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Reevaluation of RINT1 as a breast cancer predisposition gene

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Abstract

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.

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Abbreviations

RINT1:

Rad50 interactor 1

WES:

Whole exome sequencing

MAF:

Minor allele frequency

SNVs:

Single nucleotide variants

BRCAx families:

The hereditary breast cancer families with no known pathogenic variants

ExAC:

Exome Aggregation Consortium

WT:

Wild type

OR:

Odds ratio

Prob Dam:

Probably damaging

Poss Dam:

Possible damaging

Dele:

Deleterious

Neu:

Neutral

Toler:

Tolerated

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Acknowledgments

The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about.

Authors contribution

NL, IGC, PAJ, and AHT conceived of and designed the study. ERT, NL, LD, MWB, SM, PAJ, and SMR carried out experiments, acquired, and analyzed data. MWB, LD, SM, RJS, Lifepool Investigators, and PAJ provided data and samples. KLG interpreted data. DG performed the PCA analysis and extracted data from ExAC database. NL, IGC, PAJ, KLG, DG, AHT, and RJS were involved in drafting the manuscript, and all authors read and provided critical feedback on the manuscript.

Funding

This work was supported by the National Breast Cancer Foundation, Cancer Australia, the Victorian Cancer Agency, and the National Health and Medical Research Council of Australia.

Author information

Authors and Affiliations

  1. Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia

    Na Li, Ella R. Thompson, Simone M. Rowley, Lisa Devereux, David Goode, Alison H. Trainer, Kylie L. Gorringe, Paul A. James & Ian G. Campbell

  2. Cancer Biology Medical Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Na Li

  3. Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Ella R. Thompson

  4. Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Simone McInerny, Alison H. Trainer & Paul A. James

  5. LifePool, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Lisa Devereux & LifePool Investigators

  6. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia

    David Goode, Kylie L. Gorringe, Paul A. James & Ian G. Campbell

  7. Discipline of Medical Genetics and Centre for Information-Based Medicine, The University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia

    Michelle W. Wong-Brown & Rodney J. Scott

  8. Division of Molecular Medicine, Pathology North, Newcastle, NSW, Australia

    Rodney J. Scott

  9. Department of Pathology, University of Melbourne, Melbourne, VIC, Australia

    Alison H. Trainer, Paul A. James & Ian G. Campbell

Authors
  1. Na Li
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  2. Ella R. Thompson
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Corresponding author

Correspondence to Ian G. Campbell.

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Conflicts of interest

The authors have declared that they have no conflicts of interest.

Ethics approval and consent to participate

All participants gave informed consent for genetic testing, and the study was approved by the Human Research Ethics Committees at all participating centres.

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Li, N., Thompson, E.R., Rowley, S.M. et al. Reevaluation of RINT1 as a breast cancer predisposition gene. Breast Cancer Res Treat 159, 385–392 (2016). https://doi.org/10.1007/s10549-016-3944-3

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  • DOI: https://doi.org/10.1007/s10549-016-3944-3

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