Identification of Novel Breast Cancer Risk Loci

Autor: Ann Siew Gek Lee, Geok Ling Koh, Min-Han Tan, Edward Sern Yuen Wong, Prabhakaran Munusamy, Hai-Yang Law, Claire Hian Tzer Chan, Chui Sheun Yoon, Peter Ang, Yoon Sim Yap, Sau Yeen Loke
Rok vydání: 2017
Předmět:
Adult
0301 basic medicine
Cancer Research
Genotype
Protein Conformation
Receptor
ErbB-2
Population
Breast Neoplasms
Single-nucleotide polymorphism
Biology
Polymorphism
Single Nucleotide
Young Adult
03 medical and health sciences
Breast cancer
Biomarkers
Tumor
medicine
Humans
SNP
Genetic Predisposition to Disease
education
Receptor
Notch3
Genotyping
Aged
Neoplasm Staging
Aged
80 and over
Genetics
education.field_of_study
Protein Stability
Carcinoma
Ductal
Breast
High-Throughput Nucleotide Sequencing
Janus Kinase 2
Middle Aged
Hypoxia-Inducible Factor 1
alpha Subunit
Prognosis
medicine.disease
Minor allele frequency
Carcinoma
Lobular
030104 developmental biology
HIF1A
Receptors
Estrogen
Oncology
Genetic Loci
Case-Control Studies
Female
Neoplasm Grading
Receptors
Progesterone
Ovarian cancer
Follow-Up Studies
Zdroj: Cancer Research. 77:5428-5437
ISSN: 1538-7445
0008-5472
Popis: It has been estimated that >1,000 genetic loci have yet to be identified for breast cancer risk. Here we report the first study utilizing targeted next-generation sequencing to identify single-nucleotide polymorphisms (SNP) associated with breast cancer risk. Targeted sequencing of 283 genes was performed in 240 women with early-onset breast cancer (≤40 years) or a family history of breast and/or ovarian cancer. Common coding variants with minor allele frequencies (MAF) >1% that were identified were presumed initially to be SNPs, but further database inspections revealed variants had MAF of ≤1% in the general population. Through prioritization and stringent selection criteria, we selected 24 SNPs for further genotyping in 1,516 breast cancer cases and 1,189 noncancer controls. Overall, we identified the JAK2 SNP rs56118985 to be significantly associated with overall breast cancer risk. Subtype analysis performed for patient subgroups defined by ER, PR, and HER2 status suggested additional associations of the NOTCH3 SNP rs200504060 and the HIF1A SNP rs142179458 with breast cancer risk. In silico analysis indicated that coding amino acids encoded at these three SNP sites were conserved evolutionarily and associated with decreased protein stability, suggesting a likely impact on protein function. Our results offer proof of concept for identifying novel cancer risk loci from next-generation sequencing data, with iterative data analysis from targeted, whole-exome, or whole-genome sequencing a wellspring to identify new SNPs associated with cancer risk. Cancer Res; 77(19); 5428–37. ©2017 AACR.
Databáze: OpenAIRE
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