Age- and Tumor Subtype–Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers

Schmidt, Marjanka K.; Hogervorst, Frans B.L.; Hien, Richard van; Cornelissen, Sten; Broeks, Annegien; Adank, Muriel A.; Meijers, Hanne; Waisfisz, Quinten; Hollestelle, Antoinette; Schutte, Mieke; Ouweland, Ans M.W. van den; Hooning, Maartje J.; Andrulis, Irene L.; Anton‐Culver, Hoda; Antonenkova, Natalia; Antoniou, Antonis C.; Arndt, Volker; Bermisheva, Marina; Bogdanova, Natalia; Bolla, Manjeet K.; Brauch, Hiltrud; Brenner, Hermann; Brüning, Thomas; Burwinkel, Barbara; Chang‐Claude, Jenny; Chenevix-Trench, Georgia; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Dunning, Alison M.; Fasching, Peter A.; Figueroa, Jonine D.; Fletcher, Olivia; Flyger, Henrik; Galle, Eva; García‐Closas, Montserrat; Giles, Graham G.; Haeberle, Lothar; Hall, Per; Hillemanns, Peter; Hopper, John L.; Jakubowska, Anna; John, Esther M.; Jones, Michael E.; Хуснутдинова, Э. К.; Knight, Julia A.; Kosma, Veli‐Matti; Kristensen, Vessela N.; Lee, Andrew; Lindblom, Annika; Lubiński, Jan; Mannermaa, Arto; Margolin, Sara; Meindl, Alfons; Milne, Roger L.; Muranen, Taru; Newcomb, Polly A.; Offit, Kenneth; Park‐Simon, Tjoung‐Won; Peto, Julian; Pharoah, Paul D.P.; Robson, Mark E.; Rudolph, Anja; Sawyer, Elinor J.; Schmutzler, Rita K.; Seynaeve, Caroline; Soens, Julie; Southey, Melissa C.; Spurdle, Amanda B.; Surowy, Harald; Swerdlow, Anthony; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Trentham‐Dietz, Amy; Vachon, Celine M.; Wang, Qin; Whittemore, Alice S.; Ziogas, Argyrios; Kolk, Lizet E. van der; Nevanlinna, Heli; Dörk, Thilo; Bojesen, Stig E.; Easton, Douglas F.

doi:10.1200/jco.2016.66.5844

Cited by 164 publications

(140 citation statements)

References 26 publications

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“…2, 14 Adjusting for positive family history markedly attenuated the CHEK2 *1100delC associated OR, suggestive of some oversampling of familial cases. The PRS OR was also slightly attenuated after the adjustment.…”

Section: Discussionmentioning

confidence: 97%

“…14 Assuming that the relative effect of the PRS is the same in carriers and non-carriers (OR higher than 1.48 [1.39–1.57] or lower than 0.65 [0.60–0.70] for percentiles above 80% or lower than 20%, respectively), 8 20% of the 1100delC carriers with highest PRS would have life-time risk higher than 32.6% [30.6%–34.5%] exceeding the threshold for the high-risk category (>30%) according to the UK NICE guidelines for familial breast cancer. 20 Similarly, for the 20% of 1100delC carriers with lowest PRS, the life-time risk would be lower than 14.3% [13.2%–15.4%], i.e.…”

Section: Discussionmentioning

confidence: 99%

“…The cumulative life-time breast cancer risk of CHEK2 *1100delC carriers in different PRS-percentiles was derived assuming an average life-time risk of 22% for CHEK2*1100delC carriers 14 and previously published relative risk estimates associated with the PRS. 8 …”

Section: Methodsmentioning

confidence: 99%

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Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

Muranen¹,

Greco²,

Blomqvist³

et al. 2017

Genetics in Medicine

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PurposeCHEK2*1100delC is a founder variant in European populations conferring a 2–3 fold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).MethodsWith genotype data of 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.ResultsThe PRS conferred an odds ratio (OR) of 1.59 [95% CI 1.21–2.09] per standard deviation for BC for CHEK2*1100delC carriers and 1.58 [1.55–1.62] for non-carriers. No evidence for deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 [0.86–4.78] for CHEK2*1100delC carriers placing them to the high risk category according to UK NICE guidelines. OR for the lowest quintile was 0.52 [0.16–1.74], indicating life-time risk close to population average.ConclusionOur results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify the carriers at a high life-time risk for clinical actions.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

