al., 2007), which is higher than the rate at which Brca1+/- mice spontaneously develop tumours (Jeng et al., 2007).
   Screening an additional 798 multiple-case breast cancer families identified six occurrences (each in different families) of very rare genetic variants (minor allele frequency (MAF) <0.5% in all public sequencing database populations): p.A138V (2), p.R256Q (1), p.P419R (1) and p.S462L (1), all predicted to be possibly pathogenic by PolyPhen2 or Align-GVGD in silico analysis; and c.1333+1G>A (1), which affects a splice donor core dinucleotide.
   To further assess the association of rare RINT1 genetic variants with breast cancer predisposition, we screened a population-based sample of 1313 women with early-onset breast cancer and 1123 age and ethnicity-matched controls. A total of 23 breast cancer cases were found to be carriers of rare (MAF < 0.5%), possibly pathogenic variants (in-frame insertion/deletion (2) or Align-GVGD grade >C0 missense variants (21)), compared with 6 controls found to carry variants that fulfilled these criteria (OR=3.32, 95%CI (1.31, 10.00); Fischers Exact Test P-value for the null hypothesis=0.0040). These data indicate that rare, evolutionarily unlikely genetic variants in RINT1 are associated with increased risk for early-onset breast cancer.

You may contact the first author (during and after the meeting) at