The Experts below are selected from a list of 7113 Experts worldwide ranked by ideXlab platform
Cezary Cybulski - One of the best experts on this subject based on the ideXlab platform.
-
Survival of Bladder or Renal Cancer in Patients With CHEK2 Mutations
2020Co-Authors: Elżbieta Złowocka-perłowska, Tadeusz Dębniak, Dominika Wokołorczyk, Marcin Słojewski, Artur Lemiński, Michał Soczawa, Thierry Van De Wetering, Joanna Trubicka, Wojcech Kluźniak, Cezary CybulskiAbstract:Abstract Purpose: The purpose of this study was to compare the survival of CHEK2 mutations positive and CHEK2 mutations negative patients with bladder or kidney cancer. Materials and methods: 1419 patients with bladder and 835 cases with kidney cancer and 8302 controls were genotyped for four CHEK2 variants: 1100delC, del5395, IVS2+1G>A and I157T. Predictors of survival were determined among CHEK2 carriers using the Cox proportional hazards model. The median follow-up was 17 years. Covariates included age (≤65; >66), smoking status (non-smoking; smoking), cancer family history (negative; positive) and gender (females; males). Results: Of the 1419 bladder patients enrolled in the study, 118 (8.32%) carried a CHEK2 mutation (all variants combined) (OR=1.4; 95% CI 1.17–1.78; p=0.0006), including 25 (1.76%) cases with a truncating mutation (OR=1.84; 95% CI, 1.17-2.89; p=0.01) and 93 (6.55%) patients with a missense mutation (OR=1.35; 95% CI, 1.07-1.7; p=0.01). We found no impact of CHEK2 mutations on bladder or kidney cancer survival. The 10-year survival for all CHEK2 mutation for bladder cancer carriers was 19% and for non-carriers was 13% (p=0.7). The 10-year survival for kidney cancer carriers was 6% and for non-carriers was 4% (p=0.9). Conclusion: We found no impact of CHEK2 mutations on bladder or kidney cancer survival regardless of their age, sex, cancer family history and smoking status.
-
CHEK2 mutations and the risk of papillary thyroid cancer.
International journal of cancer, 2015Co-Authors: Monika Siołek, Cezary Cybulski, Dominika Wokołorczyk, Danuta Gąsior-perczak, Artur Kowalik, Beata Kozak-klonowska, Aldona Kowalska, Małgorzata Chłopek, Wojciech Kluźniak, Iwona PałygaAbstract:Mutations in the cell cycle checkpoint kinase 2 (CHEK2) tumor suppressor gene are associated with multi-organ cancer susceptibility including cancers of the breast and prostate. A genetic association between thyroid and breast cancer has been suggested, however little is known about the determinants of this association. To characterize the association of CHEK2 mutations with thyroid cancer, we genotyped 468 unselected patients with papillary thyroid cancer and 468 (matched) cancer-free controls for four founder mutations of CHEK2 (1100delC, IVS2 + 1G>A, del5395 and I157T). We compared the family histories reported by patients with a CHEK2 mutation to those of non-carriers. A CHEK2 mutation was seen in 73 of 468 (15.6%) unselected patients with papillary thyroid cancer, compared to 28 of 460 (6.0%) age- and sex-matched controls (OR 3.3; p A, 1100delC or del5395) was associated with a higher risk of thyroid cancer (OR = 5.7; p = 0.006), than was the missense mutation I157T (OR = 2.8; p = 0.0001). CHEK2 mutation carriers reported a family history of breast cancer 2.2 times more commonly than non-carriers (16.4% vs.8.1%; p = 0.05). A CHEK2 mutation was found in seven of 11 women (63%) with multiple primary cancers of the breast and thyroid (OR = 10; p = 0.0004). These results suggest that CHEK2 mutations predispose to thyroid cancer, familial aggregations of breast and thyroid cancer and to double primary cancers of the breast and thyroid.
