Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2016
Oxidative DNA damage is considered to be a major cause of neurodegeneration and internal tumors o... more Oxidative DNA damage is considered to be a major cause of neurodegeneration and internal tumors observed in syndromes that result from nucleotide excision repair (NER) deficiencies, such as Xeroderma Pigmentosum (XP) and Cockayne Syndrome (CS). Recent evidence has shown that NER aids in removing oxidized DNA damage and may interact with base excision repair (BER) enzymes. Here, we investigated APE1 and OGG1 expression, localization and activity after oxidative stress in XPC-deficient cells. The endogenous APE1 and OGG1 mRNA levels were lower in XPC-deficient fibroblasts. However, XPC-deficient cells did not show hypersensitivity to oxidative stress compared with NER-proficient cells. To confirm the impact of an XPC deficiency in regulating APE1 and OGG1 expression and activity, we established an XPC-complemented cell line. Although the XPC complementation was only partial and transient, the transfected cells exhibited greater OGG1 expression and activity compared with XPC-deficient cells. However, the APE1 expression and activity did not significantly change. Furthermore, we observed a physical interaction between the XPC and APE1 proteins. Together, the results indicate that the responses of XPC-deficient cells under oxidative stress may not only be associated with NER deficiency per se but may also include new XPC functions in regulating BER proteins.
The Brazilian National Regulatory Agency for Private Health Insurance and Plans has recently publ... more The Brazilian National Regulatory Agency for Private Health Insurance and Plans has recently published a technical note defining the criteria for the coverage of genetic testing to diagnose hereditary cancer. In this study we show the case of a patient with a breast lesion and an extensive history of cancer referred to a private service of genetic counseling. The patient met both criteria for hereditary breast and colorectal cancer syndrome screening. Her private insurance denied coverage for genetic testing because she lacks current or previous cancer diagnosis. After she appealed by lawsuit, the court was favorable and the test was performed using next-generation sequencing. A deletion of MLH1 exon 8 was found. We highlight the importance to offer genetic testing using multigene analysis for noncancer patients.
Germ-line mutation in CDH1 gene is associated with high risk for Hereditary Diffuse Gastric Cance... more Germ-line mutation in CDH1 gene is associated with high risk for Hereditary Diffuse Gastric Cancer (HDGC) and Infiltrative Lobular Carcinoma (ILC). Although somatic CDH1mutationswere also detected in ILCwith a frequency ranging from 10 to 56%, CDH1 alterations in more frequent infiltrative ductal carcinoma (IDC) appear to be rare, and no association with germ-line CDH1 mutation and IDC has been established. Here we report the case of a woman diagnosed with IDC at 39 years of age, presenting extensive familial history of cancer at multiple sites with early-age onset and with no case of HDGC. Deep sequencing have revealed CDH1 missense mutation c.1849GNA (p.Ala617Thr) in heterozygous and four BRCA2 single nucleotide polymorphism in homozygosis. In this family, the mutation c.1849GNA in the CDH1 gene is not related to HDGC nor ILC. Therefore, here we highlight that multigene analysis is important to detect germ-line mutations and genetic variants in patients with cancers at multiple sites in the family, even if inconclusive genetic counseling can be offered, since hereafter, medical awareness will be held.
