Reevaluation of RINT1 as a breast cancer predisposition gene

• Published in: Breast cancer research and treatment 2016-09, Vol.159 (2), p.385-392
• Main Authors: Li, Na, Thompson, Ella R., Rowley, Simone M., McInerny, Simone, Devereux, Lisa, Goode, David, Investigators, LifePool, Wong-Brown, Michelle W., Scott, Rodney J., Trainer, Alison H., Gorringe, Kylie L., James, Paul A., Campbell, Ian G.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Breast cancer; Breast Neoplasms - genetics; Brief Report; Cancer genetics; Cancer research; Cell Cycle Proteins - genetics; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; Disease susceptibility; European Continental Ancestry Group - genetics; Female; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetic research; Humans; Medicine; Medicine & Public Health; Middle Aged; Mutation; Mutation Rate; Oncology; Penetrance; Risk factors; Sequence Analysis, DNA - methods; Young Adult
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-016-3944-3

Rad50 interactor 1 ( RINT1 ) has recently been reported as an intermediate-penetrance (odds ratio 3.24) breast cancer susceptibility gene, as well as a risk factor for Lynch syndrome. The coding regions and exon–intron boundaries of RINT1 were sequenced in 2024 familial breast cancer cases previously tested negative for BRCA1 , BRCA2 , and PALB2 mutations and 1886 population-matched cancer-free controls using HaloPlex Targeted Enrichment Assays. Only one RINT1 protein-truncating variant was detected in a control. No excess was observed in the total number of rare variants (truncating and missense) (28, 1.38 %, vs. 27, 1.43 %. P  > 0.999) or in the number of variants predicted to be pathogenic by various in silico tools (Condel, Polyphen2, SIFT, and CADD) in the cases compared to the controls. In addition, there was no difference in the incidence of classic Lynch syndrome cancers in RINT1 rare variant-carrying families compared to RINT1 wild-type families. This study had 90 % power to detect an odds ratio of at least 2.06, and the results do not provide any support for RINT1 being a moderate-penetrance breast cancer susceptibility gene, although larger studies will be required to exclude more modest effects. This study emphasizes the need for caution before designating a cancer predisposition role for any gene based on very rare truncating variants and in silico-predicted missense variants.