Comparative analysis of BRCA1/2 gene mutation rates between breast cancer and non-breast cancer populations

doi:10.3877/cma.j.issn.1674-0807.2025.03.005

Abstract

Abstract:

Objective

To compare the BRCA1/2 mutation rates between breast cancer and non-breast cancer populations and analyze the clinicopathological factors related to BRCA1/2 mutations in breast cancer patients.

Methods

The clinical study of 463 breast cancer patients and 321 non-breast cancer individuals in the Department of Thyroid, Breast and Vascular Surgery, the First Affiliated Hospital of Air Force Medical University between January 2021 and August 2023 were collected for a retrospective analysis. Germline BRCA mutations were screening out using the human BRCA1/2 mutation detection kit. Intergroup comparisons of BRCA1/2 mutation rates (breast cancer vs non-breast cancer) and clinicopathological characteristics (BRCA1/2-mutated vs non-mutated patients) were performed using chi-square test or Fisher’s exact test. For ordinal data (T/N/M stage, histological grade) , Wilcoxon rank-sum test was applied.

Results

Among 463 breast cancer patients, BRCA1 pathogenic mutations were identified in 15 cases (3.2%) . The most frequent mutation sites were c.3288_3289del and c.5470_5477del (3/15 each) , followed by c.5155del and c.5074+1G>T. BRCA2 pathogenic mutations were detected in 16 cases (3.5%) , with c.9097del and c.7681C>T being the most common (2/16 each) . In the non-breast cancer cohort (321 cases) , BRCA1 and BRCA2 pathogenic mutations were observed in 1 (0.3%) and 2 cases (0.6%) , respectively. Variants of uncertain significance (VUS) in BRCA1 were identified in 13 breast cancer patients (2.8%) and 8 non-breast cancer individuals (2.5%) , while BRCA2 variants of uncertain significance (VUS) occurred in 28 breast cancer patients (6.0%) and 21 non-breast cancer individuals (6.5%) . The overall BRCA1/2 mutation rate was significantly higher in breast cancer patients than in non-breast cancer individuals (15.6% vs 10.0%, P=0.039) . BRCA1/2-mutated breast cancer patients had a higher proportion of diagnosis under the age of 45 (48.4% vs 31.5%, P=0.001) , family cancer history (32.3% vs 6.2%, P<0.001) , and bilateral breast cancer (9.7% vs 1.9%, P=0.014) compared with non-mutated patients. Tumor histological grade and Ki-67 expression also differed significantly between mutation carriers and non-carriers (P=0.016, 0.040) . BRCA1 mutation carriers had a higher proportion of early-onset diagnoses (<45 years) than BRCA2 mutation carriers (66.7% vs 31.2%, χ²=4.841, P=0.028) . Significant differences were observed between BRCA1 and BRCA2 mutation carriers in histologic grade, ER/PR status, Ki-67 expression, and molecular subtypes (P=0.023, 0.010, 0.020, 0.035, 0.004) .

Conclusion

BRCA1/2 pathogenic mutations in breast cancer patients are linked to early-onset breast cancer, family cancer history and bilateral breast cancer. Breast cancer patients with BRCA1 and BRCA2 mutations exhibit considerable differences in their clinicopathological characteristics, highlighting the need for further research into their distinct pathogenesis.

Key words: Breast neoplasms, Genes, BRCA1, Genes, BRCA1

Jialing Luo, Dongdong Xu, Dikun Si, Wenyu Hu, Nanlin Li. Comparative analysis of BRCA1/2 gene mutation rates between breast cancer and non-breast cancer populations[J]. Chinese Journal of Breast Disease(Electronic Edition), 2025, 19(03): 160-166.

