Family History, Genetic Testing, and Clinical Risk Prediction: Pooled Analysis of CHEK2*1100delC in 1,828 Bilateral Breast Cancers and 7,030 Controls

Abstract

If breast cancers arise independently in each breast the odds ratio (OR) for bilateral breast cancer for carriers of CHEK2*1100delC should be f5.5, the square of the reported OR for a first primary (OR, 2.34). In the subset of bilateral cases with one or more affected relatives, the predicted carrier OR should be f9. We have tested these predictions in a pooled set of 1,828 cases with 2 primaries and 7,030 controls from 8 studies. The second primary OR for CHEK2*1100-delC carriers was 6.43 (95% confidence interval, 4.33-9.56; P < 0.0001), significantly greater than the published estimate for a first primary (P < 0.001) but consistent with its square. The predicted increase in carrier OR with increasing numbers of affected relatives was seen using bilateral cases from the UK (P trend = 0.0003) and Finland (P trend = 0.37), although not using those from the Netherlands and Russia (P = 0.001 for heterogeneity between countries). Based on a standard genetic model, we predict lifetime risks for CHEK2*1100delC carrier and noncarrier daughters of bilateral breast cancer cases of 37% and 18%, respectively. Our results imply that clinical management of the daughter of a woman with bilateral breast cancer should depend on her CHEK2*1100delC carrier status. This and other moderate penetrance breast cancer susceptibility alleles, together with family history data, will thus identify increasing numbers of women at potentially very high risk. Before such predictions are accepted by clinical geneticists, however, further population-based evidence is needed on the effect of CHEK2*1100delC and other moderate penetrance alleles in women with a family history of breast cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(1):230 -4)

CHEK2*1100delC homozygosity in the Netherlands—prevalence and risk of breast and lung cancer

“…5,[13][14][15][16][17][18][19] For homozygous carriers, our observations indicate that (contralateral) breast cancer risk may be as high as to justify preventive mastectomy (or at least intensified screening), but longitudinal studies on more cases are needed to arrive at more accurate risk estimates.…”

“…Homozygous wild-type patients are all homozygous wild-type patients from the ORIGO cohort for whom follow-up was available. 15,18,20 In 1100delC homozygotes, this risk seems comparable or even higher, with potential consequences for clinical management.…”

“…3,[10][11][12][13] Breast cancer patients heterozygous for 1100delC also have an increased risk of developing contralateral breast cancer when compared with wild-type breast cancer patients. 5,[13][14][15][16][17][18][19][20] The contralateral breast cancer risk may be even higher when radiotherapy has been given to treat the first tumor. 15,19 It must be noted that in women who also carry a pathogenic BRCA1/2 mutation the 1100delC allele does not seem to modify breast cancer risk.…”

CHEK2 1100delC Variant and Breast Cancer Risk in Caucasians: A Meta-analysis Based on 25 Studies with 29,154 Cases and 37,064 Controls

“…After the BRCA1 and BRCA2 proteins were cloned and their association with family breast cancer was detected (Miki Y et al, 1994;Wooster R et al, 1995), greater emphasis was placed on the candidate gene of breast cancer. The cell cycle-checkpoint kinase 2 gene, or CHEK2, was widely researched as a strong candidate gene for breast cancer susceptibility (Vahteristo et al, 2002;Sodha et al, 2002;Offit et al, 2003;CHEK2 Breast Cancer Consortium, 2004;Dufault et al, 2004;Friedrichsen et al, 2004;Mateus Pereira et al, 2004;Baeyens et al, 2005;Kleibl et al, 2005;Rashid et al, 2005;Bernstein et al, 2006;Einarsdóttir et al, 2006;Cybulski et al, 2007;Weischer et al, 2007;Zhang et al, 2008;Fletcher et al, 2009;McInerney et al, 2010;Iniesta et al, 2010).…”

Novel Nonsense Variants c.58C>T (p.Q20X) and c.256G>T (p.E85X) in the CHEK2 Gene Identified dentified in Breast Cancer Patients from Balochistan

“…Various sporadic and hereditary cancers in human are reported to be caused by mutations in gene CHEK2 Chaturvedi et al, 1999;Matsouka et al, 2000;Ingvarsson et al, 2002;Craig and Hupp, 2004;Bartek, Hollestelle et al, 2010and Lukas, 2003and Nevanlinna and Bartek, 2006. CHEK2 1100delC most widely been study and suggested to increase the risk of breast cancer in women who have a positive family history of breast cancer, however this mutation has not been reported in Asian populations (Wu et al, 2001;Weischer et al, 2008;Fletcher et al, 2009;Baloch et al, 2014). Different missense mutations other than 1100delC may lead to loss of function and cause cancer (Narod, 2010 andLe Calviz-Kem et al, 2011).…”