-
Survival from breast cancer in patients with CHEK2 mutations.
Breast cancer research and treatment, 2014Co-Authors: Tomasz Huzarski, Cezary Cybulski, Tomasz Byrski, Jacek Gronwald, Anna Jakubowska, Dominika Wokołorczyk, Pawel Domagala, Marek Szwiec, Dariusz Godlewski, E. KilarAbstract:The purpose of this study is to estimate 10-year survival rates for patients with early onset breast cancer, with and without a CHEK2 mutation and to identify prognostic factors among CHEK2-positive breast cancer patients. 3,592 women with stage I to stage III breast cancer, diagnosed at or below age 50, were tested for four founder mutations in the CHEK2 gene. Information on tumor characteristics and on treatments received was retrieved from medical records. Dates of death were obtained from the Poland Vital Statistics Registry. Survival curves were generated for the mutation-positive and -negative sub-cohorts. Predictors of survival were determined among CHEK2 carriers using the Cox proportional hazards model. 3,592 patients were eligible for the study, of whom 140 (3.9 %) carried a CHEK2-truncating mutation and 347 (9.7 %) carried a missense mutation. The mean follow-up was 8.9 years. The 10-year survival for all CHEK2 mutation carriers was 78.8 % (95 % CI 74.6-83.2 %) and for non-carriers was 80.1 % (95 % CI 78.5-81.8 %). Among women with a CHEK2-positive breast cancer, the adjusted hazard ratio associated with ER-positive status was 0.88 (95 % CI 0.48-1.62). Among women with an ER-positive breast cancer, the adjusted hazard ratio associated with a CHEK2 mutation was 1.31 (95 % CI 0.97-1.77). The survival of women with breast cancer and a CHEK2 mutation is similar to that of patients without a CHEK2 mutation.
-
the risk of gastric cancer in carriers of CHEK2 mutations
Familial Cancer, 2013Co-Authors: Urszula Teodorczyk, Cezary Cybulski, Dominika Wokolorczyk, Anna Jakubowska, Teresa Starzynska, Malgorzata ławniczak, Pawel Domagala, Katarzyna Ferenc, K Marlicz, Zbigniew BanaszkiewiczAbstract:CHEK2 is a tumor suppressor gene whose functions are central to the induction of cell cycle arrest and apoptosis following DNA damage. Mutations in CHEK2 have been associated with cancers at many sites, including breast and prostate cancers, but the relationship between CHEK2 and gastric cancer has not been extensively studied. In Poland, there are four known founder alleles of CHEK2; three alleles are protein truncating (1100delC, IVS2G>A, del5395) and the other is a missense variant (I157T). We examined the frequencies of four Polish founder mutations in the CHEK2 gene in 658 unselected gastric cancer patients, in 154 familial gastric cancer patients and in 8,302 controls. A CHEK2 mutation was seen in 57 of 658 (8.7 %) unselected patients with gastric cancer compared to 480 of 8,302 (5.8 %) controls (OR 1.6, p = 0.004). A CHEK2 mutation was present in 19 of 154 (12.3 %) familial cases (OR = 2.3, p = 0.001). The odds ratio for early onset (<50 years) gastric cancer was higher (2.1, p = 0.01), than for cases diagnosed at age of 50 or above (OR 1.4, p = 0.05). Truncating mutations of CHEK2 were associated with higher risk (OR = 2.1, p = 0.02) than the missense mutation I157T (OR = 1.4, p = 0.04). CHEK2 mutations predispose to gastric cancer, in particular to young-onset cases.
