Absence of the CHEK2 c.1100delC mutation in familial breast and ovarian cancer in Colombia: a case-control study

Background: BRCA1 and BRCA2 have been identified as high-penetrance breast cancer predisposition genes, but they only account for a small fraction of the inherited component of breast cancer. To explain the remaining cases, a polygenic model with a large number of low- to moderate-penetrance genes have been proposed; one of these, is the CHEK2 gene (Checkpoint Kinase 2). The objective of this study was to determine the role of the CHEK2 gene, specifically the c.1100delC mutation in familial breast cancer susceptibility in Colombian patients. Methods: We screened 131 high-risk breast and/or ovarian cancer patients (negative for mutations in BRCA1 and BRCA2) and 131 controls for the germline mutation CHEK2 c.1100delC by allele-specific PCR. Results: None of the cases or controls showed the CHEK2 c.1100delC mutation, neither as a homozygote nor as a heterozygote. Conclusions: Our results suggest that the CHEK2 c.1100delC mutation is not a risk factor for genetic susceptibility to familial breast or ovarian cancer in the Colombian population. The absence of the CHEK2 c.1100delC mutation in our population show the importance of considering ethnic background before offering a genetic test.

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Clinical Implications of the Breast Cancer Susceptibility Genes BRCA1 and BRCA2

Women s Health ◽

10.1517/17455057.1.1.027 ◽

2005 ◽

Vol 1 (1) ◽

pp. 27-34

Author(s):

Steven A Narod

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Cancer Susceptibility ◽

Cancer Chemoprevention ◽

Breast Cancer Susceptibility ◽

High Risk Population ◽

Clinical Genetics ◽

Breast And Ovarian Cancer ◽

Brca1 And Brca2 ◽

Cancer Susceptibility Genes

Genetic testing for BRCA1 and BRCA2 mutations has become an important part of the practice of medical oncology and clinical genetics over the past decade. Increasing numbers of women are requesting a genetic test so that they may better understand their personal risks of breast and ovarian cancer, and so that they may take appropriate measures to reduce the risk. Several of the risk factors can be modified, including breastfeeding and the use of oral contraceptives. A significant number of women opt for preventive mastectomy or oophorectomy, which will dramatically reduce the risks of breast and ovarian cancer. Chemoprevention with tamoxifen is still uncommon, largely due to women's fears of the side effects of the drug. A number of studies have shown that magnetic resonance imaging is superior to conventional mammography in terms of the early detection of breast cancer in the high-risk population. This article explores what is known about assessing genetic risk and the evidence supporting a range of preventive strategies.

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Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2015.65.0747 ◽

2016 ◽

Vol 34 (13) ◽

pp. 1460-1468 ◽

Cited By ~ 216

Author(s):

Nadine Tung ◽

Nancy U. Lin ◽

John Kidd ◽

Brian A. Allen ◽

Nanda Singh ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Triple Negative ◽

Cancer Susceptibility ◽

Germline Mutations ◽

Cancer Predisposition ◽

Ashkenazi Jewish ◽

Breast Cancer Predisposition ◽

Cancer Susceptibility Genes ◽

Predisposition Genes

Purpose Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population. Methods Patients with stages I to III breast cancer who were seen at a single cancer center between 2010 and 2012, and who agreed to participate in research DNA banking, were included (N = 488). Personal and family cancer histories were collected and germline DNA was sequenced with NGS to identify mutations. Results Deleterious mutations were identified in 10.7% of women, including 6.1% in BRCA1/2 (5.1% in non-Ashkenazi Jewish patients) and 4.6% in other breast/ovarian cancer predisposition genes including CHEK2 (n = 10), ATM (n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2. Whereas young age (P < .01), Ashkenazi Jewish ancestry (P < .01), triple-negative breast cancer (P = .01), and family history of breast/ovarian cancer (P = .01) predicted for BRCA1/2 mutations, no factors predicted for mutations in other breast cancer predisposition genes. Conclusion Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group. Additional cohorts will be helpful to define individuals at higher risk of carrying mutations in genes other than BRCA1/2.

