J. Gronwald - Profile on Academia.edu (original) (raw)

Papers by J. Gronwald

Research paper thumbnail of Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

Scope-We re-evaluated previously reported associations between variants in pathways of onecarbon ... more Scope-We re-evaluated previously reported associations between variants in pathways of onecarbon (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. Methods and Results-Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls and among 2,281 cases and 3,444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for DPYD variants rs11587873 (OR=0.92, P=6x10 -5 ) and rs828054 (OR=1.06, P=1x10 -4 ). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT and TYMS, also interacted significantly with folate in a multi-variant analysis (corrected P=9.9x10 -6 ) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in one-carbon transfer, previously reported with OC, suggested lower risk at higher folate (P interaction =0.03-0.006). Conclusions-Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-byfolate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Research paper thumbnail of The risk of breast cancer in women with a CHEK2 mutation

Hereditary Cancer in Clinical Practice, 2012

Research paper thumbnail of Population Screening of CHEK2 Mutations in Poland

Hereditary Cancer in Clinical Practice, 2006

Research paper thumbnail of The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions

British Journal of Cancer, 2008

Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously dev... more Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920 -1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program ().

Research paper thumbnail of Duration of tamoxifen use and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers

Purpose-Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approxim... more Purpose-Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80%. Tamoxifen treatment of the first cancer has been associated with a reduction in the risk of a subsequent contralateral cancer. Methods-We studied 1504 women with a known BRCA1 or BRCA2 mutation, 411 women with bilateral breast cancer (cases) and 1093 women with unilateral breast cancer (controls) in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of first breast cancer as the cases. For each woman who used tamoxifen, the starting and stopping dates were abstracted and the duration of tamoxifen use was calculated. Results-331 women had used tamoxifen (22%); of these 84 (25%) had completed four or more years of tamoxifen, the remainder stopped prematurely or were current users. For women with up to one year of tamoxifen use, the odds ratio for contralateral breast cancer was 0.37 (95% CI: 0.20 -0.69; p = 0.001) compared to women with no tamoxifen use. Among women with one to four years of tamoxifen use the odds ratio was 0.53 (95% CI: 0.32-0.87; p = 0.01). Among women with four or more years of tamoxifen use the odds ratio was 0.83 (95% CI: 0.44 -1.55; p = 0.55). Conclusion-Short-term use of tamoxifen for chemoprevention in BRCA1 and BRCA2 mutation carriers may be as effective as a conventional five year course of treatment.

Research paper thumbnail of Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

British Journal of Cancer, 2012

BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that o... more BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C4T (rs6917) polymorphism and the MTHFR 677 C4T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C4T and MTHFR 677 C4T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C4T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

Research paper thumbnail of Management of ovarian and endometrial cancers in women belonging to HNPCC carrier families: review of the literature and results of cancer risk assessment in Polish HNPCC families

Hereditary cancer in clinical practice, 2015

Over half the cancer deaths in HNPCC families are due to extra-colonic malignancies that include ... more Over half the cancer deaths in HNPCC families are due to extra-colonic malignancies that include endometrial and ovarian cancers. The benefits of surveillance for gynecological cancers are not yet proven and there is no consensus on the optimal surveillance recommendations for women with MMR mutations. We performed a systematic review of the literature and evaluated gynecological cancer risk in a series of 631 Polish HNPCC families classified into either Lynch Syndrome (LS, MMR mutations detected) or HNPCC (fulfillment of the Amsterdam or modified Amsterdam criteria). Published data clearly indicates no benefit for ovarian cancer screening in contrast to risk reducing surgery. We confirmed a significantly increased risk of OC in Polish LS families (OR = 4,6, p < 0.001) and an especially high risk of OC was found for women under 50 years of age: OR = 32,6, p < 0.0001 (95% CI 12,96-81,87). The cumulative OC risk to 50 year of life was calculated to be 10%. Six out of 19 (32%) ea...