-
The risk of gastric cancer in carriers of CHEK2 mutations
Familial cancer, 2013Co-Authors: Urszula Teodorczyk, Cezary Cybulski, Anna Jakubowska, Dominika Wokołorczyk, Teresa Starzynska, Pawel Domagala, Katarzyna Ferenc, K Marlicz, Małgorzata Ławniczak, Zbigniew BanaszkiewiczAbstract:CHEK2 is a tumor suppressor gene whose functions are central to the induction of cell cycle arrest and apoptosis following DNA damage. Mutations in CHEK2 have been associated with cancers at many sites, including breast and prostate cancers, but the relationship between CHEK2 and gastric cancer has not been extensively studied. In Poland, there are four known founder alleles of CHEK2; three alleles are protein truncating (1100delC, IVS2G>A, del5395) and the other is a missense variant (I157T). We examined the frequencies of four Polish founder mutations in the CHEK2 gene in 658 unselected gastric cancer patients, in 154 familial gastric cancer patients and in 8,302 controls. A CHEK2 mutation was seen in 57 of 658 (8.7 %) unselected patients with gastric cancer compared to 480 of 8,302 (5.8 %) controls (OR 1.6, p = 0.004). A CHEK2 mutation was present in 19 of 154 (12.3 %) familial cases (OR = 2.3, p = 0.001). The odds ratio for early onset (
Ranjan Chrisanthar - One of the best experts on this subject based on the ideXlab platform.
-
low expression levels of atm may substitute for CHEK2 tp53 mutations predicting resistance towards anthracycline and mitomycin chemotherapy in breast cancer
Breast Cancer Research, 2012Co-Authors: Stian Knappskog, Ranjan Chrisanthar, Erik Lokkevik, Gun Anker, Bjorn Ostenstad, Steinar LundgrenAbstract:Mutations affecting p53 or its upstream activator Chk2 are associated with resistance to DNA-damaging chemotherapy in breast cancer. ATM (Ataxia Telangiectasia Mutated protein) is the key activator of p53 and Chk2 in response to genotoxic stress. Here, we sought to evaluate ATM's potential role in resistance to chemotherapy. We sequenced ATM and assessed gene expression levels in pre-treatment biopsies from 71 locally advanced breast cancers treated in the neoadjuvant setting with doxorubicin monotherapy or mitomycin combined with 5-fluorouracil. Findings were confirmed in a separate patient cohort treated with epirubicin monotherapy. Each tumor was previously analyzed for CHEK2 and TP53 mutation status. While ATM mutations were not associated with chemo-resistance, low ATM expression levels predicted chemo-resistance among patients with tumors wild-type for TP53 and CHEK2 (P = 0.028). Analyzing the ATM-chk2-p53 cascade, low ATM levels (defined as the lower 5 to 50% percentiles) or mutations inactivating TP53 or CHEK2 robustly predicted anthracycline resistance (P-values varying between 0.001 and 0.027 depending on the percentile used to define "low" ATM levels). These results were confirmed in an independent cohort of 109 patients treated with epirubicin monotherapy. In contrast, ATM-levels were not suppressed in resistant tumors harboring TP53 or CHEK2 mutations (P > 0.5). Our data indicate loss of function of the ATM-Chk2-p53 cascade to be strongly associated with resistance to anthracycline/mitomycin-containing chemotherapy in breast cancer.