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BRCAPRO Validation, Sensitivity of Genetic Testing of BRCA1/BRCA2, and Prevalence of Other Breast Cancer Susceptibility Genes

Journal of Clinical Oncology ◽

10.1200/jco.2002.05.121 ◽

2002 ◽

Vol 20 (11) ◽

pp. 2701-2712 ◽

Cited By ~ 332

Author(s):

Donald A. Berry ◽

Edwin S. Iversen ◽

Daniel F. Gudbjartsson ◽

Elaine H. Hiller ◽

Judy E. Garber ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Genetic Testing ◽

Cancer Susceptibility ◽

Breast Cancer Susceptibility ◽

Susceptibility Genes ◽

Breast And Ovarian Cancer ◽

Brca1 And Brca2 ◽

Cancer Susceptibility Genes ◽

Breast Cancer Susceptibility Genes

PURPOSE: To compare genetic test results for deleterious mutations of BRCA1 and BRCA2 with estimated probabilities of carrying such mutations; to assess sensitivity of genetic testing; and to assess the relevance of other susceptibility genes in familial breast and ovarian cancer. PATIENTS AND METHODS: Data analyzed were from six high-risk genetic counseling clinics and concern individuals from families for which at least one member was tested for mutations at BRCA1 and BRCA2. Predictions of genetic predisposition to breast and ovarian cancer for 301 individuals were made using BRCAPRO, a statistical model and software using Mendelian genetics and Bayesian updating. Model predictions were compared with the results of genetic testing. RESULTS: Among the test individuals, 126 were Ashkenazi Jewish, three were male subjects, 243 had breast cancer, 49 had ovarian cancer, 34 were unaffected, and 139 tested positive for BRCA1 mutations and 29 for BRCA2 mutations. BRCAPRO performed well: for the 150 probands with the smallest BRCAPRO carrier probabilities (average, 29.0%), the proportion testing positive was 32.7%; for the 151 probands with the largest carrier probabilities (average, 95.2%), 78.8% tested positive. Genetic testing sensitivity was estimated to be at least 85%, with false-negatives including mutations of susceptibility genes heretofore unknown. CONCLUSION: BRCAPRO is an accurate counseling tool for determining the probability of carrying mutations of BRCA1 and BRCA2. Genetic testing for BRCA1 and BRCA2 is highly sensitive, missing an estimated 15% of mutations. In the populations studied, breast cancer susceptibility genes other than BRCA1 and BRCA2 either do not exist, are rare, or are associated with low disease penetrance.

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Inherited Mutations in 17 Breast Cancer Susceptibility Genes Among a Large Triple-Negative Breast Cancer Cohort Unselected for Family History of Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2014.57.1414 ◽

2015 ◽

Vol 33 (4) ◽

pp. 304-311 ◽

Cited By ~ 304

Author(s):

Fergus J. Couch ◽

Steven N. Hart ◽

Priyanka Sharma ◽

Amanda Ewart Toland ◽

Xianshu Wang ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Testing ◽

Family History ◽

Triple Negative ◽

Cancer Susceptibility ◽

Breast Cancer Susceptibility ◽

Deleterious Mutations ◽

Brca1 And Brca2 ◽

Predisposition Genes ◽

History Of

Purpose Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC. Patients and Methods Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations. Results Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P < .001) and had higher-grade tumors (P = .01) than those without mutations. Conclusion Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives.

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Unclassified Variants in the Breast Cancer Susceptibility Genes BRCA1 and BRCA2

The Role of Genetics in Breast and Reproductive Cancers ◽

10.1007/978-1-4419-0477-5_3 ◽

2009 ◽

pp. 49-73 ◽

Cited By ~ 1

Author(s):

Sean V. Tavtigian

Keyword(s):

Breast Cancer ◽

Cancer Susceptibility ◽

Breast Cancer Susceptibility ◽

Susceptibility Genes ◽

Brca1 And Brca2 ◽

Unclassified Variants ◽

Cancer Susceptibility Genes ◽

Breast Cancer Susceptibility Genes

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Risk Estimation as a Decision-Making Tool for Genetic Analysis of the Breast Cancer Susceptibility Genes

Disease Markers ◽

10.1155/1999/238375 ◽

1999 ◽

Vol 15 (1-3) ◽

pp. 53-65 ◽

Cited By ~ 5

Author(s):