Research paper thumbnail of Molecular Analyses in Diagnosis of High Genetic Predispositions to Malignancies

Journal of Clinical Biochemistry and Nutrition, 2000

This publication summarizes recent progress in DNA testing of genes related to high predispositio... more This publication summarizes recent progress in DNA testing of genes related to high predisposition to malignancies achieved

Research paper thumbnail of A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2

Nature Genetics, 2009

Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes exp... more Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk 1 . We performed a genome wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817 cases and 2,353 controls from the UK and ~2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P<10 -8 ). The most significant SNP (rs3814113; P = 2.5 × 10 -17 ) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls confirming its association (combined data odds ratio = 0.82 95% CI 0.79 -0.86, P -trend = 5.1 × 10 -19 ). The association differs by histological subtype, being strongest for serous ovarian cancers (OR 0.77 95% CI 0.73 -0.81, P trend = 4.1 × 10 -21 ). Women with a first-degree relative diagnosed with epithelial ovarian cancer have a three-fold increased risk of developing the disease 2 . Environmental and genetic factors contribute to this increased risk, but studies of twins suggest that genetic factors are more important. BRCA1 and BRCA2 mutations confer high risk of ovarian cancer and are responsible for most families with three or more ovarian cancer cases. They account for less than half the excess familial risk and it is likely that the residual risk is due to a combination of common and/or rare alleles that confer moderate to low penetrance susceptibility 5 .

Research paper thumbnail of Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies

Journal of Medical Genetics, 2005

Research paper thumbnail of Cancer risks in first degree relatives of BRCA1 mutation carriers: effects of mutation and proband disease status

Cancer risks in first degree relatives of BRCA1 mutation carriers: effects of mutation and proband disease status

Journal of Medical Genetics, 2005

Research paper thumbnail of A protein truncating BRCA1 allele with a low penetrance of breast cancer

Journal of Medical Genetics, 2004

Research paper thumbnail of Germline MSH2 and MLH1 mutational spectrum in HNPCC families from Poland and the Baltic States

Journal of Medical Genetics, 2002

Research paper thumbnail of Pathologic Complete Response Rates in Young Women With BRCA1-Positive Breast Cancers After Neoadjuvant Chemotherapy

Journal of Clinical Oncology, 2010

Purpose To estimate the rate of pathologic complete response (pCR) to neoadjuvant chemotherapy in... more Purpose To estimate the rate of pathologic complete response (pCR) to neoadjuvant chemotherapy in BRCA1 mutation carriers according to chemotherapy regimen. Patients and Methods From a registry of 6,903 patients, we identified 102 women who carried a BRCA1 founder mutation and who had been treated for breast cancer with neoadjuvant chemotherapy. Pathologic complete response was evaluated using standard criteria. Results Twenty-four (24%) of the 102 BRCA1 mutation carriers experienced a pCR. The response rate varied widely with treatment: a pCR was observed in one (7%) of 14 women treated with cyclophosphamide, methotrexate, and fluorouracil (CMF); in two (8%) of 25 women treated with doxorubicin and docetaxel (AT); in 11 (22%) of 51 women treated with doxorubicin and cyclophosphamide (AC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC), and in 10 (83%) of 12 women treated with cisplatin. Conclusion A low rate of pCR was observed in women with breast cancer and a BRCA1 mutat...

Research paper thumbnail of Risk of Breast Cancer in Women With a CHEK2 Mutation With and Without a Family History of Breast Cancer

Journal of Clinical Oncology, 2011

Purpose To estimate the risk of breast cancer in a woman who has a CHEK2 mutation depending on he... more Purpose To estimate the risk of breast cancer in a woman who has a CHEK2 mutation depending on her family history of breast cancer. Patients and Methods Seven thousand four hundred ninety-four BRCA1 mutation–negative patients with breast cancer and 4,346 control women were genotyped for four founder mutations in CHEK2 (del5395, IVS2+1G>A, 1100delC, and I157T). Results A truncating mutation (IVS2+1G>A, 1100delC, or del5395) was present in 227 patients (3.0%) and in 37 female controls (0.8%; odds ratio [OR], 3.6; 95% CI, 2.6 to 5.1). The OR was higher for women with a first- or second-degree relative with breast cancer (OR, 5.0; 95% CI, 3.3 to 7.6) than for women with no family history (OR, 3.3; 95% CI, 2.3 to 4.7). If both a first- and second-degree relative were affected with breast cancer, the OR was 7.3 (95% CI, 3.2 to 16.8). Assuming a baseline risk of 6%, we estimate the lifetime risks for carriers of CHEK2 truncating mutations to be 20% for a woman with no affected relati...