-
CHEK2 mutations affecting kinase activity together with mutations in tp53 indicate a functional pathway associated with resistance to epirubicin in primary breast cancer
PLOS ONE, 2008Co-Authors: Stian Knappskog, Ranjan Chrisanthar, Erik Lokkevik, Gun Anker, Bjorn Ostenstad, Steinar Lundgren, Elisabet Ognedal BergeAbstract:Background: Chemoresistance is the main obstacle to cure in most malignant diseases. Anthracyclines are among the main drugs used for breast cancer therapy and in many other malignant conditions. Single parameter analysis or global gene expression profiles have failed to identify mechanisms causing in vivo resistance to anthracyclines. While we previously found TP53 mutations in the L2/L3 domains to be associated with drug resistance, some tumors harboring wild-type TP53 were also therapy resistant. The aim of this study was; 1) To explore alterations in the TP53 gene with respect to resistance to a regular dose epirubicin regimen (90 mg/m 2 every 3 week) in patients with primary, locally advanced breast cancer; 2) Identify critical mechanisms activating p53 in response to DNA damage in breast cancer; 3) Evaluate in vitro function of Chk2 and p14 proteins corresponding to identified mutations in the CHEK2 and p14 (ARF) genes; and 4) Explore potential CHEK2 or p14 (ARF) germline mutations with respect to family cancer incidence. Methods and Findings: Snap-frozen biopsies from 109 patients collected prior to epirubicin (as preoperative therapy were investigated for TP53, CHEK2 and p14 (ARF) mutations by sequencing the coding region and p14 (ARF) promoter methylations. TP53 mutastions were associated with chemoresistance, defined as progressive disease on therapy (p = 0.0358; p = 0.0136 for mutations affecting p53 loop domains L2/L3). Germline CHEK2 mutations (n = 3) were associated with therapy resistance (p = 0.0226). Combined, mutations affecting either CHEK2 or TP53 strongly predicted therapy resistance (p = 0.0101; TP53 mutations restricted to the L2/L3 domains: p = 0.0032). Two patients progressing on therapy harbored the CHEK2 mutation, Arg95Ter, completely abrogating Chk2 protein dimerization and kinase activity. One patient (Epi132) revealed family cancer occurrence resembling families harboring CHEK2 mutations in general, the other patient (epi203) was non-conclusive. No mutation or promoter hypermethylation in p14 (ARF) were detected. Conclusion: This study is the first reporting an association between CHEK2 mutations and therapy resistance in human cancers and to document mutations in two genes acting direct up/down-stream to each other to cause therapy failure, emphasizing the need to investigate functional cascades in future studies.
Stian Knappskog - One of the best experts on this subject based on the ideXlab platform.
-
low expression levels of atm may substitute for CHEK2 tp53 mutations predicting resistance towards anthracycline and mitomycin chemotherapy in breast cancer
Breast Cancer Research, 2012Co-Authors: Stian Knappskog, Ranjan Chrisanthar, Erik Lokkevik, Gun Anker, Bjorn Ostenstad, Steinar LundgrenAbstract:Mutations affecting p53 or its upstream activator Chk2 are associated with resistance to DNA-damaging chemotherapy in breast cancer. ATM (Ataxia Telangiectasia Mutated protein) is the key activator of p53 and Chk2 in response to genotoxic stress. Here, we sought to evaluate ATM's potential role in resistance to chemotherapy. We sequenced ATM and assessed gene expression levels in pre-treatment biopsies from 71 locally advanced breast cancers treated in the neoadjuvant setting with doxorubicin monotherapy or mitomycin combined with 5-fluorouracil. Findings were confirmed in a separate patient cohort treated with epirubicin monotherapy. Each tumor was previously analyzed for CHEK2 and TP53 mutation status. While ATM mutations were not associated with chemo-resistance, low ATM expression levels predicted chemo-resistance among patients with tumors wild-type for TP53 and CHEK2 (P = 0.028). Analyzing the ATM-chk2-p53 cascade, low ATM levels (defined as the lower 5 to 50% percentiles) or mutations inactivating TP53 or CHEK2 robustly predicted anthracycline resistance (P-values varying between 0.001 and 0.027 depending on the percentile used to define "low" ATM levels). These results were confirmed in an independent cohort of 109 patients treated with epirubicin monotherapy. In contrast, ATM-levels were not suppressed in resistant tumors harboring TP53 or CHEK2 mutations (P > 0.5). Our data indicate loss of function of the ATM-Chk2-p53 cascade to be strongly associated with resistance to anthracycline/mitomycin-containing chemotherapy in breast cancer.
