Research ExplorerPublicationsENIGMA CHEK2gether Project: A Comprehensive Study Identifies...

ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk

Standard

ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk. / Stolarova, Lenka; Kleiblova, Petra; Zemankova, Petra; Stastna, Barbora; Janatova, Marketa; Soukupova, Jana; Achatz, Maria Isabel; Ambrosone, Christine; Apostolou, Paraskevi; Arun, Banu K; Auer, Paul; Barnard, Mollie; Bertelsen, Birgitte; Blok, Marinus J; Boddicker, Nicholas; Brunet, Joan; Burnside, Elizabeth S; Calvello, Mariarosaria; Campbell, Ian; Chan, Sock Hoai; Chen, Fei; Chiang, Jian Bang; Coppa, Anna; Cortesi, Laura; Crujeiras-González, Ana; De Leeneer, Kim; De Putter, Robin; DePersia, Allison; Devereux, Lisa; Domchek, Susan; Efremidis, Anna; Engel, Christoph; Ernst, Corinna; Evans, D Gareth R; Feliubadaló, Lidia; Fostira, Florentia; Fuentes-Ríos, Olivia; Gómez-García, Encarna B; González, Sara; Haiman, Christopher; Hansen, Thomas van Overeem; Hauke, Jan; Hodge, James; Hu, Chunling; Huang, Hongyan; Ishak, Nur Diana Binte; Iwasaki, Yusuke; Konstantopoulou, Irene; Kraft, Peter; Lacey, James; Lázaro, Conxi; Li, Na; Lim, Weng Khong; Lindstrom, Sara; Lori, Adriana; Martinez, Elana; Martins, Alexandra; Matsuda, Koichi; Matullo, Giuseppe; McInerny, Simone; Michailidou, Kyriaki; Montagna, Marco; Monteiro, Alvaro N A; Mori, Luigi; Nathanson, Katherine; Neuhausen, Susan L; Nevanlinna, Heli; Olson, Janet E; Palmer, Julie; Pasini, Barbara; Patel, Alpa; Piane, Maria; Poppe, Bruce; Radice, Paolo; Renieri, Alessandra; Resta, Nicoletta; Richardson, Marcy E; Rosseel, Toon; Ruddy, Kathryn J; Santamariña, Marta; Dos Santos, Elizabeth Santana; Teras, Lauren; Toland, Amanda E; Trentham-Dietz, Amy; Vachon, Celine M; Volk, Alexander E; Weber-Lassalle, Nana; Weitzel, Jeffrey N; Wiesmuller, Lisa; Winham, Stacey; Yadav, Siddhartha; Yannoukakos, Drakoulis; Yao, Song; Zampiga, Valentina; Zethoven, Magnus; Zhang, Ze Wen; Zima, Tomas; Spurdle, Amanda B; Vega, Ana; Rossing, Maria; Del Valle, Jesús; De Nicolo, Arcangela; Hahnen, Eric; Claes, Kathleen B M; Ngeow, Joanne; Biobank Japan; Momozawa, Yukihide; James, Paul A; Couch, Fergus J; Macurek, Libor; Kleibl, Zdenek.

In: CLIN CANCER RES, Vol. 29, No. 16, 15.08.2023, p. 3037-3050.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Stolarova, L, Kleiblova, P, Zemankova, P, Stastna, B, Janatova, M, Soukupova, J, Achatz, MI, Ambrosone, C, Apostolou, P, Arun, BK, Auer, P, Barnard, M, Bertelsen, B, Blok, MJ, Boddicker, N, Brunet, J, Burnside, ES, Calvello, M, Campbell, I, Chan, SH, Chen, F, Chiang, JB, Coppa, A, Cortesi, L, Crujeiras-González, A, De Leeneer, K, De Putter, R, DePersia, A, Devereux, L, Domchek, S, Efremidis, A, Engel, C, Ernst, C, Evans, DGR, Feliubadaló, L, Fostira, F, Fuentes-Ríos, O, Gómez-García, EB, González, S, Haiman, C, Hansen, TVO, Hauke, J, Hodge, J, Hu, C, Huang, H, Ishak, NDB, Iwasaki, Y, Konstantopoulou, I, Kraft, P, Lacey, J, Lázaro, C, Li, N, Lim, WK, Lindstrom, S, Lori, A, Martinez, E, Martins, A, Matsuda, K, Matullo, G, McInerny, S, Michailidou, K, Montagna, M, Monteiro, ANA, Mori, L, Nathanson, K, Neuhausen, SL, Nevanlinna, H, Olson, JE, Palmer, J, Pasini, B, Patel, A, Piane, M, Poppe, B, Radice, P, Renieri, A, Resta, N, Richardson, ME, Rosseel, T, Ruddy, KJ, Santamariña, M, Dos Santos, ES, Teras, L, Toland, AE, Trentham-Dietz, A, Vachon, CM, Volk, AE, Weber-Lassalle, N, Weitzel, JN, Wiesmuller, L, Winham, S, Yadav, S, Yannoukakos, D, Yao, S, Zampiga, V, Zethoven, M, Zhang, ZW, Zima, T, Spurdle, AB, Vega, A, Rossing, M, Del Valle, J, De Nicolo, A, Hahnen, E, Claes, KBM, Ngeow, J, Biobank Japan, Momozawa, Y, James, PA, Couch, FJ, Macurek, L & Kleibl, Z 2023, 'ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk', CLIN CANCER RES, vol. 29, no. 16, pp. 3037-3050. https://doi.org/10.1158/1078-0432.CCR-23-0212

