Table 1.
Analyses of the entire CHEK2 coding sequence (separately or as part of panel next-generation sequencing (NGS)) or analyses of specific variant(s) in breast cancer (BC) patients.
| Reference | Population | P: Patients C: Controls |
Analysis * | Odds Ratio (95% Confidence Interval); p—Remark (Statistically Insignificant in Italics) |
|---|---|---|---|---|
| Female breast cancer | ||||
| Fostira 2020 [146] |
GR | P: 1382 high-risk BC patients C: ExAC/FLOSSIES |
CHEK2 (panel NGS) |
1.7 (0.98–2.7); 0.11—all LoF variants/ExAC 2.6 (1.44–4.68); 0.003—all LoF variants/FLOSSIES 3.8 (1.86–7.12); 1.2 × 10−3—missense deleterious/ExAC 5.9 (2.38–14.8); 1.2 × 10−4—missense deleterious/FLOSSIES |
| Kurian 2020 [147] |
US (66% white) |
P: 2,195 postmenopausal BC C: 2322 age-matched PMC |
CHEK2 (panel NGS) | N.D.; CHEK2 PV found in 0.59% P and 0.26% C |
| Rogoza-Janiszewska 2020 [148] | PL | P. 2,464 BC diagnosed at <41 C: from Cybulski 2019 |
c.1100delC; c.444+1G>A; del5395 | 3.8 (2.53–5.58); <0.0001—BC at < 41 y; all truncations 4.6 (2.44–8.80); <0.0001—BC at < 31 y; all truncations |
| Kleiblova 2019 [115] |
CZ | P: 1526 high-risk female BC C: 3360 PMC |
CHEK2 (panel NGS) | 7.94 (3.90–17.47); 4.1 × 10−11—unilat. BC: truncations 3.90 (1.24–13.35); 0.009—unilat. BC: deleterious missense 8.39 (1.92–28.74); 0.003—bilat. BC: truncations 3.77 (0.08–31.42); 0.26—bilat BC: deleterious missense |
| Cybulski 2019 [149] |
PL | P: 1,018 hereditary BC C: 4346 PMC |
c.1100delC c.444+1G>A del5395 |
6.9 (3.2–14.7); <0.0001—for c.1100delC 8.4 (3.0–23.3); <0.0001—for c.444+1G>A 6.5 (3.2–13.4); <0.0001—for del53957.2 (4.5–11.6); <0.0001—for all above truncations |
| Nurmi 2019 [150] |
FI | P: 3156 BC C: 2089 PMC |
c.319+2T>A; c.444+1G>A; c.1100delC | 5.40 (1.58–18.45); 0.007—for c.319+2T>A unselected BC 6.04 (1.65–22.10); 0.007—for c.319+2T>A familial BC |
| Girard 2019 [151] |
FR | P: 1207 BRCA1/2−ve BC pts having sister with BC C: 1199 non-cancer PMC |
CHEK2 (WES + panel NGS) |
3.0 (1.9–5.0); 1 × 10−5—any rare variant 5.8 (2.0–16.9); 0.001—LoF variants 2.4 (1.4–4.3); 0.002—likely-deleterious missense |
| Hauke 2018 [126] |
DE | P: 5589 BRCA1/2−ve BC C: 2189 non-cancer PMC |
CHEK2 (panel NGS) | 3.72 (1.99–6.94); <0.0001—truncations |
| Momozawa 2018 [145] |
JP | P: 7051 BC C: 11,241 PMC |
CHEK2 (panel NGS) | 3.2 (1.6–6.8); 3.2 × 10−4 |
| Decker 2017 [152] |
UK | P: 13,087 BC C: 5488 PMC |
CHEK2 (& 3 other genes) |
3.11 (2.15–4.69); 5.6 × 10−11—truncations 1.36 (0.99–1.87); 0.066—all rare missense 1.51 (1.02–2.24); 0.047—rare missense in any domain 3.27 (1.66–5.83); 0.0014—bilateral BC 3.42 (2.33–5.21); 1.5 × 10−11—ER+ve BC 3.98 (2.62–6.21)—age at dg < 50 years 3.37 (2.24–5.22)—age at dg = 50–60 years 2.12 (1.35–3.41)—age at dg > 60 years |
| Slavin 2017 [153] |
US (80% white) |
P: 2266 BRCA1/2−ve fam. BC C: ExAC |
CHEK2 (panel NGS) |
1.62 (1.03–2.51); 0.004 – truncations |
| Couch 2017 [154] |
US (white) |
P: 29,090 BC C: 25,215 ExAC-NFE |
CHEK2 (panel NGS) |
2.31 (1.88–2.85); 3.04 × 10−17—c.1100delC 2.26 (1.89–2.72); 1.75 × 10−20—PVs (w/o p.I157T, p.S428F) 1.48 (1.31–1.67); 1.11 × 10−10—any var (w p.I157T, p.S428F) 1.35 (1.1–1.63); 0.0002; bilateral BC |