Jenny Chang-Claude ◽

Heiko Becher ◽

Maria Caligo ◽

Diana Eccles ◽

Gareth Evans ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Familial Breast Cancer ◽

Genetic Model ◽

Germ Line ◽

Cancer Susceptibility ◽

Breast Cancer Susceptibility ◽

Cancer Gene ◽

Brca2 Mutations ◽

Breast Cancer Gene

For genetic counselling of a woman on familial breast cancer, an accurate evaluation of the probability that she carries a germ-line mutation is needed to assist in making decisions about genetic-testing.We used data from eight collaborating centres comprising 618 families (346 breast cancer only, 239 breast or ovarian cancer) recruited as research families or counselled for familial breast cancer, representing a broad range of family structures. Screening was performed in affected women from 618 families for germ-line mutations in BRCA1 and in 176 families for BRCA2 mutations, using different methods including SSCP, CSGE, DGGE, FAMA and PTT analysis followed by direct sequencing. Germ-line BRCA1 mutations were detected in 132 families and BRCA2 mutations in 16 families. The probability of being a carrier of a dominant breast cancer gene was calculated for the screened individual under the established genetic model for breast cancer susceptibility, first, with parameters for age-specific penetrances for breast cancer only [7] and, second, with age-specific penetrances for ovarian cancer in addition [20]. Our results indicate that the estimated probability of carrying a dominant breast cancer gene gives a direct measure of the likelihood of detecting mutations in BRCA1 and BRCA2. For breast/ovarian cancer families, the genetic model according to Narod et al. [20] is preferable for calculating the proband's genetic risk, and gives detection rates that indicate a 50% sensitivity of the gene test. Due to the incomplete BRCA2 screening of the families, we cannot yet draw any conclusions with respect to the breast cancer only families.

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PALB2 Functionally Connects the Breast Cancer Susceptibility Proteins BRCA1 and BRCA2

Molecular Cancer Research ◽

10.1158/1541-7786.mcr-09-0123 ◽

2009 ◽

Vol 7 (7) ◽

pp. 1110-1118 ◽

Cited By ~ 168

Author(s):

Fan Zhang ◽

Qiang Fan ◽

Keqin Ren ◽

Paul R. Andreassen

Keyword(s):

Breast Cancer ◽

Cancer Susceptibility ◽

Breast Cancer Susceptibility ◽

Brca1 And Brca2

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Detection of „Hotspot Mutations in Catalytic Subunit of Phosphatidylinositol 3-Kinase (Pik3ca) by Allele-Specific Polymerase Chain Reaction

Acta Medica Martiniana ◽

10.2478/acm-2014-0007 ◽

2014 ◽

Vol 14 (2) ◽

pp. 10-15 ◽

Cited By ~ 1

Author(s):

Mendelova A. ◽

Holubekova V. ◽

Zubor P. ◽

Jezkova E. ◽

Gemzova K. ◽

...

Keyword(s):

Breast Cancer ◽

Direct Sequencing ◽

Chain Reaction ◽

Pik3ca Gene ◽

Specific Polymerase Chain Reaction ◽

Specific Pcr ◽

Allele Specific ◽

Hotspot Mutations ◽

Polymerase Chain ◽

Allele Specific Pcr

Abstract The phosphatidylinositol 3-kinases (PI3Ks) are a family of proteins involved in the regulation of cell survival, growth, metabolism, and glucose homeostasis. Increased PI3K activity is associated with many cancers. PIK3CA gene (encoding p110 , the catalytic subunit of PI3K) is commonly mutated in breast cancer. In our study we focused on the detection of “hotspot” mutations in exons 9 and 20 of the PIK3CA gene in paraffin-embedded tissue of patients with breast cancer. We optimized conditions of allele specific polymerase chain reaction (PCR) and we used direct sequencing to verify our results. Overall, three “hotspot” mutations in PIK3CA gene in paraffin-embadded tissue from breast cancer were detected by allele-specific PCR. All results were verified by direct sequencing of PCR products and we observed 100% agreement between those two methods. We confirmed that allele-specific PCR assay is low cost method usefull for accurate detection of PIK3CA mutations.

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