@article{01H7JM0R79WAX4MJG5D4WJ4JE8,
  abstract     = {{Purpose:
Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT).

Experimental Design:
We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1–CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls.

Results:
A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)–like (N = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results.

Conclusions:
We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.}},
  author       = {{Stolarova, Lenka and Kleiblova, Petra and Zemankova, Petra and Stastna, Barbora and Janatova, Marketa and Soukupova, Jana and Achatz, Maria Isabel and Ambrosone, Christine and Apostolou, Paraskevi and Arun, Banu K. and Auer, Paul and Barnard, Mollie and Bertelsen, Birgitte and Matsuda, Koichi and Kamatani, Yoichiro and Morisaki, Takayuki and Nagai, Akiko and Muto, Kaori and Murakami, Yoshinori and Furukawa, Yoichi and Yamanashi, Yuji and Nakamura, Yusuke and Mushiroda, Taisei and Momozawa, Yukihide and Tanaka, Toshihiro and Ohnishi, Yozo and Kubo, Michiaki and Higashiue, Shinichi and Kobayashi, Shuzo and Minami, Shiro and Yamaguhci, Hiroki and Arai, Hajime and Yamaji, Ken and Okazaki, Yasushi and Asai, Satoshi and Takahashi, Yasuo and Fujioka, Tomoaki and Obara, Wataru and Mori, Seijiro and Murayama, Shigeo and Nagayama, Satoshi and Miki, Yoshio and Masumoto, Akihide and Yamada, Akira and Nishizawa, Yasuko and Higashiyama, Masahiko and Kutsumi, Hiromu and Koretsune, Yukihiro and Yoshiyama, Takashi and Blok, Marinus J. and Boddicker, Nicholas and Brunet, Joan and Burnside, Elizabeth S. and Calvello, Mariarosaria and Campbell, Ian and Chan, Sock Hoai and Chen, Fei and Chiang, Jian Bang and Coppa, Anna and Cortesi, Laura and Crujeiras-González, Ana and Borecka, Marianna and Cerna, Marta and Hovhannisyan, Milena and Jelinkova, Sandra and Nehasil, Petr and Foretova, Lenka and Machackova, Eva and Krutilkova, Vera and Tavandzis, Spiros and Cerna, Leona and Chvojka, Stepan and Koudova, Monika and Puchmajerova, Alena and Havranek, Ondrej and Novotny, Jan and Vesela, Kamila and Vocka, Michal and Hruskova, Lucie and Michalovska, Renata and Schwetzova, Denisa and Vlckova, Zdenka and Cerna, Monika and Hejnalova, Marketa and Jedlickova, Nikol and Subrt, Ivan and Zavoral, Tomas and Kosarova, Marcela and Vacinova, Gabriela and Janikova, Maria and Kratochvilova, Romana and Curtisova, Vaclava and Vrtel, Radek and Scheinost, Ondrej and Duskova, Petra and Stranecky, Viktor and De Leeneer, Kim and De Putter, Robin and DePersia, Allison and Devereux, Lisa and Domchek, Susan and Efremidis, Anna and Engel, Christoph and Ernst, Corinna and Evans, D. Gareth R. and Feliubadaló, Lidia and Fostira, Florentia and Fuentes-Ríos, Olivia and Gómez-García, Encarna B. and González, Sara and Haiman, Christopher and Hansen, Thomas van Overeem and Hauke, Jan and Hodge, James and Hu, Chunling and Huang, Hongyan and Ishak, Nur Diana Binte and Iwasaki, Yusuke and Konstantopoulou, Irene and Kraft, Peter and Lacey, James and Lázaro, Conxi and Li, Na and Lim, Weng Khong and Lindstrom, Sara and Lori, Adriana and Martinez, Elana and Martins, Alexandra and Matsuda, Koichi and Matullo, Giuseppe and McInerny, Simone and Michailidou, Kyriaki and Montagna, Marco and Monteiro, Alvaro N.A. and Mori, Luigi and Nathanson, Katherine and Neuhausen, Susan L. and Nevanlinna, Heli and Olson, Janet E. and Palmer, Julie and Pasini, Barbara and Patel, Alpa and Piane, Maria and Poppe, Bruce and Radice, Paolo and Renieri, Alessandra and Resta, Nicoletta and Richardson, Marcy E. and Rosseel, Toon and Ruddy, Kathryn J. and Santamariña, Marta and Dos Santos, Elizabeth Santana and Teras, Lauren and Toland, Amanda E. and Trentham-Dietz, Amy and Vachon, Celine M. and Volk, Alexander E. and Weber-Lassalle, Nana and Weitzel, Jeffrey N. and Wiesmuller, Lisa and Winham, Stacey and Yadav, Siddhartha and Yannoukakos, Drakoulis and Yao, Song and Zampiga, Valentina and Zethoven, Magnus and Zhang, Ze Wen and Zima, Tomas and Spurdle, Amanda B. and Vega, Ana and Rossing, Maria and Del Valle, Jesús and De Nicolo, Arcangela and Hahnen, Eric and Claes, Kathleen and Ngeow, Joanne and Momozawa, Yukihide and James, Paul A. and Couch, Fergus J. and Macurek, Libor and Kleibl, Zdenek and Biobank Japan, [missing] and Consortium CZECANCA, [missing]}},
  issn         = {{1078-0432}},
  journal      = {{CLINICAL CANCER RESEARCH}},
  keywords     = {{Cancer Research,Oncology}},
  language     = {{eng}},
  number       = {{16}},
  pages        = {{3037--3050}},
  publisher    = {{American Association for Cancer Research (AACR)}},
  title        = {{ENIGMA CHEK2gether Project : a comprehensive study identifies functionally impaired CHEK2 germline missense variants associated with increased breast cancer risk}},
  url          = {{http://doi.org/10.1158/1078-0432.ccr-23-0212}},
  volume       = {{29}},
  year         = {{2023}},
}

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