-
CHEK2 mutations affecting kinase activity together with mutations in tp53 indicate a functional pathway associated with resistance to epirubicin in primary breast cancer
PLOS ONE, 2008Co-Authors: Stian Knappskog, Ranjan Chrisanthar, Erik Lokkevik, Gun Anker, Bjorn Ostenstad, Steinar Lundgren, Elisabet Ognedal BergeAbstract:Background: Chemoresistance is the main obstacle to cure in most malignant diseases. Anthracyclines are among the main drugs used for breast cancer therapy and in many other malignant conditions. Single parameter analysis or global gene expression profiles have failed to identify mechanisms causing in vivo resistance to anthracyclines. While we previously found TP53 mutations in the L2/L3 domains to be associated with drug resistance, some tumors harboring wild-type TP53 were also therapy resistant. The aim of this study was; 1) To explore alterations in the TP53 gene with respect to resistance to a regular dose epirubicin regimen (90 mg/m 2 every 3 week) in patients with primary, locally advanced breast cancer; 2) Identify critical mechanisms activating p53 in response to DNA damage in breast cancer; 3) Evaluate in vitro function of Chk2 and p14 proteins corresponding to identified mutations in the CHEK2 and p14 (ARF) genes; and 4) Explore potential CHEK2 or p14 (ARF) germline mutations with respect to family cancer incidence. Methods and Findings: Snap-frozen biopsies from 109 patients collected prior to epirubicin (as preoperative therapy were investigated for TP53, CHEK2 and p14 (ARF) mutations by sequencing the coding region and p14 (ARF) promoter methylations. TP53 mutastions were associated with chemoresistance, defined as progressive disease on therapy (p = 0.0358; p = 0.0136 for mutations affecting p53 loop domains L2/L3). Germline CHEK2 mutations (n = 3) were associated with therapy resistance (p = 0.0226). Combined, mutations affecting either CHEK2 or TP53 strongly predicted therapy resistance (p = 0.0101; TP53 mutations restricted to the L2/L3 domains: p = 0.0032). Two patients progressing on therapy harbored the CHEK2 mutation, Arg95Ter, completely abrogating Chk2 protein dimerization and kinase activity. One patient (Epi132) revealed family cancer occurrence resembling families harboring CHEK2 mutations in general, the other patient (epi203) was non-conclusive. No mutation or promoter hypermethylation in p14 (ARF) were detected. Conclusion: This study is the first reporting an association between CHEK2 mutations and therapy resistance in human cancers and to document mutations in two genes acting direct up/down-stream to each other to cause therapy failure, emphasizing the need to investigate functional cascades in future studies.
Gun Anker - One of the best experts on this subject based on the ideXlab platform.
-
low expression levels of atm may substitute for CHEK2 tp53 mutations predicting resistance towards anthracycline and mitomycin chemotherapy in breast cancer
Breast Cancer Research, 2012Co-Authors: Stian Knappskog, Ranjan Chrisanthar, Erik Lokkevik, Gun Anker, Bjorn Ostenstad, Steinar LundgrenAbstract:Mutations affecting p53 or its upstream activator Chk2 are associated with resistance to DNA-damaging chemotherapy in breast cancer. ATM (Ataxia Telangiectasia Mutated protein) is the key activator of p53 and Chk2 in response to genotoxic stress. Here, we sought to evaluate ATM's potential role in resistance to chemotherapy. We sequenced ATM and assessed gene expression levels in pre-treatment biopsies from 71 locally advanced breast cancers treated in the neoadjuvant setting with doxorubicin monotherapy or mitomycin combined with 5-fluorouracil. Findings were confirmed in a separate patient cohort treated with epirubicin monotherapy. Each tumor was previously analyzed for CHEK2 and TP53 mutation status. While ATM mutations were not associated with chemo-resistance, low ATM expression levels predicted chemo-resistance among patients with tumors wild-type for TP53 and CHEK2 (P = 0.028). Analyzing the ATM-chk2-p53 cascade, low ATM levels (defined as the lower 5 to 50% percentiles) or mutations inactivating TP53 or CHEK2 robustly predicted anthracycline resistance (P-values varying between 0.001 and 0.027 depending on the percentile used to define "low" ATM levels). These results were confirmed in an independent cohort of 109 patients treated with epirubicin monotherapy. In contrast, ATM-levels were not suppressed in resistant tumors harboring TP53 or CHEK2 mutations (P > 0.5). Our data indicate loss of function of the ATM-Chk2-p53 cascade to be strongly associated with resistance to anthracycline/mitomycin-containing chemotherapy in breast cancer.
