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Multigene panel analysis identified germline mutations of DNA repair genes in breast and ovarian cancer.

Hirotsu Y, Nakagomi H, Sakamoto I, Amemiya K, Oyama T, Mochizuki H, Omata M - Mol Genet Genomic Med (2015)

Bottom Line: These subjects included 11 BRCA1/2 mutation-positive cases and 144 negative cases.Of these, three patients (1.9%) had pathogenic mutations in ATM, MRE11A, or MSH6, all of which have a central role in DNA repair and the mismatch repair pathway.The MSH6 splice-site mutation (IVS6+1G>T) was predicted to be pathogenic, as demonstrated by in vitro and immunohistochemical analyses.

View Article: PubMed Central - PubMed

Affiliation: Genome Analysis Center, Yamanashi Prefectural Central Hospital 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan.

ABSTRACT
Approximately 5-10% of all breast and/or ovarian cancer cases are considered as inherited. BRCA1 and BRCA2 tumor suppressor genes account for a high penetrance of hereditary cases, but familial cases without mutations in these genes can also occur. Despite their low penetrance, other hereditary cancer-related genes are known to be associated with breast and ovarian cancer risk. However, the extent to which these genes prevail in breast and ovarian cancer remains to be elucidated. To estimate the frequency of mutations in these predisposition genes, we analyzed the germline mutations of 25 hereditary cancer-related genes in 155 patients using targeted next-generation sequencing. These subjects included 11 BRCA1/2 mutation-positive cases and 144 negative cases. Of these, three patients (1.9%) had pathogenic mutations in ATM, MRE11A, or MSH6, all of which have a central role in DNA repair and the mismatch repair pathway. The MSH6 splice-site mutation (IVS6+1G>T) was predicted to be pathogenic, as demonstrated by in vitro and immunohistochemical analyses. These results suggested deficiencies in cellular DNA repair functions result in the development of breast and ovarian cancer.

No MeSH data available.


Related in: MedlinePlus

Germline deleterious mutations identified in patients with breast and/or ovarian cancer. Representative image of read alignments visualized with IGV (upper image). Sequencing chromatograms show the mutations and frameshift insertions/deletions in peripheral blood DNA from each patient (lower image). Mutations were identified in MRE11A p.G148X (A), ATM p.I2629fs (B), and MSH6 IVS6+1G>T (C). Arrows indicate the position of the mutations in the patient genome.
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fig01: Germline deleterious mutations identified in patients with breast and/or ovarian cancer. Representative image of read alignments visualized with IGV (upper image). Sequencing chromatograms show the mutations and frameshift insertions/deletions in peripheral blood DNA from each patient (lower image). Mutations were identified in MRE11A p.G148X (A), ATM p.I2629fs (B), and MSH6 IVS6+1G>T (C). Arrows indicate the position of the mutations in the patient genome.

Mentions: Therefore, we concluded that deleterious mutations in BRCA1/2 (7.1%; 11 out of 155) genes and in non-BRCA1/2-predisposing genes (1.9%; three out of 155) were present in our subjects (Fig.1 and Table S5). All deleterious mutations in MRE11A, ATM, and MSH6 genes were confirmed by Sanger sequencing (Fig.1). Taken together, the data suggested a subpopulation of breast and ovarian cancer has a germline mutation related to DNA repair genes.


Multigene panel analysis identified germline mutations of DNA repair genes in breast and ovarian cancer.

Hirotsu Y, Nakagomi H, Sakamoto I, Amemiya K, Oyama T, Mochizuki H, Omata M - Mol Genet Genomic Med (2015)

Germline deleterious mutations identified in patients with breast and/or ovarian cancer. Representative image of read alignments visualized with IGV (upper image). Sequencing chromatograms show the mutations and frameshift insertions/deletions in peripheral blood DNA from each patient (lower image). Mutations were identified in MRE11A p.G148X (A), ATM p.I2629fs (B), and MSH6 IVS6+1G>T (C). Arrows indicate the position of the mutations in the patient genome.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585454&req=5

fig01: Germline deleterious mutations identified in patients with breast and/or ovarian cancer. Representative image of read alignments visualized with IGV (upper image). Sequencing chromatograms show the mutations and frameshift insertions/deletions in peripheral blood DNA from each patient (lower image). Mutations were identified in MRE11A p.G148X (A), ATM p.I2629fs (B), and MSH6 IVS6+1G>T (C). Arrows indicate the position of the mutations in the patient genome.
Mentions: Therefore, we concluded that deleterious mutations in BRCA1/2 (7.1%; 11 out of 155) genes and in non-BRCA1/2-predisposing genes (1.9%; three out of 155) were present in our subjects (Fig.1 and Table S5). All deleterious mutations in MRE11A, ATM, and MSH6 genes were confirmed by Sanger sequencing (Fig.1). Taken together, the data suggested a subpopulation of breast and ovarian cancer has a germline mutation related to DNA repair genes.

Bottom Line: These subjects included 11 BRCA1/2 mutation-positive cases and 144 negative cases.Of these, three patients (1.9%) had pathogenic mutations in ATM, MRE11A, or MSH6, all of which have a central role in DNA repair and the mismatch repair pathway.The MSH6 splice-site mutation (IVS6+1G>T) was predicted to be pathogenic, as demonstrated by in vitro and immunohistochemical analyses.

View Article: PubMed Central - PubMed

Affiliation: Genome Analysis Center, Yamanashi Prefectural Central Hospital 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan.

ABSTRACT
Approximately 5-10% of all breast and/or ovarian cancer cases are considered as inherited. BRCA1 and BRCA2 tumor suppressor genes account for a high penetrance of hereditary cases, but familial cases without mutations in these genes can also occur. Despite their low penetrance, other hereditary cancer-related genes are known to be associated with breast and ovarian cancer risk. However, the extent to which these genes prevail in breast and ovarian cancer remains to be elucidated. To estimate the frequency of mutations in these predisposition genes, we analyzed the germline mutations of 25 hereditary cancer-related genes in 155 patients using targeted next-generation sequencing. These subjects included 11 BRCA1/2 mutation-positive cases and 144 negative cases. Of these, three patients (1.9%) had pathogenic mutations in ATM, MRE11A, or MSH6, all of which have a central role in DNA repair and the mismatch repair pathway. The MSH6 splice-site mutation (IVS6+1G>T) was predicted to be pathogenic, as demonstrated by in vitro and immunohistochemical analyses. These results suggested deficiencies in cellular DNA repair functions result in the development of breast and ovarian cancer.

No MeSH data available.


Related in: MedlinePlus