Exome sequencing study of Russian breast cancer patients suggests a predisposing role for USP39



Germline variants in known breast cancer (BC) predisposing genes explain less than half of hereditary BC cases. This study aimed to identify missing genetic determinants of BC.


Whole exome sequencing (WES) of lymphocyte DNA was performed for 49 Russian patients with clinical signs of genetic BC predisposition, who lacked Slavic founder mutations in BRCA1, BRCA2, CHEK2, and NBS1 genes.


Bioinformatic analysis of WES data was allowed to compile a list of 229 candidate mutations. 79 of these mutations were subjected to a three-stage case–control analysis. The initial two stages, which involved up to 797 high-risk BC patients, 1504 consecutive BC cases, and 1081 healthy women, indicated a potentially BC-predisposing role for 6 candidates, i.e., USP39 c.*208G > C, PZP p.Arg680Ter, LEPREL1 p.Pro636Ser, SLIT3 p.Arg154Cys, CREB3 p.Lys157Glu, and ING1 p.Pro319Leu. USP39 c.*208G > C was strongly associated with triple-negative breast tumors (p = 0.0001). In the third replication stage, we genotyped the truncating variant of PZP (rs145240281) and the potential splice variant of USP39 (rs112653307) in three independent cohorts of Russian, Byelorussian, and German ancestry, comprising a total of 3216 cases and 2525 controls. The data obtained for USP39 rs112653307 supported the association identified in the initial stages (the combined OR 1.72, p = 0.035).


This study suggests the role of a rare splicing variant in BC susceptibility. USP39 encodes an ubiquitin-specific peptidase that regulates cancer-relevant tumor suppressors including CHEK2. Further epidemiological and functional studies involving these gene variants are warranted.

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Fig. 1
Fig. 2



Breast cancer


Whole exome sequencing


High resolution melting (HRM)


Allele-specific PCR




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Whole exome sequencing, bioinformatic analysis, and case–control validation studies have been supported by the Russian Science Foundation (Grant 19-15-00207), DST (Grant DST/INT/RUS/RSF/11), and the German Research Foundation (Grant Do761/10-1). The Hannover–Ufa Breast Cancer Study (HUBCS) was also supported by the Russian Foundation for Basic Research (Grants 17-44-020498, 17-29-06014 and 18-29-09129), the program for support of the bioresource collections (Grant N007-030164/2), and by the Ministry of Science and Higher Education of Russian Federation (Grant NAAAA-A16-116020350032-1).

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Correspondence to Ekaterina S. Kuligina.

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The study design was approved by the local Ethical Committee. All procedures performed in study were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Kuligina, E.S., Sokolenko, A.P., Bizin, I.V. et al. Exome sequencing study of Russian breast cancer patients suggests a predisposing role for USP39. Breast Cancer Res Treat 179, 731–742 (2020). https://doi.org/10.1007/s10549-019-05492-6

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  • Hereditary breast cancer
  • Non-BRCA1/2
  • Germline mutations
  • Whole exome sequencing
  • Case–control study