Muranen¹,

Greco²,

Blomqvist³

et al. 2017

Genetics in Medicine

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“…Our analysis confirmed proposed “ CHEK2 mutation‐specific” tumor phenotype, characterized by premenopausal, ductal, grade 2, luminal A or luminal B/HER2‐negative tumors, reported in other studies . These tumor characteristics lost in carriers of coincidental BRCA1/BRCA2 mutations having a stronger effect on tumor phenotype.…”

Section: Discussionmentioning

confidence: 99%

Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer

Kleiblová

Stolařová

Křížová

et al. 2019

Intl Journal of Cancer

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Germline mutations in checkpoint kinase 2 (CHEK2), a multiple cancer‐predisposing gene, increase breast cancer (BC) risk; however, risk estimates differ substantially in published studies. We analyzed germline CHEK2 variants in 1,928 high‐risk Czech breast/ovarian cancer (BC/OC) patients and 3,360 population‐matched controls (PMCs). For a functional classification of VUS, we developed a complementation assay in human nontransformed RPE1‐CHEK2‐knockout cells quantifying CHK2‐specific phosphorylation of endogenous protein KAP1. We identified 10 truncations in 46 (2.39%) patients and in 11 (0.33%) PMC (p = 1.1 × 10−14). Two types of large intragenic rearrangements (LGR) were found in 20/46 mutation carriers. Truncations significantly increased unilateral BC risk (OR = 7.94; 95%CI 3.90–17.47; p = 1.1 × 10−14) and were more frequent in patients with bilateral BC (4/149; 2.68%; p = 0.003), double primary BC/OC (3/79; 3.80%; p = 0.004), male BC (3/48; 6.25%; p = 8.6 × 10−4), but not with OC (3/354; 0.85%; p = 0.14). Additionally, we found 26 missense VUS in 88 (4.56%) patients and 131 (3.90%) PMC (p = 0.22). Using our functional assay, 11 variants identified in 15 (0.78%) patients and 6 (0.18%) PMC were scored deleterious (p = 0.002). Frequencies of functionally intermediate and neutral variants did not differ between patients and PMC. Functionally deleterious CHEK2 missense variants significantly increased BC risk (OR = 3.90; 95%CI 1.24–13.35; p = 0.009) and marginally OC risk (OR = 4.77; 95%CI 0.77–22.47; p = 0.047); however, carriers low frequency will require evaluation in larger studies. Our study highlights importance of LGR detection for CHEK2 analysis, careful consideration of ethnicity in both cases and controls for risk estimates, and demonstrates promising potential of newly developed human nontransformed cell line assay for functional CHEK2 VUS classification.

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“…For FANCM, higher mutation frequencies were observed in TNBC cases versus breast cancer cases not selected for tumor phenotype [13,15]. Other breast cancer risk genes such as CHEK2 and probably ATM are unlikely to predispose for TNBC [42]. With the rise of next generation sequencing, germline testing is nowadays not restricted to BRCA1/2 and covers the above-named and further genes that predispose for rare cancer predisposition syndromes [40].…”

Section: Other Predisposition Genes Associated With Tnbc Phenotypementioning

confidence: 99%

Germline Mutations in Triple-Negative Breast Cancer

et al. 2017

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Triple-negative breast cancer (TNBC) is associated with a poor prognosis and defines a subgroup of patients who do not benefit from endocrine or anti-HER2 therapy. Rather than being a biological entity, TNBC represents a heterogeneous disease, and further subtyping is necessary to establish targeted therapies. Germline mutational status may serve as a robust biomarker predicting therapy response, especially with respect to compounds challenging the DNA repair machinery. Patients with TNBC usually show an early onset of the disease, as well as a positive family history of breast and/or ovarian cancer in more than one third of all cases, which suggests that TNBC is closely associated with a hereditary disease cause. In unselected TNBC cases, the prevalence of pathogenic germline BRCA1/2 mutations is approximately twice as high as in breast cancer overall. Early age at diagnosis and positive family history are strong predictors for an increased BRCA1/2 mutation probability, which is up to 40% when both risk factors are considered. Apart from BRCA1/2, the rarely mutated breast cancer predisposition genes PALB2 and FANCM have been associated with TNBC. This review summarizes the role of germline mutational status in TNBC pathogenesis. Clinical trials addressing BRCA1/2 mutation carriers are discussed.

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Age- and Tumor Subtype–Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers

Cited by 164 publications

References 26 publications

Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer

Germline Mutations in Triple-Negative Breast Cancer

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