| Schmidt 2016 [155] |
BCAC | P: 44,777 population+ hospital-based BC C: 42,977 PMC |
c.1100delC | 2.26 (1.90–2.69); 2.3×10−20—invasive BC 2.55 (2.10–3.10); 4.9 × 10−21—ER+ve BC 1.32 (0.93–1.88); 0.12—ER−ve BC |
| Naslund-Koch 2016 [156] | DK | 2442 BC pts /86,975 individ. (longitudinal study); | c.1100delC | 2.08 (1.51–2.85); <0.001 |
| Southey 2016 [157] |
BCAC | P: 42,671 C: 42,164 PMC |
iCOGS array incl. 6 rare CHEK2 variants |
2.26 (1.29–3.95); 0.003—for p.R117G 1.33 (1.05–1.67); 0.016—for p.R180C 1.70 (0.73–3.93); 0.210—for p.E239K 5.06 (1.09–23.5); 0.017—for p.R346C 1.03 (0.62–1.71); 0.910—for p.D438Y |
| Liu Y 2011 [158] |
CN (Han) | P: 118 familial BC P: 909 unselected BC C: 1228 healthy PMC |
CHEK2 (dHPLC) for familial BC | 5.99 (1.98–18.11); 0.002—for p.H371Y familial BC 2.43 (1.07–5.52); 0.034—for p.H371Y unselected BC |
| Cybulski 2011 [159] |
PL | P: 7494 BRCA1−ve BC C: 4346 PMC |
c.1100delC; c.444+1G>A; del5395 |
3.6 (2.6–5.1)—all BC 3.3 (2.3–4.7)—patients with no BC family history 5.0 (3.3–7.6)—patients with BC in 1° or 2° relative 7.3 (3.2–16.8)—patients with BC in 1° and 2° relatives |
| Desrichard 2011 [122] |
FR | P: 507 BRCA1/2−ve BC C: 513 non-cancer PMC |
CHEK2 (sequencing) | 4.15 (1.38–12.50); 0.007—any variant 5.18 (1.49–18.00); 0.004—deleterious (p.K244R ex) |
| Le Calvez-Kelm 2011 [160] | US/CA/AU | P: 1242 BC ≤ 45y C: 1109 non-ca PMC female |
CHEK2 (HRM) | 6.18 (1.76–21.8)—truncations/splice mutations 2.20 (1.20–4.01)—rare missense |
| Fletcher 2009 [161] |
UK/FI/NL/ RU/DE |
P: 1828 bilateral BC C: 7030 PMC |
c.1100delC | 6.43 (4.33–9.53); <0.0001—second primary for mut. carriers |
| Weischer 2007 [162] |
DK | P + C: 9231 (prospective) P: 1101 BC/4665 PMC (case-control) |
c.1100delC | 3.2 (1.0–9.9)—BC (prospective study) 2.6 (1.3–5.4)—BC (case-control study) |
| Cybulski 2006 [163] |
PL | P: 3228 BC diagnosed at ≤50 C: 5496 PMC |
c.1100delC c.444+1G>A p.I157T |
2.3 (1.1–4.8); 0.04—for c.1100delC 2.4 (1.4–4.2); 0.002—for c.444+1G>A 2.4 (1.5–3.7); 0.0001—for any truncation 1.4 (1.1–1.6); 0.002—for p. I157T |
| Chekmariova 2006 [164] | RU | P: 660 unilat; 155 bilat BC C: 448 middle aged females; |
c.1100delC (ASO PCR) |
9.8 (1.34–198.26); 0.007 - early onset/bilat BC/C carriers frequencies: 3.4/5.2/0.2% |
| Cybulski 2004 [20] |
PL | P: 1017 BC C: 4000 PMC |
c.1100delC; c.444+1G>A; p.I157T |
2.2; p = 0.02—for c.1100delC and c.444+1G>A 1.4; p = 0.02—for p.I157T |
| Caligo 2004 [130] |
IT | P: 939 BC (incl. BRCA1/2+ve) C: 334 PMC |
c.1100delC | N.S.; frequency of carriers 0.11% (95% CI 0.00–0.59%) |
| Dufault 2004 [165] |
DE | P: 516 BRCA1/2−ve BC C: 500 PMC (1,315 PMC for c.1100delC) |
CHEK2 | 3.44 (1.19–9.95); 0.016—c.1100delC 3.9 (1.3–10.9)—c.1100delC and c.1214del4 |
| CHEK2 BC consortium 2004 [166] |
UK/NL/FI/ DE/AU |
P: 10,860 BC C: 9065 multinatl. |
c.1100delC | 2.34(1.72–3.20); 1 × 10−7—all BC 2.23 (1.60–3.11)—BC w/o BC in 1° relative 3.12 (1.90–5.15)—BC with 1 BC in 1° relative 4.17 (1.26–13.75)—BC with ≥2 BC in 1° relatives |
| CHEK2 BC consortium 2002 [167] |
UK/NL/ US/CA |
