Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Building 2-249A, Boston, MA, 02115, USA.
Breast Cancer Res. 2022 Nov 7;24(1):76. doi: 10.1186/s13058-022-01570-8.
Breast parenchymal texture features, including grayscale variation (V), capture the patterns of texture variation on a mammogram and are associated with breast cancer risk, independent of mammographic density (MD). However, our knowledge on the genetic basis of these texture features is limited.
We conducted a genome-wide association study of V in 7040 European-ancestry women. V assessments were generated from digitized film mammograms. We used linear regression to test the single-nucleotide polymorphism (SNP)-phenotype associations adjusting for age, body mass index (BMI), MD phenotypes, and the top four genetic principal components. We further calculated genetic correlations and performed SNP-set tests of V with MD, breast cancer risk, and other breast cancer risk factors.
We identified three genome-wide significant loci associated with V: rs138141444 (6q24.1) in ECT2L, rs79670367 (8q24.22) in LINC01591, and rs113174754 (12q22) near PGAM1P5. 6q24.1 and 8q24.22 have not previously been associated with MD phenotypes or breast cancer risk, while 12q22 is a known locus for both MD and breast cancer risk. Among known MD and breast cancer risk SNPs, we identified four variants that were associated with V at the Bonferroni-corrected thresholds accounting for the number of SNPs tested: rs335189 (5q23.2) in PRDM6, rs13256025 (8p21.2) in EBF2, rs11836164 (12p12.1) near SSPN, and rs17817449 (16q12.2) in FTO. We observed significant genetic correlations between V and mammographic dense area (r = 0.79, P = 5.91 × 10), percent density (r = 0.73, P = 1.00 × 10), and adult BMI (r = - 0.36, P = 3.88 × 10). Additional significant relationships were observed for non-dense area (z = - 4.14, P = 3.42 × 10), estrogen receptor-positive breast cancer (z = 3.41, P = 6.41 × 10), and childhood body fatness (z = - 4.91, P = 9.05 × 10) from the SNP-set tests.
These findings provide new insights into the genetic basis of mammographic texture variation and their associations with MD, breast cancer risk, and other breast cancer risk factors.
乳腺实质纹理特征，包括灰度变化（V），捕捉了乳房 X 光片上纹理变化的模式，与乳腺癌风险相关，独立于乳腺密度（MD）。然而，我们对这些纹理特征的遗传基础知之甚少。
我们对 7040 名欧洲血统女性的 V 进行了全基因组关联研究。V 评估是从数字化胶片乳房 X 光片中生成的。我们使用线性回归来测试 SNP-表型关联，调整年龄、体重指数（BMI）、MD 表型和前四个遗传主要成分。我们进一步计算了 V 与 MD、乳腺癌风险和其他乳腺癌风险因素的遗传相关性，并进行了 SNP 集检验。
我们确定了三个与 V 相关的全基因组显著位点：位于 ECT2L 上的 rs138141444（6q24.1）、位于 LINC01591 上的 rs79670367（8q24.22）和位于 PGAM1P5 附近的 rs113174754（12q22）。6q24.1 和 8q24.22 以前与 MD 表型或乳腺癌风险无关，而 12q22 是 MD 和乳腺癌风险的已知位点。在已知的 MD 和乳腺癌风险 SNP 中，我们确定了四个在考虑到测试的 SNP 数量的 Bonferroni 校正阈值下与 V 相关的变体：位于 PRDM6 上的 rs335189（5q23.2）、位于 EBF2 上的 rs13256025（8p21.2）、位于 SSPN 附近的 rs11836164（12p12.1）和位于 FTO 上的 rs17817449（16q12.2）。我们观察到 V 与乳腺致密区（r=0.79，P=5.91×10）、密度百分比（r=0.73，P=1.00×10）和成人 BMI（r=-0.36，P=3.88×10）之间存在显著的遗传相关性。在 SNP 集检验中，还观察到非致密区（z=-4.14，P=3.42×10）、雌激素受体阳性乳腺癌（z=3.41，P=6.41×10）和儿童体脂肪（z=-4.91，P=9.05×10）的其他显著关系。
这些发现为乳腺 X 光片纹理变化的遗传基础及其与 MD、乳腺癌风险和其他乳腺癌风险因素的关联提供了新的见解。
