rs9383935 — CCDC170

CCDC170 3' UTR — The miR-27a Switch That Modulates Estrogen-Locus Cancer Risk

At chromosome 6q25.1, the estrogen receptor alpha gene ESR1 sits next to CCDC170 (Coiled-Coil Domain Containing 170), a gene whose protein organizes the Golgi apparatus and its microtubule connections inside cells. This locus is one of the most intensively studied regions in cancer and reproductive genetics — it has been implicated in breast cancer, endometriosis, and bone mineral density across dozens of GWAS studies spanning multiple ancestries.

rs9383935 is a variant in the 3' untranslated region (3' UTR) of CCDC170. Unlike the intronic rs1971256 also at this locus, which likely acts as a regulatory tag variant, rs9383935 has a defined molecular mechanism: the T allele disrupts a binding site for microRNA-27a (miR-27a), reducing the ability of miR-27a to bind and stabilize CCDC170 mRNA, and consequently lowering CCDC170 protein levels. The variant is in high linkage disequilibrium¹¹ linkage disequilibrium
variants in LD tend to be inherited together; r² = 0.86 here means they co-occur ~86% of the time with the classic GWAS sentinel rs2046210 upstream of ESR1, but shows a strong independent effect in conditional analysis.

The Mechanism

rs9383935 sits at GRCh38 position chr6:151,618,713 in the 3' UTR of CCDC170, the last segment of CCDC170 mRNA that is not translated into protein. This region typically contains binding sites for microRNAs — small RNAs that bind mRNAs and regulate how much protein is made.

The C allele (common) preserves a functional miR-27a binding site, allowing miR-27a to help maintain CCDC170 mRNA. The T allele disrupts this binding site. Luciferase reporter assays in MCF-7 and BT-474 breast cancer cell lines²² Luciferase reporter assays in MCF-7 and BT-474 breast cancer cell lines
Wang et al. Breast Cancer Research, 2014 demonstrated that constructs carrying the T allele had significantly lower reporter activity than the C allele constructs — confirming that the T allele reduces effective CCDC170 expression. Real-time qRT-PCR in patient samples confirmed the correlation between rs9383935 genotypes and CCDC170 mRNA levels.

CCDC170 protein localizes to the Golgi apparatus and organizes perinuclear microtubule networks³³ perinuclear microtubule networks
microtubules radiating from the Golgi help polarize cells and direct protein secretion; when disrupted, cells lose the ability to migrate in an organized, directional way. In cancer-associated truncation models, loss of CCDC170 Golgi localization drives increased cell motility and anchorage-independent growth — processes that contribute to tumor cell invasion and metastasis. Reduced expression from the T allele likely tilts cells in a similar direction, through a partial loss-of-function mechanism rather than a complete deletion.

The Evidence

The primary evidence for rs9383935 comes from a 2014 study of 1,064 breast cancer cases and 1,073 controls in Chinese women⁴⁴ 2014 study of 1,064 breast cancer cases and 1,073 controls in Chinese women
Wang et al. Breast Cancer Research. Breast cancer risk was significantly associated with rs9383935-T with an odds ratio of 1.38 (95% CI 1.20–1.57, P = 2.21×10⁻⁶). This effect was identified by conditional analysis as independent of rs2046210 — the two variants tag distinct molecular mechanisms at the same locus (ESR1 transcription regulation vs. CCDC170 mRNA stability). The study is moderately sized for GWAS standards, and the evidence level is moderate pending replication in larger multi-ethnic cohorts for rs9383935 specifically.

The broader locus has been comprehensively characterized. Fine-mapping in more than 118,000 subjects⁵⁵ Fine-mapping in more than 118,000 subjects
Dunning et al. Nature Genetics, 2016 identified at least five independent causal variants at 6q25, each regulating ESR1, RMND1, or CCDC170 through distinct enhancer elements. The CCDC170/ESR1 locus is also one of the most robustly replicated endometriosis susceptibility regions: a meta-analysis of 17,045 cases and 191,596 controls⁶⁶ meta-analysis of 17,045 cases and 191,596 controls
Sapkota et al. Nature Communications, 2017 and the largest endometriosis GWAS to date in 60,674 cases⁷⁷ largest endometriosis GWAS to date in 60,674 cases
Rahmioglu et al. Nature Genetics, 2023 both confirm genome-wide significance for this region in endometriosis.

The T allele of rs9383935 is notably more common in East Asian populations (~30%) than in Europeans (~8%) or Africans (~5%), consistent with the stronger breast cancer associations initially detected in Chinese cohorts.

Practical Actions

Lower CCDC170 expression from the T allele creates two clinically relevant contexts:

For breast cancer risk, CT and TT carriers at this locus have elevated susceptibility, particularly for estrogen receptor-positive (ER+) subtypes given the co-regulatory environment at this locus. Proactive surveillance — staying current with breast cancer screening guidelines and discussing cumulative polygenic risk with a clinician — is the primary actionable step, especially when combined with risk alleles at the linked rs2046210 (ESR1 promoter) and rs1971256 (CCDC170 intron) loci.

For endometriosis, the locus context matters: rs9383935 sits within the same 6q25.1 regulatory block as rs1971256 and rs2046210, both of which have stronger independent evidence for endometriosis susceptibility. Women carrying the T allele at rs9383935 — particularly alongside risk alleles at those neighbors — are in a portion of the population with elevated estrogen-signaling genetic burden from this chromosome region.

Interactions

rs1971256 (CCDC170 intron 1) and rs2046210 (ESR1 upstream): These two variants are already characterized in the database and sit at the same 6q25.1 locus. rs9383935 adds a third independent molecular mechanism: 3' UTR mRNA regulation of CCDC170 itself (as distinct from rs1971256's intronic tagging effect and rs2046210's ESR1 transcription regulation). Women carrying risk alleles at all three variants face compounded molecular disruption of the CCDC170-ESR1 co-regulatory axis.

rs9340799 (ESR1 XbaI): The classical ESR1 polymorphism rs9340799, characterized in the reproductive_hormones and endometriosis categories, is also at 6q25.1. Compound carriers of rs9383935-T and rs9340799-G have both reduced CCDC170 expression (via disrupted miR-27a binding) and altered ESR1 XbaI signaling. The 6q25.1 block compound action for women carrying multiple risk alleles is proposed in the harvesting notes.