A genetic risk predictor for breast cancer using a combination of low-penetrance polymorphisms in a Japanese population

Abstract

Genome-wide association studies (GWASs) have identified genetic variants associated with breast cancer. Most GWASs to date have been conducted in women of European descent, however, and the contribution of these variants as predictors in Japanese women is unknown. Here, we analyzed 23 genetic variants identified in previous GWASs and conducted a case-control study with 697 case subjects and 1,394 age- and menopausal status-matched controls. We fit conditional regression models with genetic variants and conventional risk factors. In addition, we created a polygenetic risk score, using those variants with a statistically significant association with breast cancer risk, and also evaluated the contribution of these genetic predictors using the c statistic. Eleven single-nucleotide polymorphisms (SNPs) revealed significant associations with breast cancer risk. A dose-dependent association was observed between the risk of breast cancer and the genetic risk score, which was an aggregate measure of alleles in seven selected variants, namely FGFR2-rs2981579, TOX3/TNRC9-rs3803662, C6orf97-rs2046210, 8q24-rs13281615, SLC4A7-rs4973768, LSP1-rs38137198, and CASP8-rs10931936. Compared to women with scores of 3 or less, odds ratios (ORs) for women with scores of 4-5, 6-7, 8-9, and 10 or more were 1.33 (95% confidence interval, 1.00-1.80), 1.71 (1.26-2.30), 3.01 (1.97-4.58), and 8.69 (2.75-27.5), respectively (P (trend) = 1.9 × 10(-9)). The c statistic for a model including the genetic risk score in addition to the conventional risk factors was 0.6933, versus 0.6652 with the conventional risk factors only (P = 1.3 × 10(-4)). Population-attributable fraction of the risk score was 33.0%. In conclusion, we identified a genetic risk predictor of breast cancer in a Japanese population. Risk models which include a genetic risk score are possibly useful in distinguishing women at high risk of breast cancer from those at low risk, particularly in the context of targeted prevention.

Cumulative Risk Impact of Five Genetic Variants Associated with Papillary Thyroid Carcinoma

“…For instance, in a study of seven low penetrance breast cancer variants, ORs in women with the highest numbers of risk alleles rose to 8.69 and the measure of discriminative ability or AUC rose from 0.665 to 0.693 when the genetic risk score information was added to the model with conventional risk factors (10). In a breast cancer study, the AUC rose from 0.63 to 0.667 when genotype data from five markers were added to conventional risk data (11).…”

“…This suggests that easy-to-find high-penetrance mutations probably do not exist or are rare. In contrast, accumulating evidence from other malignancies (10)(11)(12) and multifactorial diseases and traits (13)(14)(15)(16) suggests that the genetic predisposition often consists of a multitude of low-penetrance alleles (16,17). The first few years of GWASs appear to have amply confirmed this assumption.…”

A family-based, genome-wide association study of young-onset breast cancer: inherited variants and maternally mediated effects

“…The SNP in TOX3 (rs4784227:C4T) that was ranked fourth in the main analysis and second in the analysis that excluded the known BRCA-positive families, is a known susceptibility locus first identified in a breast cancer GWAS by Long et al 28 It has since been replicated in investigations among women of many ethnicities. [29][30][31][32][33] Presence of the variant allele (T) increases the chromatin's affinity for FOXA1, 34 a pioneer factor that can bind to chromatin and recruit the ER, thereby facilitating estrogen-driven transcription and cellular changes. 35 The other highly ranked TOX3 SNP, rs3803662:G4A, was also originally identified in a GWAS study 36 and the association was successfully replicated.…”

Breast Cancer Association Studies in a Han Chinese Population using 10 European-ancestry-associated Breast Cancer Susceptibility SNPs

“…High-quality validation studies are necessary to ensure that real associations with the disease are identified. Furthermore, as the majority of GWAS have been performed in European populations, the replication of GWAS-identified loci in specific Asian populations such as the Chinese or Japanese is also necessary (Easton et al, 2007;Hunter et al, 2007;Sueta et al, 2012). Therefore, we performed a verification study in a Chinese Han population using 10 susceptibility SNPs that had been reported previously in European populations.…”