HOTAIR rs920778 single nucleotide polymorphism is associated with breast cancer susceptibility and HER2-targeted therapy resistance in Chinese population

doi:10.12122/j.issn.1673-4254.2025.10.23

Abstract

Abstract:

Objective To investigate the association of HOTAIR gene rs920778 single nucleotide polymorphism (SNP) with breast cancer susceptibility and response to HER2-targeted therapy in a Chinese population. Methods TaqMan probe-based real-time quantitative PCR was used for genotyping of the rs920778 locus (chr12:54,376,218) in peripheral blood genomic DNA from 287 breast cancer patients and 260 healthy individuals from northern Anhui Province. The genotype (GG, GT and TT) and allele (G/T) distribution frequencies were compared between the two groups to evaluate their association with breast cancer risk. Multivariate logistic regression analysis was conducted to assess the relationship between SNP at this locus and aggressive clinicopathological features (including tumor size, lymph node metastasis, ER/PR/HER2 status, and molecular subtypes) of breast cancer. For the HER2-positive subgroup, the association between rs920778 genotype and responses to dual-targeted therapy (trastuzumab [6 mg/kg q3w]+pertuzumab [420 mg q3w] + docetaxel [75 mg/m²]) was analyzed. The primary endpoints included pathological complete response rate (pCR), objective response rate (ORR), and progression-free survival (PFS). Results The TT genotype of rs920778 was associated with a significantly increased breast cancer susceptibility (OR=1.54, 95% CI: 1.09-2.19; P=0.017), an advanced tumor stage (P<0.001), lymph node metastasis (P<0.001), and the triple-negative subtype (P<0.001). In HER2-positive patients, TT genotype carriers had a markedly reduced objective response rate to dual HER2-targeted therapy (33.3% vs 89.3%, P=0.001) and a lower pathological complete response rate after neoadjuvant therapy (P=0.018). Conclusion The TT genotype of HOTAIR rs920778 serves as an independent risk factor for breast cancer susceptibility and aggressive progression in Chinese population and may predict the resistance to HER2-targeted therapies, suggesting its potential as a prognostic biomarker for precision oncology.

Key words: HOTAIR, single nucleotide polymorphism, breast cancer susceptibility, therapeutic sensitivity, prognostic biomarker

Mingliang ZHANG, Feifan SUN, Zhuoqi HAN, Yue GAO, Yi LUO. HOTAIR rs920778 single nucleotide polymorphism is associated with breast cancer susceptibility and HER2-targeted therapy resistance in Chinese population[J]. Journal of Southern Medical University, 2025, 45(10): 2270-2276.

Figures/Tables 5

References 31

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Genotype	Case group (n=287)	Normal group (n=260)	OR (95% CI)	χ²	P
CC	128 (44.8%)	160 (61.7%)	1
CT	99 (34.5%)	74 (28.3%)	1.67 (1.15-2.44)	7.06	0.008
TT	60 (20.7%)	26 (10.0%)	2.88 (1.83-4.56)	16.98	<0.001
Allele
C	174 (60.5%)	183 (70.3%)	1
T	113 (39.5%)	77 (29.7%)	1.54 (1.09-2.19)	5.73	0.017

Genotype	Case group (n=287)	Normal group (n=260)	OR (95% CI)	χ²	P
CC	128 (44.8%)	160 (61.7%)	1
CT	99 (34.5%)	74 (28.3%)	1.67 (1.15-2.44)	7.06	0.008
TT	60 (20.7%)	26 (10.0%)	2.88 (1.83-4.56)	16.98	<0.001
Allele
C	174 (60.5%)	183 (70.3%)	1
T	113 (39.5%)	77 (29.7%)	1.54 (1.09-2.19)	5.73	0.017

