Genome wide association study identifies a novel putative mammographic density locus at 1q12‐q21

Abstract

Mammographic density (MD) is an intermediate phenotype for breast cancer. Previous studies have identified genetic variants associated with MD; however, much of the genetic contribution to MD is unexplained. We conducted a two-stage genomewide association analysis among the participants in the "Determinants of Density in Mammographies in Spain" study, together with a replication analysis in women from the Australian MD Twins and Sisters Study. Our discovery set covered a total of 3,351 Caucasian women aged 45 to 68 years, recruited from Spanish breast cancer screening centres. MD was blindly assessed by a single reader using Boyd's scale. A two-stage approach was employed, including a feature selection phase exploring 575,374 SNPs in 239 pairs of women with extreme phenotypes and a verification stage for the 183 selected SNPs in the remaining sample (2,873 women). Replication was conducted in 1,786 women aged 40 to 70 years old recruited via the Australian Twin Registry, where MD were measured using Cumulus-3.0, assessing 14 SNPs with a p value <0.10 in stage 2.

Identification of 31 loci for mammographic density phenotypes and their associations with breast cancer risk

“…We confirmed associations with SNPs at 13 of 15 previously identified MD loci [10][11][12][13][14] at P < 0.05, nine of which reached genome-wide significance in this study (Supplementary Table 7). Of the two remaining prior loci, rs7289126 at the TMEM184B locus on 22q13.1 had suggestive associations with DA (P = 0.085) and PD (P = 0.083) in the same directions as previously reported 13 .…”

“…We also report new MD phenotype associations at P < 5 × 10 −8 with SNPs at five prior loci. At the MTMR11 locus on 1q21.1 previously associated with PD 12 , we found that rs11205303 was associated with both DA (P = 6.8 × 10 −20 ) and PD (P = 1.5 × 10 −11 ). At the RALB/INHBB locus on 2q14.2 recently associated with absolute dense volume 10 , we found that rs4849864 was associated with NDA (P = 2.6 × 10 −13 ) and rs17625845 was associated with DA (P = 2.8 × 10 −9 ).…”

“…PD, DA, and NDA each have heritability estimates of over 50% in twin studies [7][8][9] . However, only 15 independent genome-wide significant loci with P < 5 × 10 −8 have been identified to date, together explaining less than 1-3% of the total variance of mammographic density (MD) phenotypes [10][11][12][13][14] .…”

Raised mammographic density: causative mechanisms and biological consequences

“…These include: lymphocyte-specific protein 1 ( LSP1 ), which binds f-actin and may be involved with cell migration); RAD51-like 1 ( RAD51L1 ), which is involved in DNA repair and may sense DNA damage; XNF365; and chromosome 12q24 [ 42 – 44 ]. More recently, the density-associated genes have been extended to include: amphiregulin ( AREG ), an epidermal growth factor (EGF) family member strongly active in breast; ESR1 (estrogen receptor); transmembrane protein 184B ( TMEM184B ), a receptor that can activate MAP kinase; megakaryoblastic leukemia 1 protein ( MKL1 ), which transduces signals from the cytoskeleton to the nucleus, and may trans -activate serum response factor which is downstream of stiffness signals; PR domain containing 6 ( PRDM6 ), a histone methyltransferase that may contribute to proliferation [ 45 ]; early B-cell Factor 1 ( EBF1 ), a transcriptional activator; MIR1972-2 (microRNA), netrin-4, a laminin-related ECM protein; myotubularin-related protein 11 ( MTMR11 ), a pseudophosphatase that can be altered in some breast tumours; and Cezanne, which deubiquitinates EGF receptor and might also be involved in controlling high MD [ 46 , 47 ]. Tab2 , at the 6q25.1 locus, which binds ESR1 and is also involved with interleukin-1 activation of NFκB and MAPK8, is an additional genetic marker for high MD [ 48 ].…”

Identification of two novel mammographic density loci at 6Q25.1

“…MD is highly heritable ( h 2 = 0.60 – 0.65) [ 2 – 5 ] and genetic loci associated with MD can provide insight into the biological mechanisms leading to breast cancer, which may serve as targets for treatment and preventive strategies [ 6 ]. Despite the high heritability, a large proportion of the genetic variation of MD remains unexplained [ 7 – 9 ]. The Marker of Density (MODE) consortium recently identified nine loci ( AREG , ESR1 , ZNF365 , LSP1/TNNT3 , IGF1 , TMEM184B , SGSM3/MKL1 , PRDM6 , 8p11.23) associated with area-based MD [ 7 , 8 ] as obtained with the semiautomated thresholding method Cumulus [ 10 ].…”