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Exome sequencing in a breast cancer family without BRCA mutation.

Noh JM, Kim J, Cho DY, Choi DH, Park W, Huh SJ - Radiat Oncol J (2015)

Bottom Line: After filtering out 12,843 synonymous variations and 12,105 known variations with indels found in the dbSNP135 or 1000 Genomes Project database, we selected 73 variations in the samples from the affected sisters that did not occur in the sample from the unaffected mother.Using the Sorting Intolerant From Tolerant (SIFT), PolyPhen-2, and MutationTaster algorithms to predict amino acid substitutions, the XCR1, DLL1, TH, ACCS, SPPL3, CCNF, and SRL genes were risky among all three algorithms, while definite candidate genes could not be conclusively determined.Genetic evidence of disease association should be confirmed by future studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

ABSTRACT

Purpose: We performed exome sequencing in a breast cancer family without BRCA mutations.

Materials and methods: A family that three sisters have a history of breast cancer was selected for analysis. There were no family members with breast cancer in the previous generation. Genetic testing for BRCA mutation was negative, even by the multiplex ligation-dependent probe amplification method. Two sisters with breast cancer were selected as affected members, while the mother of the sisters was a non-affected member. Whole exome sequencing was performed on the HiSeq 2000 platform with paired-end reads of 101 bp in the three members.

Results: We identified 19,436, 19,468, and 19,345 single-nucleotide polymorphisms (SNPs) in the coding regions. Among them, 8,759, 8,789, and 8,772 were non-synonymous SNPs, respectively. After filtering out 12,843 synonymous variations and 12,105 known variations with indels found in the dbSNP135 or 1000 Genomes Project database, we selected 73 variations in the samples from the affected sisters that did not occur in the sample from the unaffected mother. Using the Sorting Intolerant From Tolerant (SIFT), PolyPhen-2, and MutationTaster algorithms to predict amino acid substitutions, the XCR1, DLL1, TH, ACCS, SPPL3, CCNF, and SRL genes were risky among all three algorithms, while definite candidate genes could not be conclusively determined.

Conclusion: Using exome sequencing, we found 7 variants for a breast cancer family without BRCA mutations. Genetic evidence of disease association should be confirmed by future studies.

No MeSH data available.


Related in: MedlinePlus

Number of variants filtered against several criteria determining causative alleles. SIFT, Sorting Intolerant From Tolerant.
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Figure 2: Number of variants filtered against several criteria determining causative alleles. SIFT, Sorting Intolerant From Tolerant.

Mentions: The missense prediction programs, SIFT, PolyPhen-2, and MutationTaster were used and the different scores from these tools were derived for the final 73 candidate variants. SIFT predicts whether an amino acid substitution in a protein will have a phenotypic effect, and the score less than 0.05 are predicted to be deleterious, those greater than or equal to 0.05 are predicted to be tolerated. PolyPhen-2 predicts the functional significance of an allele replacement, and the score more than 0.85 are interpreted as probably damaging and scores 0.15-0.85 as possibly damaging. MutationTaster predicts the disease potential of an alteration, and the predicted value close to 1 indicates a high 'security' of the prediction. Results from the three different tools were compared, and we identified that 7 variants were reported risky among all three algorithms: XCR1, DLL1, TH, ACCS, SPPL3, CCNF, and SRL (Fig. 2, Table 2). The variants were confirmed by Sanger sequencing.


Exome sequencing in a breast cancer family without BRCA mutation.

Noh JM, Kim J, Cho DY, Choi DH, Park W, Huh SJ - Radiat Oncol J (2015)

Number of variants filtered against several criteria determining causative alleles. SIFT, Sorting Intolerant From Tolerant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493427&req=5

Figure 2: Number of variants filtered against several criteria determining causative alleles. SIFT, Sorting Intolerant From Tolerant.
Mentions: The missense prediction programs, SIFT, PolyPhen-2, and MutationTaster were used and the different scores from these tools were derived for the final 73 candidate variants. SIFT predicts whether an amino acid substitution in a protein will have a phenotypic effect, and the score less than 0.05 are predicted to be deleterious, those greater than or equal to 0.05 are predicted to be tolerated. PolyPhen-2 predicts the functional significance of an allele replacement, and the score more than 0.85 are interpreted as probably damaging and scores 0.15-0.85 as possibly damaging. MutationTaster predicts the disease potential of an alteration, and the predicted value close to 1 indicates a high 'security' of the prediction. Results from the three different tools were compared, and we identified that 7 variants were reported risky among all three algorithms: XCR1, DLL1, TH, ACCS, SPPL3, CCNF, and SRL (Fig. 2, Table 2). The variants were confirmed by Sanger sequencing.

Bottom Line: After filtering out 12,843 synonymous variations and 12,105 known variations with indels found in the dbSNP135 or 1000 Genomes Project database, we selected 73 variations in the samples from the affected sisters that did not occur in the sample from the unaffected mother.Using the Sorting Intolerant From Tolerant (SIFT), PolyPhen-2, and MutationTaster algorithms to predict amino acid substitutions, the XCR1, DLL1, TH, ACCS, SPPL3, CCNF, and SRL genes were risky among all three algorithms, while definite candidate genes could not be conclusively determined.Genetic evidence of disease association should be confirmed by future studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

ABSTRACT

Purpose: We performed exome sequencing in a breast cancer family without BRCA mutations.

Materials and methods: A family that three sisters have a history of breast cancer was selected for analysis. There were no family members with breast cancer in the previous generation. Genetic testing for BRCA mutation was negative, even by the multiplex ligation-dependent probe amplification method. Two sisters with breast cancer were selected as affected members, while the mother of the sisters was a non-affected member. Whole exome sequencing was performed on the HiSeq 2000 platform with paired-end reads of 101 bp in the three members.

Results: We identified 19,436, 19,468, and 19,345 single-nucleotide polymorphisms (SNPs) in the coding regions. Among them, 8,759, 8,789, and 8,772 were non-synonymous SNPs, respectively. After filtering out 12,843 synonymous variations and 12,105 known variations with indels found in the dbSNP135 or 1000 Genomes Project database, we selected 73 variations in the samples from the affected sisters that did not occur in the sample from the unaffected mother. Using the Sorting Intolerant From Tolerant (SIFT), PolyPhen-2, and MutationTaster algorithms to predict amino acid substitutions, the XCR1, DLL1, TH, ACCS, SPPL3, CCNF, and SRL genes were risky among all three algorithms, while definite candidate genes could not be conclusively determined.

Conclusion: Using exome sequencing, we found 7 variants for a breast cancer family without BRCA mutations. Genetic evidence of disease association should be confirmed by future studies.

No MeSH data available.


Related in: MedlinePlus