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References 35

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染色体位置	例数	转录本	变异区域（内含子/外显子）	核酸变异	氨基酸变异
BRCA1	15
chr17：41244260	3	NM_007294.3	exon11	c.3288_3289del	p.L1098Sfs*4
chr17：41197813	3	NM_007294.4	exon24	c.5470_5477del	p.I1824Dfs*3
chr17：41215391	2	NM_007294.3	exon19	c.5155del	p.V1719*
chr17：41219624	2	NM_007294.4	intron17	c.5074+1G>T	/
chr17：41219625	1	NM_007294.4	exon17	c.5074G>A	p.D1692N
chr17：41267761	1	NM_007294.4	exon3	c.116G>A	p.C39Y
chr17：41246620	1	NM_007294.4	exon11	c.928C>T	p.Q310*
chr17：41215918	1	NM_007294.4	exon18	c.5125G>T	p.G1709*
chr17：41244185	1	NM_007294.4	exon11	c.3359_3363del	p.V1120Dfs*11
BRCA2	16
chr13：32954030	2	NM_007294.4	exon18	c.9097del	p.T3033Lfs*29
chr13：32931942	2	NM_000059.3	exon16	c.7681C>T	p.Q2561*
chr13：32907411	1	NM_000059.3	exon10	c.1796_1800del	p.S599*
chr13：32905145	1	NM_000059.3	exon9	c.771_775del	p.N257Kfs*17
chr13：32914902	1	NM_000059.3	exon11	c.6410del	p.N2137Mfs*31
chr13：32944607	1	NM_000059.3	exon19	c.8400_8402delinsAAAA	p.F2801Kfs*11
chr13：32911601	1	NM_000059.3	exon11	c.3109C>T	p.Q1037*
chr13：32914113	1	NM_000059.3	exon11	c.5621_5624del	p.I1874Rfs*34
chr13：32932067	1	NM_000059.3	intron16	c.7805+1G>A	/
chr17：41243482	1	NM_007294.4	exon11	c.4065_4068del	p.N1355Kfs*10
chr13：32893239	1	NM_000059.3	exon3	c.93G>A	p.W31*
chr13：32911410	1	NM_000059.3	exon11	c.2918C>A	p.S973*
chr13：32914451	1	NM_000059.3	exon11	c.5959C>T	p.Q1987*
chr13：32968950	1	NM_000059.3	exon25	c.9381G>A	p.W3127*

染色体位置	例数	转录本	变异区域（内含子/外显子）	核酸变异	氨基酸变异
BRCA1	15
chr17：41244260	3	NM_007294.3	exon11	c.3288_3289del	p.L1098Sfs*4
chr17：41197813	3	NM_007294.4	exon24	c.5470_5477del	p.I1824Dfs*3
chr17：41215391	2	NM_007294.3	exon19	c.5155del	p.V1719*
chr17：41219624	2	NM_007294.4	intron17	c.5074+1G>T	/
chr17：41219625	1	NM_007294.4	exon17	c.5074G>A	p.D1692N
chr17：41267761	1	NM_007294.4	exon3	c.116G>A	p.C39Y
chr17：41246620	1	NM_007294.4	exon11	c.928C>T	p.Q310*
chr17：41215918	1	NM_007294.4	exon18	c.5125G>T	p.G1709*
chr17：41244185	1	NM_007294.4	exon11	c.3359_3363del	p.V1120Dfs*11
BRCA2	16
chr13：32954030	2	NM_007294.4	exon18	c.9097del	p.T3033Lfs*29
chr13：32931942	2	NM_000059.3	exon16	c.7681C>T	p.Q2561*
chr13：32907411	1	NM_000059.3	exon10	c.1796_1800del	p.S599*
chr13：32905145	1	NM_000059.3	exon9	c.771_775del	p.N257Kfs*17
chr13：32914902	1	NM_000059.3	exon11	c.6410del	p.N2137Mfs*31
chr13：32944607	1	NM_000059.3	exon19	c.8400_8402delinsAAAA	p.F2801Kfs*11
chr13：32911601	1	NM_000059.3	exon11	c.3109C>T	p.Q1037*
chr13：32914113	1	NM_000059.3	exon11	c.5621_5624del	p.I1874Rfs*34
chr13：32932067	1	NM_000059.3	intron16	c.7805+1G>A	/
chr17：41243482	1	NM_007294.4	exon11	c.4065_4068del	p.N1355Kfs*10
chr13：32893239	1	NM_000059.3	exon3	c.93G>A	p.W31*
chr13：32911410	1	NM_000059.3	exon11	c.2918C>A	p.S973*
chr13：32914451	1	NM_000059.3	exon11	c.5959C>T	p.Q1987*
chr13：32968950	1	NM_000059.3	exon25	c.9381G>A	p.W3127*

