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

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

1. Daniel J Park1, 
2. Kayoko Tao2, 
3. Florence Le Calvez-Kelm3, 
4. Tu Nguyen-Dumont1,
5. Nivonirina Robinot3, 
6. Fleur Hammet1, 
7. Fabrice Odefrey1, 
8. Helen Tsimiklis1,
9. Zhi L Teo1, 
10. Louise B Thingholm1, 
11. Erin L Young2, 
12. Catherine Voegele3,
13. Andrew Lonie4, 
14. Bernard J Pope4, 
15. Terrell C Roane5, 
16. Russell Bell6, 
17. Hao Hu7,
18. _ Shankaracharya7, 
19. Chad D Huff7, 
20. Jonathan Ellis8, 
21. Jun Li8, 
22. Igor V Makunin8,
23. Esther M. John9, 
24. Irene L. Andrulis10, 
25. Mary Beth Terry11, 
26. Mary Daly12,
27. Saundra S. Buys13, 
28. Carrie Snyder14, 
29. Henry T Lynch14, 
30. Peter Devilee15,
31. Graham G. Giles16, 
32. John L. Hopper17, 
33. Bing-Jian Feng13, 
34. Fabienne Lesueur3,
35. Sean Tavtigian18, 
36. Melissa C. Southey1 and 
37. David E Goldgar13,*

+Author Affiliations

1. ¹Genetic Epidemiology Laboratory, The University of Melbourne
2. ²Oncological Sciences, University of Utah School of Medicine
3. ³Genetic Cancer Susceptibility Group, International Agency for Research on Cancer
4. ⁴Victorian Life Sciences Computation Initiative, The University of Melbourne
5. ⁵Natural Sciences, University of Texas at Austin
6. ⁶Oncological Science, University of Utah School of Medicine
7. ⁷Epidemiology, The University of Texas M.D. Anderson Cancer Center
8. ⁸Cancer Genetics, The QIMR Berghofer Medical Research Institute
9. ⁹Epidemiology, Cancer Prevention Institute of California
10. ¹⁰Molecular Genetics, Mount Sinai Hospital
11. ¹¹Epidemiology, Columbia University
12. ¹²Clinical Genetics, Fox Chase Cancer Center
13. ¹³Huntsman Cancer Institute, University of Utah Health Sciences Center
14. ¹⁴Preventive Medicine, Creighton University
15. ¹⁵Human Genetics, Leiden University Medical Center
16. ¹⁶Centre for Cancer Epidemiology, The Cancer Council Victoria
17. ¹⁷Centre for Epidemiology and Biostatistics, The University of Melbourne
18. ¹⁸University of Utah School of Medicine, Oncological Sciences

1. ↵* 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.