Importance: Germline CHEK2 pathogenic variants (PVs) are frequently detected by multigene cancer panel testing (MGPT), but our understanding of PVs beyond c.1100del has been limited. Objective: To compare cancer phenotypes of frequent CHEK2 PVs individually and collectively by variant type. Design, Setting, and Participants: This retrospective cohort study was carried out in a single diagnostic testing laboratory from 2012 to 2019. Overall, 3783 participants with CHEK2 PVs identified via MGPT were included. Medical histories of cancer in participants with frequent PVs, negative MGPT (wild type), loss-of-function (LOF), and missense were compared. Main Outcomes and Measures: Participants were stratified by CHEK2 PV type. Descriptive statistics were summarized including median (IQR) for continuous variables and proportions for categorical characteristics. Differences in age and proportions were assessed with Wilcoxon rank sum and Fisher exact tests, respectively. Frequencies, odds ratios (ORs), 95% confidence intervals were calculated, and P values were corrected for multiple comparisons where appropriate. Results: Of the 3783 participants with CHEK2 PVs, 3473 (92%) were female and most reported White race. Breast cancer was less frequent in participants with p.I157T (OR, 0.66; 95% CI, 0.56-0.78; P<.001), p.S428F (OR, 0.59; 95% CI. 0.46-0.76; P<.001), and p.T476M (OR, 0.74; 95% CI, 0.56-0.98; P = .04) PVs compared with other PVs and an association with nonbreast cancers was not found. Following the exclusion of p.I157T, p.S428F, and p.T476M, participants with monoallelic CHEK2 PV had a younger age at first cancer diagnosis (P < .001) and were more likely to have breast (OR, 1.83; 95% CI, 1.66-2.02; P < .001), thyroid (OR, 1.63; 95% CI, 1.26-2.08; P < .001), and kidney cancer (OR, 2.57; 95% CI, 1.75-3.68; P < .001) than the wild-type cohort. Participants with a CHEK2 PV were less likely to have a diagnosis of colorectal cancer (OR, 0.62; 95% CI, 0.51-0.76; P < .001) compared with those in the wild-type cohort. There were no significant differences between frequent CHEK2 PVs and c.1100del and no differences between CHEK2 missense and LOF PVs. Conclusions and Relevance: CHEK2 PVs, with few exceptions (p.I157T, p.S428F, and p.T476M), were associated with similar cancer phenotypes irrespective of variant type. CHEK2 PVs were not associated with colorectal cancer, but were associated with breast, kidney, and thyroid cancers. Compared with other CHEK2 PVs, the frequent p.I157T, p.S428F, and p.T476M alleles have an attenuated association with breast cancer and were not associated with nonbreast cancers. These data may inform the genetic counseling and care of individuals with CHEK2 PVs.
