Liede Alexander, Malik Imtiaz A, Aziz Zeba, Rios Pd Patricia de los, Kwan Elaine, Narod Steven A
University of Toronto, Sunnybrook & Women's College Health Sciences Centre, Toronto, Ontario, Canada.
Am J Hum Genet. 2002 Sep;71(3):595-606. doi: 10.1086/342506. Epub 2002 Aug 13.
The population of Pakistan has been reported to have the highest rate of breast cancer of any Asian population (excluding Jews in Israel) and one of the highest rates of ovarian cancer worldwide. To explore the contribution that genetic factors make to these high rates, we have conducted a case-control study of 341 case subjects with breast cancer, 120 case subjects with ovarian cancer, and 200 female control subjects from two major cities of Pakistan (Karachi and Lahore). The prevalence of BRCA1 or BRCA2 mutations among case subjects with breast cancer was 6.7% (95% confidence interval [CI] 4.1%-9.4%), and that among case subjects with ovarian cancer was 15.8% (95% CI 9.2%-22.4%). Mutations of the BRCA1 gene accounted for 84% of the mutations among case subjects with ovarian cancer and 65% of mutations among case subjects with breast cancer. The majority of detected mutations are unique to Pakistan. Five BRCA1 mutations (2080insA, 3889delAG, 4184del4, 4284delAG, and IVS14-1A-->G) and one BRCA2 mutation (3337C-->T) were found in multiple case subjects and represent candidate founder mutations. The penetrance of deleterious mutations in BRCA1 and BRCA2 is comparable to that of Western populations. The cumulative risk of cancer to age 85 years in female first-degree relatives of BRCA1-mutation-positive case subjects was 48% and was 37% for first-degree relatives of the BRCA2-mutation-positive case subjects. A higher proportion of case subjects with breast cancer than of control subjects were the progeny of first-cousin marriages (odds ratio [OR] 2.1; 95% CI 1.4-3.3; P=.001). The effects of consanguinity were significant for case subjects with early-onset breast cancer (age <40 years) (OR=2.7; 95% CI 1.5-4.9; P=.0008) and case subjects with ovarian cancer (OR=2.4; 95% CI 1.4-4.2; P=.002). These results suggest that recessively inherited genes may contribute to breast and ovarian cancer risk in Pakistan.
据报道，巴基斯坦人口的乳腺癌发病率在所有亚洲人群（不包括以色列的犹太人）中最高，卵巢癌发病率在全球也位居前列。为探究遗传因素对这些高发病率的影响，我们在巴基斯坦两个主要城市（卡拉奇和拉合尔）开展了一项病例对照研究，研究对象包括341例乳腺癌患者、120例卵巢癌患者以及200名女性对照者。乳腺癌患者中BRCA1或BRCA2基因突变的发生率为6.7%（95%置信区间[CI] 4.1%-9.4%），卵巢癌患者中该突变发生率为15.8%（95% CI 9.2%-22.4%）。BRCA1基因突变在卵巢癌患者的突变中占84%，在乳腺癌患者的突变中占65%。检测到的大多数突变是巴基斯坦特有的。在多名病例中发现了5种BRCA1突变（2080insA、3889delAG、4184del4、4284delAG和IVS14-1A→G）以及1种BRCA2突变（3337C→T），这些代表了候选的始祖突变。BRCA1和BRCA2有害突变的外显率与西方人群相当。BRCA1突变阳性病例的女性一级亲属到85岁时的累积癌症风险为48%，BRCA2突变阳性病例的一级亲属为37%。与对照者相比，乳腺癌患者中有更高比例是近亲通婚的后代（优势比[OR] 2.1；95% CI 1.4-3.3；P = 0.001）。近亲通婚对早发性乳腺癌（年龄<40岁）患者（OR = 2.7；95% CI 1.5-4.9；P = 0.0008）和卵巢癌患者（OR = 2.4；95% CI 1.4-4.2；P = 0.002）的影响显著。这些结果表明，隐性遗传基因可能导致巴基斯坦人群患乳腺癌和卵巢癌的风险增加。
