JAMA:10000例样本证实，患癌风险≈精准基因突变+家族史(来源：生物探索)

6月21日，剑桥大学科学家在《美国医学会杂志》（JAMA）上发表了一项大样本队列研究报告，分析包括了近1万名BRCA1或 BRCA2 基因突变的妇女，评估了突变携带者发生乳腺癌、卵巢癌、对侧乳腺癌的年龄相关风险，旨在预估有这些基因突变的女性罹患乳腺癌或卵巢癌的年龄特异性风险。患癌风险≈精准基因突变+家族史研究人员发现：携带BRCA1基因缺陷的女性中有72%会患乳腺癌，44%的人在80岁时会患上卵巢癌；同样他们发现69%的携带BRCA2基因缺陷的妇女会患乳腺癌，17%会在80岁患上卵巢癌。然而，对于这两种癌症，女性的家族史都会影响这种风险——换句话说，如果一个女性的亲属患上乳腺癌，那么她自己的风险就会比没有家族病史的携带者高。这说明，罹患癌症的风险也受患者家族史和突变位点的不同而出现差异。试验数据分析据悉，该研究涉及1997～2011年入组BRCA突变携带女性9856例，其中94%来自癌症家族遗传门诊、6%来自人群研究，BRCA1突变者6036例、BRCA2突变者3820例，入组时无癌症人数5046例、已有单侧乳腺癌或卵巢癌人数4810例。

对BRCA1或BRCA2突变妇女进行最佳的临床管理依赖于对年龄特异性罹患癌症风险作出精确的估测。这些数据可被用来估计得益于预防措施的患癌绝对风险的降幅，并能对决定在什么年龄开始做癌症筛检提供信息。在中位时间为5的追踪期内，有426名女性被诊断罹患乳腺癌，109人罹患卵巢癌，245人罹患对侧乳腺癌（即新出现的乳腺癌与先前诊断的乳腺癌位于不同的乳房）。

其中，乳腺癌发病率从成年后早期迅速增加，携带BRCA1基因突变者的发病高峰期在30～40岁，携带BRCA2基因突变者的发病高峰期在40～50岁，然后他们保持近似恒定的发病率（每年20～30‰）直至80岁。如上表所示，试验结果体现在以下几点：

1）受试者到80岁时的累计乳腺癌罹患风险为：72%（BRCA1携带者）和 69%（BRCA2携带者）；受试者到 80 岁时的累计卵巢癌罹患风险为 44%（BRCA1携带者）及 17%（BRCA2携带者）；在最先诊断罹患乳腺癌后 20 年时发生对侧乳腺癌的累计风险为 40%（BRCA1携带者）和 26%（BRCA2携带者）。

2）BRCA1 携带者在成年后早期到30-40 岁时（BRCA2 携带者则从成年后早期到40-50 岁时）的乳腺癌发病率会快速增加，但此后直到 80 岁时的乳腺癌发病率则会维持在相同的恒定水平。

3）BRCA1 和 BRCA2 携带者罹患乳腺癌的风险会随着其一级亲属（父母、子女、同父母的兄弟姐妹）和和二级亲属（叔、伯、舅、姑、姨、祖父母、外祖父母）被诊断乳腺癌人数增加而增加。

4）罹患癌症的风险会随着突变位于BRCA1或BRCA2基因内的部位而异。

研究意义

迄今为止公布的BRCA1和BRCA2基因的妇女的前瞻性研究非常小，最大的仅基于64例乳腺癌。这项研究对携带乳腺癌易感基因（BRCA1、BRCA2）突变女性进行最佳临床管理，有赖于对不同年龄的癌症风险及其影响因素进行精准评估，这些数据可被用于评估相关预防措施对癌症风险的降低程度，并为决定什么年龄开始癌症筛查提供依据。因此，个性化咨询应该结合家族史档案和基因突变部位。

研究的主要作者、来自剑桥大学公共卫生和基础保健部门Antonis Antoniou教授表示，我们已经能够提供不同年龄层的风险，最精确的估计的日期，这些措施将有助于对BRCA1和BRCA2基因缺陷妇女的咨询和临床管理提供更多的信心。

英国癌症研究中心的高级临床顾问Arnie Purushotham教授则表示，携带BRCA基因的女性更易患乳腺癌或卵巢癌，该研究可以帮助妇女和她们的医生，更好地了解他们罹患癌症的风险。结合家族史和BRCA基因突变位点可以帮助妇女决定他们可能想要降低乳腺癌风险的措施，如预防性手术、药物治疗或改变生活方式。

4）罹患癌症的风险会随着突变位于BRCA1或BRCA2基因内的部位而异。

研究意义

4）罹患癌症的风险会随着突变位于BRCA1或BRCA2基因内的部位而异。

研究意义

4）罹患癌症的风险会随着突变位于BRCA1或BRCA2基因内的部位而异。

研究意义

JAMA. 2017 Jun 20;317(23):2402-2416. doi: 10.1001/jama.2017.7112.

Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 MutationCarriers.

Kuchenbaecker KB1, Hopper JL2, Barnes DR3, Phillips KA4, Mooij TM5, Roos-Blom MJ6, Jervis S7, van Leeuwen FE5, Milne RL8, Andrieu N9, Goldgar DE10, Terry MB11, Rookus MA5, Easton DF3, Antoniou AC3; and the BRCA1 and BRCA2 Cohort Consortium, McGuffog L3, Evans DG12, Barrowdale D3,Frost D3, Adlard J13, Ong KR14, Izatt L15, Tischkowitz M16, Eeles R17, Davidson R18, Hodgson S19, Ellis S3, Nogues C20, Lasset C21, Stoppa-Lyonnet D22, Fricker JP23, Faivre L24, Berthet P25, Hooning MJ26, van der Kolk LE27, Kets CM28, Adank MA29, John EM30, Chung WK31, Andrulis IL32, Southey M33, Daly MB34, Buys SS35, Osorio A36, Engel C37, Kast K38, Schmutzler RK39, Caldes T40, Jakubowska A41, Simard J42, Friedlander ML43,McLachlan SA44, Machackova E45, Foretova L45, Tan YY46, Singer CF47, Olah E48, Gerdes AM49, Arver B50, Olsson H51.

Abstract

IMPORTANCE:

The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates.

OBJECTIVES:

To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluaterisk modification by family cancer history and mutation location.

DESIGN, SETTING, AND PARTICIPANTS:

Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years.

EXPOSURES:

BRCA1/2 mutations, family cancer history, and mutation location.

MAIN OUTCOMES AND MEASURES:

Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, andcontralateral breast cancer.

RESULTS:

Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovariancancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001).

CONCLUSIONS AND RELEVANCE:

These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in riskassessment.

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