Importance: Germline CHEK2 pathogenic variants (PVs) are frequently detected by multigene cancer panel testing (MGPT), but our understanding of PVs beyond c.1100del has been limited. Objective: To compare cancer phenotypes of frequent CHEK2 PVs individually and collectively by variant type. Design, Setting, and Participants: This retrospective cohort study was carried out in a single diagnostic testing laboratory from 2012 to 2019. Overall, 3783 participants with CHEK2 PVs identified via MGPT were included. Medical histories of cancer in participants with frequent PVs, negative MGPT (wild type), loss-of-function (LOF), and missense were compared. Main Outcomes and Measures: Participants were stratified by CHEK2 PV type. Descriptive statistics were summarized including median (IQR) for continuous variables and proportions for categorical characteristics. Differences in age and proportions were assessed with Wilcoxon rank sum and Fisher exact tests, respectively. Frequencies, odds ratios (ORs), 95% confidence intervals were calculated, and P values were corrected for multiple comparisons where appropriate. Results: Of the 3783 participants with CHEK2 PVs, 3473 (92%) were female and most reported White race. Breast cancer was less frequent in participants with p.I157T (OR, 0.66; 95% CI, 0.56-0.78; P<.001), p.S428F (OR, 0.59; 95% CI. 0.46-0.76; P<.001), and p.T476M (OR, 0.74; 95% CI, 0.56-0.98; P = .04) PVs compared with other PVs and an association with nonbreast cancers was not found. Following the exclusion of p.I157T, p.S428F, and p.T476M, participants with monoallelic CHEK2 PV had a younger age at first cancer diagnosis (P < .001) and were more likely to have breast (OR, 1.83; 95% CI, 1.66-2.02; P < .001), thyroid (OR, 1.63; 95% CI, 1.26-2.08; P < .001), and kidney cancer (OR, 2.57; 95% CI, 1.75-3.68; P < .001) than the wild-type cohort. Participants with a CHEK2 PV were less likely to have a diagnosis of colorectal cancer (OR, 0.62; 95% CI, 0.51-0.76; P < .001) compared with those in the wild-type cohort. There were no significant differences between frequent CHEK2 PVs and c.1100del and no differences between CHEK2 missense and LOF PVs. Conclusions and Relevance: CHEK2 PVs, with few exceptions (p.I157T, p.S428F, and p.T476M), were associated with similar cancer phenotypes irrespective of variant type. CHEK2 PVs were not associated with colorectal cancer, but were associated with breast, kidney, and thyroid cancers. Compared with other CHEK2 PVs, the frequent p.I157T, p.S428F, and p.T476M alleles have an attenuated association with breast cancer and were not associated with nonbreast cancers. These data may inform the genetic counseling and care of individuals with CHEK2 PVs.
Authors: S B Lee; S H Kim; D W Bell; D C Wahrer; T A Schiripo; M M Jorczak; D C Sgroi; J E Garber; F P Li; K E Nichols; J M Varley; A K Godwin; K M Shannon; E Harlow; D A Haber Journal: Cancer Res Date: 2001-11-15 Impact factor: 12.701
Authors: Nilah M Ioannidis; Joseph H Rothstein; Vikas Pejaver; Sumit Middha; Shannon K McDonnell; Saurabh Baheti; Anthony Musolf; Qing Li; Emily Holzinger; Danielle Karyadi; Lisa A Cannon-Albright; Craig C Teerlink; Janet L Stanford; William B Isaacs; Jianfeng Xu; Kathleen A Cooney; Ethan M Lange; Johanna Schleutker; John D Carpten; Isaac J Powell; Olivier Cussenot; Geraldine Cancel-Tassin; Graham G Giles; Robert J MacInnis; Christiane Maier; Chih-Lin Hsieh; Fredrik Wiklund; William J Catalona; William D Foulkes; Diptasri Mandal; Rosalind A Eeles; Zsofia Kote-Jarai; Carlos D Bustamante; Daniel J Schaid; Trevor Hastie; Elaine A Ostrander; Joan E Bailey-Wilson; Predrag Radivojac; Stephen N Thibodeau; Alice S Whittemore; Weiva Sieh Journal: Am J Hum Genet Date: 2016-09-22 Impact factor: 11.025