-
CHEK2 mutations affecting kinase activity together with mutations in tp53 indicate a functional pathway associated with resistance to epirubicin in primary breast cancer
PLOS ONE, 2008Co-Authors: Stian Knappskog, Ranjan Chrisanthar, Erik Lokkevik, Gun Anker, Bjorn Ostenstad, Steinar Lundgren, Elisabet Ognedal BergeAbstract:Background: Chemoresistance is the main obstacle to cure in most malignant diseases. Anthracyclines are among the main drugs used for breast cancer therapy and in many other malignant conditions. Single parameter analysis or global gene expression profiles have failed to identify mechanisms causing in vivo resistance to anthracyclines. While we previously found TP53 mutations in the L2/L3 domains to be associated with drug resistance, some tumors harboring wild-type TP53 were also therapy resistant. The aim of this study was; 1) To explore alterations in the TP53 gene with respect to resistance to a regular dose epirubicin regimen (90 mg/m 2 every 3 week) in patients with primary, locally advanced breast cancer; 2) Identify critical mechanisms activating p53 in response to DNA damage in breast cancer; 3) Evaluate in vitro function of Chk2 and p14 proteins corresponding to identified mutations in the CHEK2 and p14 (ARF) genes; and 4) Explore potential CHEK2 or p14 (ARF) germline mutations with respect to family cancer incidence. Methods and Findings: Snap-frozen biopsies from 109 patients collected prior to epirubicin (as preoperative therapy were investigated for TP53, CHEK2 and p14 (ARF) mutations by sequencing the coding region and p14 (ARF) promoter methylations. TP53 mutastions were associated with chemoresistance, defined as progressive disease on therapy (p = 0.0358; p = 0.0136 for mutations affecting p53 loop domains L2/L3). Germline CHEK2 mutations (n = 3) were associated with therapy resistance (p = 0.0226). Combined, mutations affecting either CHEK2 or TP53 strongly predicted therapy resistance (p = 0.0101; TP53 mutations restricted to the L2/L3 domains: p = 0.0032). Two patients progressing on therapy harbored the CHEK2 mutation, Arg95Ter, completely abrogating Chk2 protein dimerization and kinase activity. One patient (Epi132) revealed family cancer occurrence resembling families harboring CHEK2 mutations in general, the other patient (epi203) was non-conclusive. No mutation or promoter hypermethylation in p14 (ARF) were detected. Conclusion: This study is the first reporting an association between CHEK2 mutations and therapy resistance in human cancers and to document mutations in two genes acting direct up/down-stream to each other to cause therapy failure, emphasizing the need to investigate functional cascades in future studies.
Dominika Wokołorczyk - One of the best experts on this subject based on the ideXlab platform.