P: 636 unselected BC P: 718 BRCA1/2-ve BC C: 1620 multinatl. |
c.1100delC |
2.52 (0.78–8.18)—unselected BC 1.70 (1.32–3.38)—BRCA1/2−ve BC |
| Vahteristo 2002 [110] |
FI | P: 1035 unselected BC C: 1885 PMC (blood donors) |
c.1100delC |
1.48 (0.83–2.65); 0.182—unselected BC 2.27 (1.11–4.63); 0.021—familial BC 6.17 (1.87–20.32); 0.007 bilat. vs. unilat. BC |
| Male breast cancer | ||||
| Kleiblova 2019 [115] |
CZ | P: 48 male BC C: 3360 PMC |
CHEK2 (panel NGS) | 20.21 (3.50–80.00); 8.6 × 10−4—truncations 11.87 (0.25–100.83); 0.1—deleterious missense |
| Liang 2018 [168] |
meta | P: 1063 male BC C: 31,571 |
c.1100delC | 3.13 (1.94–5.07) |
| Hallamies 2017 [169] |
FI | P: 68 male BC C: 1885 from [110] |
c.1100delC | 4.47 (1.51–13.18); 0.019 |
| Wasielewski 2009 [170] |
NL | P: 71 male BC C: 1692 |
c.1100delC | 4.1 (1.2–14.3); 0.05 |
| CHEK2 consortium 2002 [167] |
UK/NL/US/CA | P: 52 male BC families C: 1620 multinatl. |
c.1100delC | 10.28 (3.54–29.87) |
| Meta-analyses | ||||
| Yang 2019 [171] |
BCAC+ ABCC meta |
P: 122,977 + 24,206 BC C: 105,974 + 24,775 PMC |
p.I157T | 1.28 (1.17–1.39); 9.66 × 10−9—for Europeans only 1.35 (1.18–1.54); 9.82 × 10−6—for ER+ve BC 0.95 (0.81–1.12); 0.55—for ER−ve BC |
| Liang 2018 [168] |
meta | P: 118,735 BC C: 195,807 |
c.1100delC | 2.88 (2.65–3.22)—female BC 2.87 (1.85–4.47)—early-onset BC 3.21 (2.41–4.29)—familial BC 3.13 (1.94–5.07)—male BC |
| Aloraifi 2015 [113] |
meta | P. 7283 C: 13,785 |
CHEK2 truncations | 3.25 (2.55–4.13) |
| Han 2013 [172] |
meta | P: 15,985 BC C: 18,609 |
p.I157T | 1.58 (1.42–1.75); <0.0001 |
| Liu 2012 [173] |
meta | P: 19,621 BC C: 27,001 |
p.I157T | 1.48 (1.31–1.68); <0.0001—unselected BC 1.48 (1.16–1.89); <0.0001—familiar BC 1.47 (1.29–1.66); <0.0001—early onset BC 4.17 (2.89–6.03); <0.0001—lobular BC |
| Yang 2012 [174] |
meta | P: 29,154 BC C: 37,064 |
c.1100delC | 2.33 (1.79–3.05)—unselected BC 3.72 (2.61–5.31)—familiar BC 2.78 (2.28–3.39)—early onset BC |
| Zhang 2011 [175] |
meta | P: 9970/C:7526 P: 13,331/C: 10,817 P: 10,543/C:10,817 P: 41,791/C: 50,910 |
c.444+1G>A del5395 c.1100delC p.I157T |
3.07 (2.03–4.63); 9.82 × 10−8—for variant c.444+1G>A 2.53 (1.61–3.97); 6.33 × 10−5—for variant del5395 3.10 (2.59–3.71); <10−20—for variant c.1100delC 1.52 (1.31–1.77); 4.76 × 10−8—for variant p.I157T |
| Weischer 2008 [176] |
meta | P: 26,488 C: 27,402 |
c.1100delC | 2.7 (2.1–3.4)—unselected BC 2.6 (1.3–5.5)—early onset BC 4.8 (3.3–7.2)—familial BC |
* CHEK2 = an analysis of the entire coding sequence (dominantly without copy number variations (CNV)); otherwise specified if certain CHEK2 variants were genotyped. AU—Australia; ABCC—Asian Breast Cancer Consortium; BC—breast cancer; BCAC—Breast Cancer Association Consortium; CA—Canada; CN—China; CZ—Czech Republic; DE—Germany; DK—Denmark; ES—Spain; EU—European Union; ExAC—Exome Aggregation Consortium; FI—Finland; FLOSSIES—Fabulous Ladies Over Seventy; FR—France; meta—meta-analysis; GR—Greece; IT—Italy; LoF—loss-of-function; JP—Japan; NL—Netherlands; PL—Poland; PMC—population-matched control; RU—Russia; US—the USA. The analyses that failed to demonstrate an association are shown in italics.