Research paper thumbnail of Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

Human Molecular Genetics, 2011

Research paper thumbnail of Long polymerase chain reaction in detection of germline deletions in the von Hippel-Lindau tumour suppressor gene

Human Genetics, 1999

Experimental conditions for detection of germline deletions of the von Hippel-Lindau (VHL) gene b... more Experimental conditions for detection of germline deletions of the von Hippel-Lindau (VHL) gene by means of long polymerase chain reaction have been established. Primers were designed to analyse the VHL gene in three overlapping fragments: 12.5 kb in length containing promoter and exons 1 and 2; 8.7 kb in length containing exons 2 and 3; and 16 kb in length containing exons 2 and 3 and the 3' untranslated region. Using the described procedure, it was possible to detect large deletions in four of five cases with such mutations previously detected by Southern blotting and in 5 of 11 unrelated Polish VHL patients in whom constitutional VHL gene mutations were not found by sequencing.

Research paper thumbnail of Common variants at 19p13 are associated with susceptibility to ovarian cancer

Nature genetics, 2010

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in th... more Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10⁻⁴ and P = 6 × 10⁻⁴, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10⁻⁹ and P = 4 × 10⁻¹¹, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.

Research paper thumbnail of A high frequency of BRCA2 gene mutations in Polish families with ovarian and stomach cancer

European Journal of Human Genetics, 2003

Germ-line mutations in the BRCA2 gene are associated with a wide range of cancer types, including... more Germ-line mutations in the BRCA2 gene are associated with a wide range of cancer types, including the breast, ovary, pancreas, prostate and melanoma. In this study, we evaluated the importance of a family history of stomach cancer in predicting the presence of a BRCA2 mutation in Polish patients with ovarian cancer. A BRCA2 mutation was found in eight of 34 women with ovarian cancer and a family history of stomach cancer versus three of 75 women with ovarian cancer and a family history of ovarian cancer, but not of stomach cancer (odds ratio ¼ 7.4; 95% CI 1.8-30; P ¼ 0.004). The results of this study suggest that, in the Polish population, the constellation of ovarian and stomach cancer predicts the presence of a germ-line BRCA2 mutation and confirms that stomach cancer is part of the spectrum of BRCA2 mutations. It is expected that the penetrance of BRCA2 mutations for stomach cancer will vary from country to country, reflecting local environmental and lifestyle factors.

Research paper thumbnail of NOD2 variants and the risk of malignant melanoma

European Journal of Cancer Prevention, 2005

Both hereditary and environmental factors are important in the aetiology of malignant melanoma. A... more Both hereditary and environmental factors are important in the aetiology of malignant melanoma. Among the risk factors for malignant melanoma are immunodeficiency and immunosuppression. The recently identified NOD2 gene is involved in the regulation of immune function through activation of the transcription factor nuclear factor-jB (NF-jB). Three common NOD2 mutations -3020insC, G908R and R702W -have been shown to be associated with chronic inflammatory disease such as Crohn's disease, the 3020insC also with human malignancy colorectal cancer. We examined the frequency of the NOD2 variants in 424 patients with malignant melanoma and 649 controls. The 3020insC mutation was present in 6.9% of unselected cases and 7% of the controls (odds ratio (OR) 1.0; P not significant). The mutation was present in 6.8% of 162 cases diagnosed under the age of 50 and in 7.1% of cases diagnosed after the age of 50. A mutation was present in the index case in 5% of 40 familial melanomas (OR 0.7; P not significant). There were no statistically significant differences between prevalence of G908R and R702W in malignant melanoma patients and controls. In conclusion, the three common NOD2 mutations are not associated with increased risk of development of malignant melanoma.