Clinicopathological characteristics	HOTAIR rs920778 polymorphism			χ²	P
Clinicopathological characteristics	CC (n=128)	CT (n=60)	TT (n=50)	χ²	P
Age (year)				0.02	0.993
≤50	65 (50.8%)	30 (50%)	25 (50%)
>50	63 (49.2%)	30 (50%)	25 (50%)
Clinical stage				19.49	<0.001
I+Ⅱ	85 (66.4%)	35 (58%)	15 (30%)
Ⅲ+IV	43 (33.6%)	25 (42%)	35 (70%)
Histological grade				37.16	<0.001
I+Ⅱ	90 (70.3%)	35 (58%)	10 (20%)
Ⅲ	38 (29.7%)	25 (42%)	40 (80%)
Molecular subtype				13.69	0.008
HR+/HER2-	55 (43.0%)	25 (42%)	10 (20%)
HER2+	42 (32.8%)	15 (25%)	15 (30%)
HR-/HER2-	31 (24.2%)	20 (33%)	25 (50%)
Lymphovascular invasion				0.38	0.827
Yes	40 (31.2%)	20 (33%)	18 (36%)
No	88 (68.8%)	40 (67%)	32 (64%)
Lymph node metastasis				29.04	<0.001
Yes	45 (35.2%)	30 (50%)	40 (80%)
No	83 (64.8%)	30 (50%)	10 (20%)
Menopausal status				0.27	0.874
Postmenopausal	90 (70.3%)	40 (67%)	35 (70%)
Premenopausal	38 (29.7%)	20 (33%)	15 (30%)
Marital status				0.18	0.915
Married	100 (78%)	45 (75%)	38 (76%)
Unmarried	28 (22%)	15 (25%)	12 (24%)
Parity status				0.25	0.881
Parous	100 (78%)	45 (75%)	38 (76%)
Nulliparous	28 (22%)	15 (25%)	12 (24%)
Smoking history				0.55	0.973
Smoker	30 (23.4%)	15 (25%)	12 (24%)
Non-smoker	98 (76.6%)	45 (75%)	38 (76%)

Clinicopathological characteristics	HOTAIR rs920778 polymorphism			χ²	P
Clinicopathological characteristics	CC (n=128)	CT (n=60)	TT (n=50)	χ²	P
Age (year)				0.02	0.993
≤50	65 (50.8%)	30 (50%)	25 (50%)
>50	63 (49.2%)	30 (50%)	25 (50%)
Clinical stage				19.49	<0.001
I+Ⅱ	85 (66.4%)	35 (58%)	15 (30%)
Ⅲ+IV	43 (33.6%)	25 (42%)	35 (70%)
Histological grade				37.16	<0.001
I+Ⅱ	90 (70.3%)	35 (58%)	10 (20%)
Ⅲ	38 (29.7%)	25 (42%)	40 (80%)
Molecular subtype				13.69	0.008
HR+/HER2-	55 (43.0%)	25 (42%)	10 (20%)
HER2+	42 (32.8%)	15 (25%)	15 (30%)
HR-/HER2-	31 (24.2%)	20 (33%)	25 (50%)
Lymphovascular invasion				0.38	0.827
Yes	40 (31.2%)	20 (33%)	18 (36%)
No	88 (68.8%)	40 (67%)	32 (64%)
Lymph node metastasis				29.04	<0.001
Yes	45 (35.2%)	30 (50%)	40 (80%)
No	83 (64.8%)	30 (50%)	10 (20%)
Menopausal status				0.27	0.874
Postmenopausal	90 (70.3%)	40 (67%)	35 (70%)
Premenopausal	38 (29.7%)	20 (33%)	15 (30%)
Marital status				0.18	0.915
Married	100 (78%)	45 (75%)	38 (76%)
Unmarried	28 (22%)	15 (25%)	12 (24%)
Parity status				0.25	0.881
Parous	100 (78%)	45 (75%)	38 (76%)
Nulliparous	28 (22%)	15 (25%)	12 (24%)
Smoking history				0.55	0.973
Smoker	30 (23.4%)	15 (25%)	12 (24%)
Non-smoker	98 (76.6%)	45 (75%)	38 (76%)

Treatment response	rs920778 polymorphism		χ²	P
Treatment response	TT	CC+CT	χ²	P
CR+PR	5 (33.3%)	25 (89.3%)	14.53	0.001
SD+PD	10 (66.7%)	3 (10.7%)	14.53	0.001