Authors: Mary B Daly; Robert Pilarski; Matthew B Yurgelun; Michael P Berry; Saundra S Buys; Patricia Dickson; Susan M Domchek; Ahmed Elkhanany; Susan Friedman; Judy E Garber; Michael Goggins; Mollie L Hutton; Seema Khan; Catherine Klein; Wendy Kohlmann; Allison W Kurian; Christine Laronga; Jennifer K Litton; Julie S Mak; Carolyn S Menendez; Sofia D Merajver; Barbara S Norquist; Kenneth Offit; Tuya Pal; Holly J Pederson; Gwen Reiser; Kristen Mahoney Shannon; Kala Visvanathan; Jeffrey N Weitzel; Myra J Wick; Kari B Wisinski; Mary A Dwyer; Susan D Darlow Journal: J Natl Compr Canc Netw Date: 2020-04 Impact factor: 11.908
Authors: Sue Richards; Nazneen Aziz; Sherri Bale; David Bick; Soma Das; Julie Gastier-Foster; Wayne W Grody; Madhuri Hegde; Elaine Lyon; Elaine Spector; Karl Voelkerding; Heidi L Rehm Journal: Genet Med Date: 2015-03-05 Impact factor: 8.822
Authors: Maren Weischer; Børge G Nordestgaard; Paul Pharoah; Manjeet K Bolla; Heli Nevanlinna; Laura J Van't Veer; Montserrat Garcia-Closas; John L Hopper; Per Hall; Irene L Andrulis; Peter Devilee; Peter A Fasching; Hoda Anton-Culver; Diether Lambrechts; Maartje Hooning; Angela Cox; Graham G Giles; Barbara Burwinkel; Annika Lindblom; Fergus J Couch; Arto Mannermaa; Grethe Grenaker Alnæs; Esther M John; Thilo Dörk; Henrik Flyger; Alison M Dunning; Qin Wang; Taru A Muranen; Richard van Hien; Jonine Figueroa; Melissa C Southey; Kamila Czene; Julia A Knight; Rob A E M Tollenaar; Matthias W Beckmann; Argyrios Ziogas; Marie-Rose Christiaens; Johanna Margriet Collée; Malcolm W R Reed; Gianluca Severi; Frederik Marme; Sara Margolin; Janet E Olson; Veli-Matti Kosma; Vessela N Kristensen; Alexander Miron; Natalia Bogdanova; Mitul Shah; Carl Blomqvist; Annegien Broeks; Mark Sherman; Kelly-Anne Phillips; Jingmei Li; Jianjun Liu; Gord Glendon; Caroline Seynaeve; Arif B Ekici; Karin Leunen; Mieke Kriege; Simon S Cross; Laura Baglietto; Christof Sohn; Xianshu Wang; Vesa Kataja; Anne-Lise Børresen-Dale; Andreas Meyer; Douglas F Easton; Marjanka K Schmidt; Stig E Bojesen Journal: J Clin Oncol Date: 2012-10-29 Impact factor: 44.544
Authors: Shannon Gallagher; Elisha Hughes; Allison W Kurian; Susan M Domchek; Judy Garber; Braden Probst; Brian Morris; Placede Tshiaba; Stephanie Meek; Eric Rosenthal; Benjamin Roa; Thomas P Slavin; Susanne Wagner; Jeffrey Weitzel; Alexander Gutin; Jerry S Lanchbury; Mark Robson Journal: JCO Precis Oncol Date: 2021-06-24
Authors: Taru A Muranen; Carl Blomqvist; Thilo Dörk; Anna Jakubowska; Päivi Heikkilä; Rainer Fagerholm; Dario Greco; Kristiina Aittomäki; Stig E Bojesen; Mitul Shah; Alison M Dunning; Valerie Rhenius; Per Hall; Kamila Czene; Judith S Brand; Hatef Darabi; Jenny Chang-Claude; Anja Rudolph; Børge G Nordestgaard; Fergus J Couch; Steven N Hart; Jonine Figueroa; Montserrat García-Closas; Peter A Fasching; Matthias W Beckmann; Jingmei Li; Jianjun Liu; Irene L Andrulis; Robert Winqvist; Katri Pylkäs; Arto Mannermaa; Vesa Kataja; Annika Lindblom; Sara Margolin; Jan Lubinski; Natalia Dubrowinskaja; Manjeet K Bolla; Joe Dennis; Kyriaki Michailidou; Qin Wang; Douglas F Easton; Paul D P Pharoah; Marjanka K Schmidt; Heli Nevanlinna Journal: Breast Cancer Res Date: 2016-10-03 Impact factor: 6.466