Research paper thumbnail of Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

Scope-We re-evaluated previously reported associations between variants in pathways of onecarbon ... more Scope-We re-evaluated previously reported associations between variants in pathways of onecarbon (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. Methods and Results-Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls and among 2,281 cases and 3,444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for DPYD variants rs11587873 (OR=0.92, P=6x10 -5 ) and rs828054 (OR=1.06, P=1x10 -4 ). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT and TYMS, also interacted significantly with folate in a multi-variant analysis (corrected P=9.9x10 -6 ) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in one-carbon transfer, previously reported with OC, suggested lower risk at higher folate (P interaction =0.03-0.006). Conclusions-Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-byfolate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Research paper thumbnail of The risk of breast cancer in women with a CHEK2 mutation

Hereditary Cancer in Clinical Practice, 2012

Research paper thumbnail of Population Screening of CHEK2 Mutations in Poland

Hereditary Cancer in Clinical Practice, 2006

Research paper thumbnail of The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions

British Journal of Cancer, 2008

Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously dev... more Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920 -1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program ().

Research paper thumbnail of Duration of tamoxifen use and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers

Purpose-Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approxim... more Purpose-Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80%. Tamoxifen treatment of the first cancer has been associated with a reduction in the risk of a subsequent contralateral cancer. Methods-We studied 1504 women with a known BRCA1 or BRCA2 mutation, 411 women with bilateral breast cancer (cases) and 1093 women with unilateral breast cancer (controls) in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of first breast cancer as the cases. For each woman who used tamoxifen, the starting and stopping dates were abstracted and the duration of tamoxifen use was calculated. Results-331 women had used tamoxifen (22%); of these 84 (25%) had completed four or more years of tamoxifen, the remainder stopped prematurely or were current users. For women with up to one year of tamoxifen use, the odds ratio for contralateral breast cancer was 0.37 (95% CI: 0.20 -0.69; p = 0.001) compared to women with no tamoxifen use. Among women with one to four years of tamoxifen use the odds ratio was 0.53 (95% CI: 0.32-0.87; p = 0.01). Among women with four or more years of tamoxifen use the odds ratio was 0.83 (95% CI: 0.44 -1.55; p = 0.55). Conclusion-Short-term use of tamoxifen for chemoprevention in BRCA1 and BRCA2 mutation carriers may be as effective as a conventional five year course of treatment.

Research paper thumbnail of Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

British Journal of Cancer, 2012

BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that o... more BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C4T (rs6917) polymorphism and the MTHFR 677 C4T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C4T and MTHFR 677 C4T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C4T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

Research paper thumbnail of Management of ovarian and endometrial cancers in women belonging to HNPCC carrier families: review of the literature and results of cancer risk assessment in Polish HNPCC families

Hereditary cancer in clinical practice, 2015

Over half the cancer deaths in HNPCC families are due to extra-colonic malignancies that include ... more Over half the cancer deaths in HNPCC families are due to extra-colonic malignancies that include endometrial and ovarian cancers. The benefits of surveillance for gynecological cancers are not yet proven and there is no consensus on the optimal surveillance recommendations for women with MMR mutations. We performed a systematic review of the literature and evaluated gynecological cancer risk in a series of 631 Polish HNPCC families classified into either Lynch Syndrome (LS, MMR mutations detected) or HNPCC (fulfillment of the Amsterdam or modified Amsterdam criteria). Published data clearly indicates no benefit for ovarian cancer screening in contrast to risk reducing surgery. We confirmed a significantly increased risk of OC in Polish LS families (OR = 4,6, p < 0.001) and an especially high risk of OC was found for women under 50 years of age: OR = 32,6, p < 0.0001 (95% CI 12,96-81,87). The cumulative OC risk to 50 year of life was calculated to be 10%. Six out of 19 (32%) ea...