Background: Male breast cancer (MBC) is an uncommon disease that has been the focus of limited re... more Background: Male breast cancer (MBC) is an uncommon disease that has been the focus of limited research. It is estimated that approximately 10% of men with breast cancer have a genetic predisposition, with BRCA2 being the most prevalent genetic mutation. Here we describe the case of MBC in a 64-year-old man who presented on physical examination a nodule in his left breast and declared to have an extensive family history of cancer. Methods and results: The patient was firstly diagnosed with an invasive ductal carcinoma (IDC) with histological grade III, nuclear grade 3, pT4N2Mx and positive for hormonal receptors and HER2. Exome sequencing was performed by massive parallel sequencing which had detected a novel BRCA2 germline mutation that is a large genomic deletion of 3,492 nucleotides including BRCA2 exon 14, and this deletion is out of frame and is predicted to lead to a stop codon in exon 15 at codon 2,496. Conclusion: Large rearrangements in BRCA1 and BRCA2 occur in a small percentage (<1%) of patients tested for hereditary breast and ovarian cancer. This is the first report of the mutation del3492 in BRCA2 exon 14, which leads to a truncated protein and therefore is clinically relevant. Mutation segregation analysis should be further done in the Brazilian population. Herein we highlight the importance of next-generation sequencing in the detection of large genomic deletions.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2016
Oxidative DNA damage is considered to be a major cause of neurodegeneration and internal tumors o... more Oxidative DNA damage is considered to be a major cause of neurodegeneration and internal tumors observed in syndromes that result from nucleotide excision repair (NER) deficiencies, such as Xeroderma Pigmentosum (XP) and Cockayne Syndrome (CS). Recent evidence has shown that NER aids in removing oxidized DNA damage and may interact with base excision repair (BER) enzymes. Here, we investigated APE1 and OGG1 expression, localization and activity after oxidative stress in XPC-deficient cells. The endogenous APE1 and OGG1 mRNA levels were lower in XPC-deficient fibroblasts. However, XPC-deficient cells did not show hypersensitivity to oxidative stress compared with NER-proficient cells. To confirm the impact of an XPC deficiency in regulating APE1 and OGG1 expression and activity, we established an XPC-complemented cell line. Although the XPC complementation was only partial and transient, the transfected cells exhibited greater OGG1 expression and activity compared with XPC-deficient cells. However, the APE1 expression and activity did not significantly change. Furthermore, we observed a physical interaction between the XPC and APE1 proteins. Together, the results indicate that the responses of XPC-deficient cells under oxidative stress may not only be associated with NER deficiency per se but may also include new XPC functions in regulating BER proteins.
The Brazilian National Regulatory Agency for Private Health Insurance and Plans has recently publ... more The Brazilian National Regulatory Agency for Private Health Insurance and Plans has recently published a technical note defining the criteria for the coverage of genetic testing to diagnose hereditary cancer. In this study we show the case of a patient with a breast lesion and an extensive history of cancer referred to a private service of genetic counseling. The patient met both criteria for hereditary breast and colorectal cancer syndrome screening. Her private insurance denied coverage for genetic testing because she lacks current or previous cancer diagnosis. After she appealed by lawsuit, the court was favorable and the test was performed using next-generation sequencing. A deletion of MLH1 exon 8 was found. We highlight the importance to offer genetic testing using multigene analysis for noncancer patients.
Germ-line mutation in CDH1 gene is associated with high risk for Hereditary Diffuse Gastric Cance... more Germ-line mutation in CDH1 gene is associated with high risk for Hereditary Diffuse Gastric Cancer (HDGC) and Infiltrative Lobular Carcinoma (ILC). Although somatic CDH1mutationswere also detected in ILCwith a frequency ranging from 10 to 56%, CDH1 alterations in more frequent infiltrative ductal carcinoma (IDC) appear to be rare, and no association with germ-line CDH1 mutation and IDC has been established. Here we report the case of a woman diagnosed with IDC at 39 years of age, presenting extensive familial history of cancer at multiple sites with early-age onset and with no case of HDGC. Deep sequencing have revealed CDH1 missense mutation c.1849GNA (p.Ala617Thr) in heterozygous and four BRCA2 single nucleotide polymorphism in homozygosis. In this family, the mutation c.1849GNA in the CDH1 gene is not related to HDGC nor ILC. Therefore, here we highlight that multigene analysis is important to detect germ-line mutations and genetic variants in patients with cancers at multiple sites in the family, even if inconclusive genetic counseling can be offered, since hereafter, medical awareness will be held.
Background: Male breast cancer (MBC) is an uncommon disease that has been the focus of limited re... more Background: Male breast cancer (MBC) is an uncommon disease that has been the focus of limited research. It is estimated that approximately 10% of men with breast cancer have a genetic predisposition, with BRCA2 being the most prevalent genetic mutation. Here we describe the case of MBC in a 64-year-old man who presented on physical examination a nodule in his left breast and declared to have an extensive family history of cancer. Methods and results: The patient was firstly diagnosed with an invasive ductal carcinoma (IDC) with histological grade III, nuclear grade 3, pT4N2Mx and positive for hormonal receptors and HER2. Exome sequencing was performed by massive parallel sequencing which had detected a novel BRCA2 germline mutation that is a large genomic deletion of 3,492 nucleotides including BRCA2 exon 14, and this deletion is out of frame and is predicted to lead to a stop codon in exon 15 at codon 2,496. Conclusion: Large rearrangements in BRCA1 and BRCA2 occur in a small percentage (<1%) of patients tested for hereditary breast and ovarian cancer. This is the first report of the mutation del3492 in BRCA2 exon 14, which leads to a truncated protein and therefore is clinically relevant. Mutation segregation analysis should be further done in the Brazilian population. Herein we highlight the importance of next-generation sequencing in the detection of large genomic deletions.