-
Survival of Bladder or Renal Cancer in Patients With CHEK2 Mutations
2020Co-Authors: Elżbieta Złowocka-perłowska, Tadeusz Dębniak, Dominika Wokołorczyk, Marcin Słojewski, Artur Lemiński, Michał Soczawa, Thierry Van De Wetering, Joanna Trubicka, Wojcech Kluźniak, Cezary CybulskiAbstract:Abstract Purpose: The purpose of this study was to compare the survival of CHEK2 mutations positive and CHEK2 mutations negative patients with bladder or kidney cancer. Materials and methods: 1419 patients with bladder and 835 cases with kidney cancer and 8302 controls were genotyped for four CHEK2 variants: 1100delC, del5395, IVS2+1G>A and I157T. Predictors of survival were determined among CHEK2 carriers using the Cox proportional hazards model. The median follow-up was 17 years. Covariates included age (≤65; >66), smoking status (non-smoking; smoking), cancer family history (negative; positive) and gender (females; males). Results: Of the 1419 bladder patients enrolled in the study, 118 (8.32%) carried a CHEK2 mutation (all variants combined) (OR=1.4; 95% CI 1.17–1.78; p=0.0006), including 25 (1.76%) cases with a truncating mutation (OR=1.84; 95% CI, 1.17-2.89; p=0.01) and 93 (6.55%) patients with a missense mutation (OR=1.35; 95% CI, 1.07-1.7; p=0.01). We found no impact of CHEK2 mutations on bladder or kidney cancer survival. The 10-year survival for all CHEK2 mutation for bladder cancer carriers was 19% and for non-carriers was 13% (p=0.7). The 10-year survival for kidney cancer carriers was 6% and for non-carriers was 4% (p=0.9). Conclusion: We found no impact of CHEK2 mutations on bladder or kidney cancer survival regardless of their age, sex, cancer family history and smoking status.
-
CHEK2 mutations and the risk of papillary thyroid cancer.
International journal of cancer, 2015Co-Authors: Monika Siołek, Cezary Cybulski, Dominika Wokołorczyk, Danuta Gąsior-perczak, Artur Kowalik, Beata Kozak-klonowska, Aldona Kowalska, Małgorzata Chłopek, Wojciech Kluźniak, Iwona PałygaAbstract:Mutations in the cell cycle checkpoint kinase 2 (CHEK2) tumor suppressor gene are associated with multi-organ cancer susceptibility including cancers of the breast and prostate. A genetic association between thyroid and breast cancer has been suggested, however little is known about the determinants of this association. To characterize the association of CHEK2 mutations with thyroid cancer, we genotyped 468 unselected patients with papillary thyroid cancer and 468 (matched) cancer-free controls for four founder mutations of CHEK2 (1100delC, IVS2 + 1G>A, del5395 and I157T). We compared the family histories reported by patients with a CHEK2 mutation to those of non-carriers. A CHEK2 mutation was seen in 73 of 468 (15.6%) unselected patients with papillary thyroid cancer, compared to 28 of 460 (6.0%) age- and sex-matched controls (OR 3.3; p A, 1100delC or del5395) was associated with a higher risk of thyroid cancer (OR = 5.7; p = 0.006), than was the missense mutation I157T (OR = 2.8; p = 0.0001). CHEK2 mutation carriers reported a family history of breast cancer 2.2 times more commonly than non-carriers (16.4% vs.8.1%; p = 0.05). A CHEK2 mutation was found in seven of 11 women (63%) with multiple primary cancers of the breast and thyroid (OR = 10; p = 0.0004). These results suggest that CHEK2 mutations predispose to thyroid cancer, familial aggregations of breast and thyroid cancer and to double primary cancers of the breast and thyroid.
-
Survival from breast cancer in patients with CHEK2 mutations.