Research paper thumbnail of Molecular Analyses in Diagnosis of High Genetic Predispositions to Malignancies

Journal of Clinical Biochemistry and Nutrition, 2000

This publication summarizes recent progress in DNA testing of genes related to high predispositio... more This publication summarizes recent progress in DNA testing of genes related to high predisposition to malignancies achieved

Research paper thumbnail of A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2

Nature Genetics, 2009

Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes exp... more Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk 1 . We performed a genome wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817 cases and 2,353 controls from the UK and ~2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P<10 -8 ). The most significant SNP (rs3814113; P = 2.5 × 10 -17 ) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls confirming its association (combined data odds ratio = 0.82 95% CI 0.79 -0.86, P -trend = 5.1 × 10 -19 ). The association differs by histological subtype, being strongest for serous ovarian cancers (OR 0.77 95% CI 0.73 -0.81, P trend = 4.1 × 10 -21 ). Women with a first-degree relative diagnosed with epithelial ovarian cancer have a three-fold increased risk of developing the disease 2 . Environmental and genetic factors contribute to this increased risk, but studies of twins suggest that genetic factors are more important. BRCA1 and BRCA2 mutations confer high risk of ovarian cancer and are responsible for most families with three or more ovarian cancer cases. They account for less than half the excess familial risk and it is likely that the residual risk is due to a combination of common and/or rare alleles that confer moderate to low penetrance susceptibility 5 .

Research paper thumbnail of Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies

Journal of Medical Genetics, 2005

Research paper thumbnail of Cancer risks in first degree relatives of BRCA1 mutation carriers: effects of mutation and proband disease status

Cancer risks in first degree relatives of BRCA1 mutation carriers: effects of mutation and proband disease status

Journal of Medical Genetics, 2005

Research paper thumbnail of A protein truncating BRCA1 allele with a low penetrance of breast cancer

Journal of Medical Genetics, 2004

Research paper thumbnail of Germline MSH2 and MLH1 mutational spectrum in HNPCC families from Poland and the Baltic States

Journal of Medical Genetics, 2002

Research paper thumbnail of Pathologic Complete Response Rates in Young Women With BRCA1-Positive Breast Cancers After Neoadjuvant Chemotherapy

Journal of Clinical Oncology, 2010

Purpose To estimate the rate of pathologic complete response (pCR) to neoadjuvant chemotherapy in... more Purpose To estimate the rate of pathologic complete response (pCR) to neoadjuvant chemotherapy in BRCA1 mutation carriers according to chemotherapy regimen. Patients and Methods From a registry of 6,903 patients, we identified 102 women who carried a BRCA1 founder mutation and who had been treated for breast cancer with neoadjuvant chemotherapy. Pathologic complete response was evaluated using standard criteria. Results Twenty-four (24%) of the 102 BRCA1 mutation carriers experienced a pCR. The response rate varied widely with treatment: a pCR was observed in one (7%) of 14 women treated with cyclophosphamide, methotrexate, and fluorouracil (CMF); in two (8%) of 25 women treated with doxorubicin and docetaxel (AT); in 11 (22%) of 51 women treated with doxorubicin and cyclophosphamide (AC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC), and in 10 (83%) of 12 women treated with cisplatin. Conclusion A low rate of pCR was observed in women with breast cancer and a BRCA1 mutat...

Research paper thumbnail of Risk of Breast Cancer in Women With a CHEK2 Mutation With and Without a Family History of Breast Cancer

Journal of Clinical Oncology, 2011

Purpose To estimate the risk of breast cancer in a woman who has a CHEK2 mutation depending on he... more Purpose To estimate the risk of breast cancer in a woman who has a CHEK2 mutation depending on her family history of breast cancer. Patients and Methods Seven thousand four hundred ninety-four BRCA1 mutation–negative patients with breast cancer and 4,346 control women were genotyped for four founder mutations in CHEK2 (del5395, IVS2+1G>A, 1100delC, and I157T). Results A truncating mutation (IVS2+1G>A, 1100delC, or del5395) was present in 227 patients (3.0%) and in 37 female controls (0.8%; odds ratio [OR], 3.6; 95% CI, 2.6 to 5.1). The OR was higher for women with a first- or second-degree relative with breast cancer (OR, 5.0; 95% CI, 3.3 to 7.6) than for women with no family history (OR, 3.3; 95% CI, 2.3 to 4.7). If both a first- and second-degree relative were affected with breast cancer, the OR was 7.3 (95% CI, 3.2 to 16.8). Assuming a baseline risk of 6%, we estimate the lifetime risks for carriers of CHEK2 truncating mutations to be 20% for a woman with no affected relati...