APA

Stolarova, L., Kleiblova, P., Zemankova, P., Stastna, B., Janatova, M., Soukupova, J., Achatz, M. I., Ambrosone, C., Apostolou, P., Arun, B. K., Auer, P., Barnard, M., Bertelsen, B., Blok, M. J., Boddicker, N., Brunet, J., Burnside, E. S., Calvello, M., Campbell, I., ... Kleibl, Z. (2023). ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk. CLIN CANCER RES, 29(16), 3037-3050. https://doi.org/10.1158/1078-0432.CCR-23-0212

Vancouver

Stolarova L, Kleiblova P, Zemankova P, Stastna B, Janatova M, Soukupova J et al. ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk. CLIN CANCER RES. 2023 Aug 15;29(16):3037-3050. https://doi.org/10.1158/1078-0432.CCR-23-0212

Bibtex

@article{38faf4f5a4034009bcac86dfdbce6ac4,
title = "ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk",
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 = "Lenka Stolarova and Petra Kleiblova and Petra Zemankova and Barbora Stastna and Marketa Janatova and Jana Soukupova and Achatz, {Maria Isabel} and Christine Ambrosone and Paraskevi Apostolou and Arun, {Banu K} and Paul Auer and Mollie Barnard and Birgitte Bertelsen and Blok, {Marinus J} and Nicholas Boddicker and Joan Brunet and Burnside, {Elizabeth S} and Mariarosaria Calvello and Ian Campbell and Chan, {Sock Hoai} and Fei Chen and Chiang, {Jian Bang} and Anna Coppa and Laura Cortesi and Ana Crujeiras-Gonz{\'a}lez and {De Leeneer}, Kim and {De Putter}, Robin and Allison DePersia and Lisa Devereux and Susan Domchek and Anna Efremidis and Christoph Engel and Corinna Ernst and Evans, {D Gareth R} and Lidia Feliubadal{\'o} and Florentia Fostira and Olivia Fuentes-R{\'i}os and G{\'o}mez-Garc{\'i}a, {Encarna B} and Sara Gonz{\'a}lez and Christopher Haiman and Hansen, {Thomas van Overeem} and Jan Hauke and James Hodge and Chunling Hu and Hongyan Huang and Ishak, {Nur Diana Binte} and Yusuke Iwasaki and Irene Konstantopoulou and Peter Kraft and James Lacey and Conxi L{\'a}zaro and Na Li and Lim, {Weng Khong} and Sara Lindstrom and Adriana Lori and Elana Martinez and Alexandra Martins and Koichi Matsuda and Giuseppe Matullo and Simone McInerny and Kyriaki Michailidou and Marco Montagna and Monteiro, {Alvaro N A} and Luigi Mori and Katherine Nathanson and Neuhausen, {Susan L} and Heli Nevanlinna and Olson, {Janet E} and Julie Palmer and Barbara Pasini and Alpa Patel and Maria Piane and Bruce Poppe and Paolo Radice and Alessandra Renieri and Nicoletta Resta and Richardson, {Marcy E} and Toon Rosseel and Ruddy, {Kathryn J} and Marta Santamari{\~n}a and {Dos Santos}, {Elizabeth Santana} and Lauren Teras and Toland, {Amanda E} and Amy Trentham-Dietz and Vachon, {Celine M} and Volk, {Alexander E} and Nana Weber-Lassalle and Weitzel, {Jeffrey N} and Lisa Wiesmuller and Stacey Winham and Siddhartha Yadav and Drakoulis Yannoukakos and Song Yao and Valentina Zampiga and Magnus Zethoven and Zhang, {Ze Wen} and Tomas Zima and Spurdle, {Amanda B} and Ana Vega and Maria Rossing and {Del Valle}, Jes{\'u}s and {De Nicolo}, Arcangela and Eric Hahnen and Claes, {Kathleen B M} and Joanne Ngeow and {Biobank Japan} and Yukihide Momozawa and James, {Paul A} and Couch, {Fergus J} and Libor Macurek and Zdenek Kleibl",
note = "{\textcopyright}2023 The Authors; Published by the American Association for Cancer Research.",
year = "2023",
month = aug,
day = "15",
doi = "10.1158/1078-0432.CCR-23-0212",
language = "English",
volume = "29",
pages = "3037--3050",
journal = "CLIN CANCER RES",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "16",