Breast cancer research and treatment, 2014Co-Authors: Tomasz Huzarski, Cezary Cybulski, Tomasz Byrski, Jacek Gronwald, Anna Jakubowska, Dominika Wokołorczyk, Pawel Domagala, Marek Szwiec, Dariusz Godlewski, E. KilarAbstract:The purpose of this study is to estimate 10-year survival rates for patients with early onset breast cancer, with and without a CHEK2 mutation and to identify prognostic factors among CHEK2-positive breast cancer patients. 3,592 women with stage I to stage III breast cancer, diagnosed at or below age 50, were tested for four founder mutations in the CHEK2 gene. Information on tumor characteristics and on treatments received was retrieved from medical records. Dates of death were obtained from the Poland Vital Statistics Registry. Survival curves were generated for the mutation-positive and -negative sub-cohorts. Predictors of survival were determined among CHEK2 carriers using the Cox proportional hazards model. 3,592 patients were eligible for the study, of whom 140 (3.9 %) carried a CHEK2-truncating mutation and 347 (9.7 %) carried a missense mutation. The mean follow-up was 8.9 years. The 10-year survival for all CHEK2 mutation carriers was 78.8 % (95 % CI 74.6-83.2 %) and for non-carriers was 80.1 % (95 % CI 78.5-81.8 %). Among women with a CHEK2-positive breast cancer, the adjusted hazard ratio associated with ER-positive status was 0.88 (95 % CI 0.48-1.62). Among women with an ER-positive breast cancer, the adjusted hazard ratio associated with a CHEK2 mutation was 1.31 (95 % CI 0.97-1.77). The survival of women with breast cancer and a CHEK2 mutation is similar to that of patients without a CHEK2 mutation.
-
The risk of gastric cancer in carriers of CHEK2 mutations
Familial cancer, 2013Co-Authors: Urszula Teodorczyk, Cezary Cybulski, Anna Jakubowska, Dominika Wokołorczyk, Teresa Starzynska, Pawel Domagala, Katarzyna Ferenc, K Marlicz, Małgorzata Ławniczak, Zbigniew BanaszkiewiczAbstract:CHEK2 is a tumor suppressor gene whose functions are central to the induction of cell cycle arrest and apoptosis following DNA damage. Mutations in CHEK2 have been associated with cancers at many sites, including breast and prostate cancers, but the relationship between CHEK2 and gastric cancer has not been extensively studied. In Poland, there are four known founder alleles of CHEK2; three alleles are protein truncating (1100delC, IVS2G>A, del5395) and the other is a missense variant (I157T). We examined the frequencies of four Polish founder mutations in the CHEK2 gene in 658 unselected gastric cancer patients, in 154 familial gastric cancer patients and in 8,302 controls. A CHEK2 mutation was seen in 57 of 658 (8.7 %) unselected patients with gastric cancer compared to 480 of 8,302 (5.8 %) controls (OR 1.6, p = 0.004). A CHEK2 mutation was present in 19 of 154 (12.3 %) familial cases (OR = 2.3, p = 0.001). The odds ratio for early onset (
-
Estrogen receptor status in CHEK2-positive breast cancers: implications for chemoprevention.
Clinical genetics, 2008Co-Authors: Cezary Cybulski, Tomasz Huzarski, Tomasz Byrski, Jacek Gronwald, Bohdan Gorski, Anna Jakubowska, Tadeusz Dębniak, Dominika Wokołorczyk, B. Masojć, Steven A. NarodAbstract:To investigate the relationship between CHEK2 mutation status and estrogen receptor (ER) status in unselected cases of early-onset breast cancer from Poland, we screened 4441 women diagnosed with breast cancer younger than 51 years and 7217 controls for three inherited mutations in CHEK2 (1100delC, IVS2+1G>A, del5395). ER status was compared between CHEK2-positive and CHEK2-negative breast cancer cases. A truncating mutation in CHEK2 was seen in 140 of 4441 cases and in 70 of 7217 controls [odds ratio (OR) = 3.3; 95% CI = 2.5-4.4; p < 0.0001]. ER status was available for 92 of 140 mutation carriers and for 3001 of 4301 non-carriers with breast cancer. The OR was higher for ER-positive cancers (OR = 3.9; 95% CI = 2.7-5.4; p < 0.0001) than for ER-negative cancers (OR = 2.1; 95% CI = 1.3-3.3; p = 0.002). Sixty-six of the 92 breast cancers in carriers of CHEK2 truncating mutations were ER positive compared with 1742 of the 3001 breast cancers in non-carriers (72% vs 58%; p = 0.01). Women with a CHEK2 mutation face a fourfold increase in the risk of ER-positive breast cancer and might be candidates for tamoxifen chemoprevention.