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Papers by Tirzah Lajus
Infiltrative Lobular Carcinoma (ILC). Although somatic CDH1mutationswere also detected in ILCwith a frequency
ranging from 10 to 56%, CDH1 alterations in more frequent infiltrative ductal carcinoma (IDC) appear to be
rare, and no association with germ-line CDH1 mutation and IDC has been established. Here we report the case
of a woman diagnosed with IDC at 39 years of age, presenting extensive familial history of cancer at multiple
sites with early-age onset and with no case of HDGC. Deep sequencing have revealed CDH1 missense mutation
c.1849GNA (p.Ala617Thr) in heterozygous and four BRCA2 single nucleotide polymorphism in homozygosis. In
this family, the mutation c.1849GNA in the CDH1 gene is not related to HDGC nor ILC. Therefore, here we highlight
that multigene analysis is important to detect germ-line mutations and genetic variants in patients with
cancers at multiple sites in the family, even if inconclusive genetic counseling can be offered, since hereafter,
medical awareness will be held.
estimated that approximately 10% of men with breast cancer have a genetic predisposition, with BRCA2 being the
most prevalent genetic mutation. Here we describe the case of MBC in a 64-year-old man who presented on physical
examination a nodule in his left breast and declared to have an extensive family history of cancer.
Methods and results: The patient was firstly diagnosed with an invasive ductal carcinoma (IDC) with histological
grade III, nuclear grade 3, pT4N2Mx and positive for hormonal receptors and HER2. Exome sequencing was performed
by massive parallel sequencing which had detected a novel BRCA2 germline mutation that is a large genomic deletion
of 3,492 nucleotides including BRCA2 exon 14, and this deletion is out of frame and is predicted to lead to a stop
codon in exon 15 at codon 2,496.
Conclusion: Large rearrangements in BRCA1 and BRCA2 occur in a small percentage (<1%) of patients tested for
hereditary breast and ovarian cancer. This is the first report of the mutation del3492 in BRCA2 exon 14, which
leads to a truncated protein and therefore is clinically relevant. Mutation segregation analysis should be
further done in the Brazilian population. Herein we highlight the importance of next-generation sequencing
in the detection of large genomic deletions.
Infiltrative Lobular Carcinoma (ILC). Although somatic CDH1mutationswere also detected in ILCwith a frequency
ranging from 10 to 56%, CDH1 alterations in more frequent infiltrative ductal carcinoma (IDC) appear to be
rare, and no association with germ-line CDH1 mutation and IDC has been established. Here we report the case
of a woman diagnosed with IDC at 39 years of age, presenting extensive familial history of cancer at multiple
sites with early-age onset and with no case of HDGC. Deep sequencing have revealed CDH1 missense mutation
c.1849GNA (p.Ala617Thr) in heterozygous and four BRCA2 single nucleotide polymorphism in homozygosis. In
this family, the mutation c.1849GNA in the CDH1 gene is not related to HDGC nor ILC. Therefore, here we highlight
that multigene analysis is important to detect germ-line mutations and genetic variants in patients with
cancers at multiple sites in the family, even if inconclusive genetic counseling can be offered, since hereafter,
medical awareness will be held.
estimated that approximately 10% of men with breast cancer have a genetic predisposition, with BRCA2 being the
most prevalent genetic mutation. Here we describe the case of MBC in a 64-year-old man who presented on physical
examination a nodule in his left breast and declared to have an extensive family history of cancer.
Methods and results: The patient was firstly diagnosed with an invasive ductal carcinoma (IDC) with histological
grade III, nuclear grade 3, pT4N2Mx and positive for hormonal receptors and HER2. Exome sequencing was performed
by massive parallel sequencing which had detected a novel BRCA2 germline mutation that is a large genomic deletion
of 3,492 nucleotides including BRCA2 exon 14, and this deletion is out of frame and is predicted to lead to a stop
codon in exon 15 at codon 2,496.
Conclusion: Large rearrangements in BRCA1 and BRCA2 occur in a small percentage (<1%) of patients tested for
hereditary breast and ovarian cancer. This is the first report of the mutation del3492 in BRCA2 exon 14, which
leads to a truncated protein and therefore is clinically relevant. Mutation segregation analysis should be
further done in the Brazilian population. Herein we highlight the importance of next-generation sequencing
in the detection of large genomic deletions.