Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility
Abstract Several known breast cancer susceptibility genes encode proteins involved in DNA damage response (DDR) and are characterized by rare loss-of-function mutations. However, these explain less than half of the familial cases. To identify novel susceptibility factors, 39 rare truncating mutation...
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2017
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oai:doaj.org-article:b72aaf16c63e42cd88fb7a2a6ef6294a2021-12-02T16:07:47ZCase-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility10.1038/s41598-017-00766-92045-2322https://doaj.org/article/b72aaf16c63e42cd88fb7a2a6ef6294a2017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00766-9https://doaj.org/toc/2045-2322Abstract Several known breast cancer susceptibility genes encode proteins involved in DNA damage response (DDR) and are characterized by rare loss-of-function mutations. However, these explain less than half of the familial cases. To identify novel susceptibility factors, 39 rare truncating mutations, identified in 189 Northern Finnish hereditary breast cancer patients in parallel sequencing of 796 DDR genes, were studied for disease association. Mutation screening was performed for Northern Finnish breast cancer cases (n = 578–1565) and controls (n = 337–1228). Mutations showing potential cancer association were analyzed in additional Finnish cohorts. c.7253dupT in TEX15, encoding a DDR factor important in meiosis, associated with hereditary breast cancer (p = 0.018) and likely represents a Northern Finnish founder mutation. A deleterious c.2715 + 1G > A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined Finnish hereditary cohort compared to controls. A deletion (c.640_644del5) in RNF168, causative for recessive RIDDLE syndrome, had high prevalence in majority of the analyzed cohorts, but did not associate with breast cancer. In conclusion, truncating variants in TEX15 and FANCD2 are potential breast cancer risk factors, warranting further investigations in other populations. Furthermore, high frequency of RNF168 c.640_644del5 indicates the need for its testing in Finnish patients with RIDDLE syndrome symptoms.Tuomo MantereAnna TervasmäkiAnna NurmiKatrin RapakkoSaila KauppilaJiangbo TangJohanna SchleutkerAnne KallioniemiJaana M. HartikainenArto MannermaaPentti NieminenRiitta HanhisaloSini LehtoMaija SuvantoMervi GripArja Jukkola-VuorinenMaria TengströmPäivi AuvinenAnders KvistÅke BorgCarl BlomqvistKristiina AittomäkiRoger A. GreenbergRobert WinqvistHeli NevanlinnaKatri PylkäsNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017) |
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Medicine R Science Q Tuomo Mantere Anna Tervasmäki Anna Nurmi Katrin Rapakko Saila Kauppila Jiangbo Tang Johanna Schleutker Anne Kallioniemi Jaana M. Hartikainen Arto Mannermaa Pentti Nieminen Riitta Hanhisalo Sini Lehto Maija Suvanto Mervi Grip Arja Jukkola-Vuorinen Maria Tengström Päivi Auvinen Anders Kvist Åke Borg Carl Blomqvist Kristiina Aittomäki Roger A. Greenberg Robert Winqvist Heli Nevanlinna Katri Pylkäs Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility |
| description |
Abstract Several known breast cancer susceptibility genes encode proteins involved in DNA damage response (DDR) and are characterized by rare loss-of-function mutations. However, these explain less than half of the familial cases. To identify novel susceptibility factors, 39 rare truncating mutations, identified in 189 Northern Finnish hereditary breast cancer patients in parallel sequencing of 796 DDR genes, were studied for disease association. Mutation screening was performed for Northern Finnish breast cancer cases (n = 578–1565) and controls (n = 337–1228). Mutations showing potential cancer association were analyzed in additional Finnish cohorts. c.7253dupT in TEX15, encoding a DDR factor important in meiosis, associated with hereditary breast cancer (p = 0.018) and likely represents a Northern Finnish founder mutation. A deleterious c.2715 + 1G > A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined Finnish hereditary cohort compared to controls. A deletion (c.640_644del5) in RNF168, causative for recessive RIDDLE syndrome, had high prevalence in majority of the analyzed cohorts, but did not associate with breast cancer. In conclusion, truncating variants in TEX15 and FANCD2 are potential breast cancer risk factors, warranting further investigations in other populations. Furthermore, high frequency of RNF168 c.640_644del5 indicates the need for its testing in Finnish patients with RIDDLE syndrome symptoms. |
| format |
article |
| author |
Tuomo Mantere Anna Tervasmäki Anna Nurmi Katrin Rapakko Saila Kauppila Jiangbo Tang Johanna Schleutker Anne Kallioniemi Jaana M. Hartikainen Arto Mannermaa Pentti Nieminen Riitta Hanhisalo Sini Lehto Maija Suvanto Mervi Grip Arja Jukkola-Vuorinen Maria Tengström Päivi Auvinen Anders Kvist Åke Borg Carl Blomqvist Kristiina Aittomäki Roger A. Greenberg Robert Winqvist Heli Nevanlinna Katri Pylkäs |
| author_facet |
Tuomo Mantere Anna Tervasmäki Anna Nurmi Katrin Rapakko Saila Kauppila Jiangbo Tang Johanna Schleutker Anne Kallioniemi Jaana M. Hartikainen Arto Mannermaa Pentti Nieminen Riitta Hanhisalo Sini Lehto Maija Suvanto Mervi Grip Arja Jukkola-Vuorinen Maria Tengström Päivi Auvinen Anders Kvist Åke Borg Carl Blomqvist Kristiina Aittomäki Roger A. Greenberg Robert Winqvist Heli Nevanlinna Katri Pylkäs |
| author_sort |
Tuomo Mantere |
| title |
Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility |
| title_short |
Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility |
| title_full |
Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility |
| title_fullStr |
Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility |
| title_full_unstemmed |
Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility |
| title_sort |
case-control analysis of truncating mutations in dna damage response genes connects tex15 and fancd2 with hereditary breast cancer susceptibility |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/b72aaf16c63e42cd88fb7a2a6ef6294a |
| work_keys_str_mv |
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