Novel germline mutations in the PTEN tumour suppressor gene found in women with multiple cancers
Novel germline mutations in the PTEN tumour suppressor gene found in women with multiple cancers
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DOI：
10.1136/jmg.37.5.336
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发表时间：
2000-05-01
影响因子：
4
通讯作者：
Hunter, DJ
中科院分区：
文献类型：
--
作者：
De Vivo, I;Gertig, DM;Hunter, DJ
PTEN的生殖系突变可使人易患考登综合征（CS）和Bannayan-Ruvalcaba-Riley（BRR）综合征，这是一种罕见的常染色体显性遗传肿瘤性疾病。为了确定是否生殖细胞突变的PTEN有助于遗传易感性，以多原发性肿瘤在一般人群中，我们进行了一项巢式病例对照研究，在32 826名成员的前瞻性护士健康研究队列;例妇女与一个以上的原发性肿瘤在不同的解剖部位。我们使用SSCP和测序筛选了所有103例符合条件的病例的所有9个PTEN外显子和侧翼内含子剪接位点。我们观察到两个新的种系杂合错义突变外显子5的5例，三个V119 L和两个V158 L。在115例未诊断癌症的对照组中未观察到突变（p=0.02）。当转染到PTEN缺失乳腺癌细胞系中时，与野生型PTEN相比，两种突变体均显示出部分肿瘤抑制活性。表型是细胞系特异性的，表明遗传背景影响突变体的生长抑制活性。这些数据提供的证据表明，生殖细胞突变的PTEN可能是一个更常见的诱发因素，为妇女癌症比以前建议。
Germline mutations in PTEN can predispose people to Cowden syndrome (CS) and Bannayan-Ruvalcaba-Riley (BRR) syndrome, rare, autosomal dominantly inherited neoplastic disorders. To determine whether germline mutations in PTEN contribute to genetic predisposition to multiple primary tumours within the general population, we conducted a nested case-control study, among 32 826 members of the prospective Nurses' Health Study cohort; cases were women with more than one primary tumour at different anatomical sites. We screened all nine exons of PTEN and flanking intronic splice sites for all 103 eligible cases using SSCP and sequencing. We observed two novel germline heterozygous missense mutations in exon 5 in five of the cases; three were V119L and two were V158L. Neither mutation was observed in 115 controls free of diagnosed cancer (p=0.02). Both mutants showed partial tumour suppressor activity when compared to wild type PTEN when transfected into a PTEN null breast cancer cell line. The phenotype was cell line specific suggesting that genetic background affects growth suppression activity of the mutants. These data provide evidence that germline mutations in PTEN may be a more frequent predisposing factor for cancers in women than previously suggested.