}

RIS

TY - JOUR

T1 - ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk

AU - Stolarova, Lenka

AU - Kleiblova, Petra

AU - Zemankova, Petra

AU - Stastna, Barbora

AU - Janatova, Marketa

AU - Soukupova, Jana

AU - Achatz, Maria Isabel

AU - Ambrosone, Christine

AU - Apostolou, Paraskevi

AU - Arun, Banu K

AU - Auer, Paul

AU - Barnard, Mollie

AU - Bertelsen, Birgitte

AU - Blok, Marinus J

AU - Boddicker, Nicholas

AU - Brunet, Joan

AU - Burnside, Elizabeth S

AU - Calvello, Mariarosaria

AU - Campbell, Ian

AU - Chan, Sock Hoai

AU - Chen, Fei

AU - Chiang, Jian Bang

AU - Coppa, Anna

AU - Cortesi, Laura

AU - Crujeiras-González, Ana

AU - De Leeneer, Kim

AU - De Putter, Robin

AU - DePersia, Allison

AU - Devereux, Lisa

AU - Domchek, Susan

AU - Efremidis, Anna

AU - Engel, Christoph

AU - Ernst, Corinna

AU - Evans, D Gareth R

AU - Feliubadaló, Lidia

AU - Fostira, Florentia

AU - Fuentes-Ríos, Olivia

AU - Gómez-García, Encarna B

AU - González, Sara

AU - Haiman, Christopher

AU - Hansen, Thomas van Overeem

AU - Hauke, Jan

AU - Hodge, James

AU - Hu, Chunling

AU - Huang, Hongyan

AU - Ishak, Nur Diana Binte

AU - Iwasaki, Yusuke

AU - Konstantopoulou, Irene

AU - Kraft, Peter

AU - Lacey, James

AU - Lázaro, Conxi

AU - Li, Na

AU - Lim, Weng Khong

AU - Lindstrom, Sara

AU - Lori, Adriana

AU - Martinez, Elana

AU - Martins, Alexandra

AU - Matsuda, Koichi

AU - Matullo, Giuseppe

AU - McInerny, Simone

AU - Michailidou, Kyriaki

AU - Montagna, Marco

AU - Monteiro, Alvaro N A

AU - Mori, Luigi

AU - Nathanson, Katherine

AU - Neuhausen, Susan L

AU - Nevanlinna, Heli

AU - Olson, Janet E

AU - Palmer, Julie

AU - Pasini, Barbara

AU - Patel, Alpa

AU - Piane, Maria

AU - Poppe, Bruce

AU - Radice, Paolo

AU - Renieri, Alessandra

AU - Resta, Nicoletta

AU - Richardson, Marcy E

AU - Rosseel, Toon

AU - Ruddy, Kathryn J

AU - Santamariña, Marta

AU - Dos Santos, Elizabeth Santana

AU - Teras, Lauren

AU - Toland, Amanda E

AU - Trentham-Dietz, Amy

AU - Vachon, Celine M

AU - Volk, Alexander E

AU - Weber-Lassalle, Nana

AU - Weitzel, Jeffrey N

AU - Wiesmuller, Lisa

AU - Winham, Stacey

AU - Yadav, Siddhartha

AU - Yannoukakos, Drakoulis

AU - Yao, Song

AU - Zampiga, Valentina

AU - Zethoven, Magnus

AU - Zhang, Ze Wen

AU - Zima, Tomas

AU - Spurdle, Amanda B

AU - Vega, Ana

AU - Rossing, Maria

AU - Del Valle, Jesús

AU - De Nicolo, Arcangela

AU - Hahnen, Eric

AU - Claes, Kathleen B M

AU - Ngeow, Joanne

AU - Biobank Japan

AU - Momozawa, Yukihide

AU - James, Paul A

AU - Couch, Fergus J

AU - Macurek, Libor

AU - Kleibl, Zdenek

N1 - ©2023 The Authors; Published by the American Association for Cancer Research.

PY - 2023/8/15

Y1 - 2023/8/15

N2 - 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.

AB - 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.

U2 - 10.1158/1078-0432.CCR-23-0212

DO - 10.1158/1078-0432.CCR-23-0212

M3 - SCORING: Journal article

C2 - 37449874

VL - 29

SP - 3037

EP - 3050

JO - CLIN CANCER RES

JF - CLIN CANCER RES

SN - 1078-0432

IS - 16

ER -