乳腺癌患者与非乳腺癌人群BRCA1/2基因突变率的差异分析

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

目的

比较乳腺癌人群与非乳腺癌人群BRCA1/2基因突变率的差异，并对乳腺癌人群BRAC1/2基因突变率相关的临床病理因素进行分析。

方法

收集2021年1月至2023年8月在空军军医大学第一附属医院甲乳血管外科就诊的463例乳腺癌患者和321例非乳腺癌人群的临床资料进行回顾性研究。采用人类BRCA1和BRCA2基因突变检测试剂盒进行胚系BRCA突变筛查。乳腺癌与非乳腺癌人群BRCA1/2基因突变率的组间比较、乳腺癌患者BRCA1/2基因突变与未突变的临床病理特征比较采用χ²检验或Fisher确切概率法，其中T分期、N分期、M分期、组织学分级为等级资料，组间比较采用Wilcoxon秩和检验。

结果

463例乳腺癌患者中BRCA1基因致病性突变为15例（3.2%），其中c.3288_3289del和c.5470_5477del位点突变频率最高，均为3/15，其次是c.5155del和c.5074+1G>T。BRCA2基因致病性突变为16例（3.5%），出现频率最高的突变位点是c.9097del、c.7681C>T，均为2/16。321例非乳腺癌人群中BRCA1和BRCA2基因致病性突变分别为1例（0.3%）和2例（0.6%）。BRCA1临床意义不明突变在乳腺癌患者中为13例（2.8%），在非乳腺癌人群中为8例（2.5%）；BRCA2临床意义不明突变在乳腺癌患者中为28例（6.0%），在非乳腺癌人群中为21例（6.5%）。乳腺癌患者的BRCA1/2基因总体突变率显著高于非乳腺癌人群（15.6%比10.0%，P=0.039）。BRCA1/2基因突变乳腺癌患者中确诊年龄<45岁的比例高于未突变者（48.4%比31.5%，χ²=10.171，P=0.001）；有乳腺癌或其他恶性肿瘤家族史的比例高于未突变者（32.3%比6.2%，χ²=23.190，P<0.001）；双侧乳腺癌的比例高于未突变者（9.7%比1.9%，P=0.014）。同时，BRCA1/2基因突变的乳腺癌患者与未突变者的肿瘤组织学分级和Ki-67表达比较，差异有统计学意义（P=0.016、0.040）。BRCA1基因致病性突变乳腺癌患者中确诊年龄<45岁的比例高于BRCA2基因致病性突变者（66.7%比31.2%，χ²=4.841，P=0.028）。BRCA1致病性突变患者与BRCA2致病性突变乳腺癌患者的组织学分级、ER、PR、Ki-67表达、分子分型比较，差异均有统计学意义（P=0.023、0.010、0.020、0.035、0.004）。

结论

在乳腺癌患者中，BRCA1/2致病性突变与早发乳腺癌、恶性肿瘤家族史和双侧乳腺癌相关，并且BRCA1和BRCA2突变的乳腺癌患者的临床病理特征差异较大，值得进一步深入研究BRCA1和BRCA2突变乳腺癌患者的不同发病机制。

关键词: 乳腺肿瘤, 基因，BRCA1, 基因，BRCA2

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

表1 31例携带胚系BRCA1/2基因致病性突变乳腺癌患者的基因突变频率

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*

表1 31例携带胚系BRCA1/2基因致病性突变乳腺癌患者的基因突变频率

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*

表2 463例接受BRCA1/2基因胚系突变检测的乳腺癌患者临床病理特征比较（例）

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

表2 463例接受BRCA1/2基因胚系突变检测的乳腺癌患者临床病理特征比较（例）

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

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