临床病理特征	BRCA1/2突变（n=432）	BRCA1/2未突变（n=31）	检验值	P值	BRCA1致病性突变（n=15）	BRCA2致病性突变（n=16）	检验值	P值
年龄
<45岁	136	15	χ²=10.171	0.001	10	5	χ²=4.841	0.028
≥45岁	296	16	χ²=10.171	0.001	5	11	χ²=4.841	0.028
绝经状态
已绝经	172	13	χ²=0.053	0.818	8	5		0.191^a
未绝经	260	18	χ²=0.053	0.818	7	11		0.191^a
Ki-67表达
高表达（>30%）	161	17	χ²=4.237	0.040	11	6		0.035^a
低表达（≤30%）	271	14	χ²=4.237	0.040	4	10		0.035^a
ER表达
阳性	274	16	χ²=1.815	0.178	4	12		0.010^a
阴性	158	15	χ²=1.815	0.178	11	4		0.010^a
PR表达
阳性	232	12	χ²=3.113	0.078	3	9		0.020^a
阴性	200	19	χ²=3.113	0.078	12	7		0.020^a
恶性肿瘤家族史
是	27	10	χ²=23.190	<0.001	5	5	χ²=0.068	0.795
否	405	21	χ²=23.190	<0.001	10	11	χ²=0.068	0.795
双侧乳腺癌
是	8	3		0.014^a	1	2		0.612^a
否	424	28		0.014^a	14	14		0.612^a
病理类型
浸润性癌	391	29		0.302^a	14	15		1.000^a
其他类型癌	10	2			1	1
导管原位癌	31	0			0	0
HER-2表达
阳性	54	4		1.000^a	2	2		1.000^a
阴性	378	27		1.000^a	13	14		1.000^a
分子分型
Luminal型	274	16		0.256^a	11	12		0.004^a
HER-2阳性型	54	4			2	2
三阴性	104	11			2	2
T分期
T1	172	13	Z=-0.789	0.430	6	7	Z=-0.207	0.836
T2	206	15			8	7
T3	44	2			1	1
T4	10	1			0	1
N分期
N0	223	13	Z=-0.634	0.526	6	7	Z=0.000	1.000
N1	144	12			6	6
N2	36	3			2	1
N3	29	3			1	2
M分期
M0	49	6	Z=-0.535	0.593	3	3	Z=-0.258	0.800
M1	383	25	Z=-0.535	0.593	12	13	Z=-0.258	0.800
组织学分级
1级	26	2	Z=-2.846	0.004	1	1	Z=-2.236	0.025
2级	286	13			3	10
3级	120	16			11	5

临床病理特征	BRCA1/2突变（n=432）	BRCA1/2未突变（n=31）	检验值	P值	BRCA1致病性突变（n=15）	BRCA2致病性突变（n=16）	检验值	P值
年龄
<45岁	136	15	χ²=10.171	0.001	10	5	χ²=4.841	0.028
≥45岁	296	16	χ²=10.171	0.001	5	11	χ²=4.841	0.028
绝经状态
已绝经	172	13	χ²=0.053	0.818	8	5		0.191^a
未绝经	260	18	χ²=0.053	0.818	7	11		0.191^a
Ki-67表达
高表达（>30%）	161	17	χ²=4.237	0.040	11	6		0.035^a
低表达（≤30%）	271	14	χ²=4.237	0.040	4	10		0.035^a
ER表达
阳性	274	16	χ²=1.815	0.178	4	12		0.010^a
阴性	158	15	χ²=1.815	0.178	11	4		0.010^a
PR表达
阳性	232	12	χ²=3.113	0.078	3	9		0.020^a
阴性	200	19	χ²=3.113	0.078	12	7		0.020^a
恶性肿瘤家族史
是	27	10	χ²=23.190	<0.001	5	5	χ²=0.068	0.795
否	405	21	χ²=23.190	<0.001	10	11	χ²=0.068	0.795
双侧乳腺癌
是	8	3		0.014^a	1	2		0.612^a
否	424	28		0.014^a	14	14		0.612^a
病理类型
浸润性癌	391	29		0.302^a	14	15		1.000^a
其他类型癌	10	2			1	1
导管原位癌	31	0			0	0
HER-2表达
阳性	54	4		1.000^a	2	2		1.000^a
阴性	378	27		1.000^a	13	14		1.000^a
分子分型
Luminal型	274	16		0.256^a	11	12		0.004^a
HER-2阳性型	54	4			2	2
三阴性	104	11			2	2
T分期
T1	172	13	Z=-0.789	0.430	6	7	Z=-0.207	0.836
T2	206	15			8	7
T3	44	2			1	1
T4	10	1			0	1
N分期
N0	223	13	Z=-0.634	0.526	6	7	Z=0.000	1.000
N1	144	12			6	6
N2	36	3			2	1
N3	29	3			1	2
M分期
M0	49	6	Z=-0.535	0.593	3	3	Z=-0.258	0.800
M1	383	25	Z=-0.535	0.593	12	13	Z=-0.258	0.800
组织学分级
1级	26	2	Z=-2.846	0.004	1	1	Z=-2.236	0.025
2级	286	13			3	10
3级	120	16			11	5

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