Association between breast cancer genetic susceptibility variants and terminal duct lobular unit involution of the breast

Abstract

Terminal duct lobular units (TDLUs) are the predominant source of future breast cancers, and lack of TDLU involution (higher TDLU counts, higher acini count per TDLU and the product of the two) is a breast cancer risk factor. Numerous breast cancer susceptibility single nucleotide polymorphisms (SNPs) have been identified, but whether they are associated with TDLU involution is unknown. In a pooled analysis of 872 women from two studies, we investigated 62 established breast cancer SNPs and relationships with TDLU involution. Poisson regression models with robust variance were used to calculate adjusted per-allele relative risks (with the non-breast cancer risk allele as the referent) and 95% confidence intervals between TDLU measures and each SNP. All statistical tests were two-sided; P<0.05 was considered statistically significant. Overall, 36 SNPs (58.1%) were related to higher TDLU counts although this was not statistically significant (P=0.25). Six of the 62 SNPs (9.7%) were nominally associated with at least one TDLU measure: rs616488 (PEX14), rs11242675 (FOXQ1) and rs6001930 (MKL1) were associated with higher TDLU count (P=0.047, 0.045 and 0.031, respectively); rs1353747 (PDE4D) and rs6472903 (8q21.11) were associated with higher acini count per TDLU (P=0.007 and 0.027, respectively); and rs1353747 (PDE4D) and rs204247 (RANBP9) were associated with the product of TDLU and acini counts (P=0.024 and 0.017, respectively). Our findings suggest breast cancer SNPs may not strongly influence TDLU involution. Agnostic genome-wide association studies of TDLU involution may provide new insights on its biologic underpinnings and breast cancer susceptibility.

Polygenic risk score for the prediction of breast cancer is related to lesser terminal duct lobular unit involution of the breast

“…Even so, prior work suggests that TDLU involution in histologically normal breast tissue may reflect a global process occurring throughout the breast 2,4,5 . Finally, despite doubling the sample size from our previous analysis 9 , additional samples may be required to detect associations between individual genetic variants and TDLU metrics.…”

“…The study pathologist measured the number of TDLUs ("TDLU count"). Acini count per TDLU was quantified using the TDLU analyzer software 17,18 as previously described 9 . A high intra-observer agreement (Spearman's r > 0.90) for the TDLU measures was previously reported 5,8 .…”

“…We previously examined whether 62 established breast cancer susceptibility loci were associated with TDLU involution and found limited evidence for an association 9 . Recently, a polygenic risk score (PRS) for the prediction of breast cancer has been derived using 313 common variants from the largest available international genome-wide association dataset 10 .…”

Proof of region-specific multipotent progenitors in human breast epithelia

“…Several lines of evidence indicate that TDLUs are the predominant source of future breast cancers and that a high TDLU count is associated with genetic susceptibility variants and predicts higher breast cancer risk ( 32 – 35 ). The present work reveals that two functionally different progenitor cells reside within the myoepithelial lineage of the breast in the adult human: one associated with TDLUs and another localized to interlobular ducts.…”

“…The exact mechanism by which aberrant TDLUs predispose to breast cancer remains unknown. However, the sheer number of TDLUs and the number of acini per TDLU have been associated with the presence of known cancer genetic susceptibility variants ( 33 ). Also, signaling pathways controlling the cellular composition of the human breast have been explored for cancer risk assessment and prevention ( 56 , 57 ).…”