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Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility

Mantere, Tuomo ; Tervasmäki, Anna ; Nurmi, Anna ; Rapakko, Katrin ; Kauppila, Saila ; Tang, Jiangbo ; Schleutker, Johanna ; Kallioniemi, Anne ; Hartikainen, Jaana M and Mannermaa, Arto , et al. (2017) In Scientific Reports 7(1).
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... (More)

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.

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type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
7
issue
1
article number
766
publisher
Nature Publishing Group
external identifiers
  • pmid:28386063
  • scopus:85018442040
ISSN
2045-2322
DOI
10.1038/s41598-017-00766-9
language
English
LU publication?
yes
id
bb74b40d-9b24-459e-994e-02b4c4d4f259
date added to LUP
2017-05-17 08:50:37
date last changed
2024-03-31 09:50:06
@article{bb74b40d-9b24-459e-994e-02b4c4d4f259,
  abstract     = {{<p>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 &gt; 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.</p>}},
  author       = {{Mantere, Tuomo and Tervasmäki, Anna and Nurmi, Anna and Rapakko, Katrin and Kauppila, Saila and Tang, Jiangbo and Schleutker, Johanna and Kallioniemi, Anne and Hartikainen, Jaana M and Mannermaa, Arto and Nieminen, Pentti and Hanhisalo, Riitta and Lehto, Sini and Suvanto, Maija and Grip, Mervi and Jukkola-Vuorinen, Arja and Tengström, Maria and Auvinen, Päivi and Kvist, Anders and Borg, Åke and Blomqvist, Carl and Aittomäki, Kristiina and Greenberg, Roger A. and Winqvist, Robert and Nevanlinna, Heli and Pylkäs, Katri}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility}},
  url          = {{http://dx.doi.org/10.1038/s41598-017-00766-9}},
  doi          = {{10.1038/s41598-017-00766-9}},
  volume       = {{7}},
  year         = {{2017}},
}