Research paper thumbnail of Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

Human Molecular Genetics, 2011

Research paper thumbnail of Long polymerase chain reaction in detection of germline deletions in the von Hippel-Lindau tumour suppressor gene

Human Genetics, 1999

Experimental conditions for detection of germline deletions of the von Hippel-Lindau (VHL) gene b... more Experimental conditions for detection of germline deletions of the von Hippel-Lindau (VHL) gene by means of long polymerase chain reaction have been established. Primers were designed to analyse the VHL gene in three overlapping fragments: 12.5 kb in length containing promoter and exons 1 and 2; 8.7 kb in length containing exons 2 and 3; and 16 kb in length containing exons 2 and 3 and the 3' untranslated region. Using the described procedure, it was possible to detect large deletions in four of five cases with such mutations previously detected by Southern blotting and in 5 of 11 unrelated Polish VHL patients in whom constitutional VHL gene mutations were not found by sequencing.

Research paper thumbnail of Common variants at 19p13 are associated with susceptibility to ovarian cancer

Nature genetics, 2010

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in th... more Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10⁻⁴ and P = 6 × 10⁻⁴, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10⁻⁹ and P = 4 × 10⁻¹¹, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.

Research paper thumbnail of A high frequency of BRCA2 gene mutations in Polish families with ovarian and stomach cancer

European Journal of Human Genetics, 2003

Germ-line mutations in the BRCA2 gene are associated with a wide range of cancer types, including... more Germ-line mutations in the BRCA2 gene are associated with a wide range of cancer types, including the breast, ovary, pancreas, prostate and melanoma. In this study, we evaluated the importance of a family history of stomach cancer in predicting the presence of a BRCA2 mutation in Polish patients with ovarian cancer. A BRCA2 mutation was found in eight of 34 women with ovarian cancer and a family history of stomach cancer versus three of 75 women with ovarian cancer and a family history of ovarian cancer, but not of stomach cancer (odds ratio ¼ 7.4; 95% CI 1.8-30; P ¼ 0.004). The results of this study suggest that, in the Polish population, the constellation of ovarian and stomach cancer predicts the presence of a germ-line BRCA2 mutation and confirms that stomach cancer is part of the spectrum of BRCA2 mutations. It is expected that the penetrance of BRCA2 mutations for stomach cancer will vary from country to country, reflecting local environmental and lifestyle factors.

Research paper thumbnail of NOD2 variants and the risk of malignant melanoma

European Journal of Cancer Prevention, 2005

Both hereditary and environmental factors are important in the aetiology of malignant melanoma. A... more Both hereditary and environmental factors are important in the aetiology of malignant melanoma. Among the risk factors for malignant melanoma are immunodeficiency and immunosuppression. The recently identified NOD2 gene is involved in the regulation of immune function through activation of the transcription factor nuclear factor-jB (NF-jB). Three common NOD2 mutations -3020insC, G908R and R702W -have been shown to be associated with chronic inflammatory disease such as Crohn's disease, the 3020insC also with human malignancy colorectal cancer. We examined the frequency of the NOD2 variants in 424 patients with malignant melanoma and 649 controls. The 3020insC mutation was present in 6.9% of unselected cases and 7% of the controls (odds ratio (OR) 1.0; P not significant). The mutation was present in 6.8% of 162 cases diagnosed under the age of 50 and in 7.1% of cases diagnosed after the age of 50. A mutation was present in the index case in 5% of 40 familial melanomas (OR 0.7; P not significant). There were no statistically significant differences between prevalence of G908R and R702W in malignant melanoma patients and controls. In conclusion, the three common NOD2 mutations are not associated with increased risk of development of malignant melanoma.