Limits...
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

Pedigrees of three families with deleterious mutations. Individuals with any cancer are shown as filled circles. Arrows show a proband with deleterious mutations of (A) MRE11A in family 1, (B) ATM in family 2 and (C) MSH6 in family 3. The age at diagnosis plus the identified mutation is shown under the relevant individuals. BC, breast cancer; OC, ovarian cancer; CRC, colorectal cancer; GC, gastric cancer; HCC, hepatocellular cancer; Bladder, bladder cancer; EC, endometrial cancer.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4585454&req=5

fig02: Pedigrees of three families with deleterious mutations. Individuals with any cancer are shown as filled circles. Arrows show a proband with deleterious mutations of (A) MRE11A in family 1, (B) ATM in family 2 and (C) MSH6 in family 3. The age at diagnosis plus the identified mutation is shown under the relevant individuals. BC, breast cancer; OC, ovarian cancer; CRC, colorectal cancer; GC, gastric cancer; HCC, hepatocellular cancer; Bladder, bladder cancer; EC, endometrial cancer.

Mentions: We identified MRE11A nonsense (p.G148X) or ATM frameshift (p.I2629fs) mutations in probands who developed breast cancer (Table1). The mutations in ATM and MRE11A were identified in breast cancer patients (Broeks et al. 2000; Bartkova et al. 2008). Family 1 included a heterozygous MRE11A nonsense mutation (p.G148X) that was present in probands and two relatives with breast cancer (Fig.2A). Family 2 included two aunts and one grandmother who developed breast cancer. A heterozygous ATM frameshift mutation (p.Ile2629fs) was identified in a proband who developed breast cancer at the age of 43 years (Fig.2B).


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)

Pedigrees of three families with deleterious mutations. Individuals with any cancer are shown as filled circles. Arrows show a proband with deleterious mutations of (A) MRE11A in family 1, (B) ATM in family 2 and (C) MSH6 in family 3. The age at diagnosis plus the identified mutation is shown under the relevant individuals. BC, breast cancer; OC, ovarian cancer; CRC, colorectal cancer; GC, gastric cancer; HCC, hepatocellular cancer; Bladder, bladder cancer; EC, endometrial cancer.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig02: Pedigrees of three families with deleterious mutations. Individuals with any cancer are shown as filled circles. Arrows show a proband with deleterious mutations of (A) MRE11A in family 1, (B) ATM in family 2 and (C) MSH6 in family 3. The age at diagnosis plus the identified mutation is shown under the relevant individuals. BC, breast cancer; OC, ovarian cancer; CRC, colorectal cancer; GC, gastric cancer; HCC, hepatocellular cancer; Bladder, bladder cancer; EC, endometrial cancer.
Mentions: We identified MRE11A nonsense (p.G148X) or ATM frameshift (p.I2629fs) mutations in probands who developed breast cancer (Table1). The mutations in ATM and MRE11A were identified in breast cancer patients (Broeks et al. 2000; Bartkova et al. 2008). Family 1 included a heterozygous MRE11A nonsense mutation (p.G148X) that was present in probands and two relatives with breast cancer (Fig.2A). Family 2 included two aunts and one grandmother who developed breast cancer. A heterozygous ATM frameshift mutation (p.Ile2629fs) was identified in a proband who developed breast cancer at the age of 43 years (Fig.2B).

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