Bartosova Z, Zavodna K, Krivulcik T, Usak J, Mlkva I, Kruzliak T, Hromec J, Usakova V, Kopecka I, Veres P, Bartosova Z, Bujalkova M
Cancer Research Institute of Slovak Academy of Science, Bratislava, Slovakia. Zdena.
Neoplasma. 2007;54(2):101-7.
Peutz-Jeghers syndrome (PJS) is characterized by number of hamartomatous polyps in the gastrointestinal tract and by mucocutaneous hypermelanocytic lesions at different sites. Older patients have an increased risk of the cancers of small intestine, stomach, pancreas, colon, esophagus, ovary, testis, uterus, breast and lung. In majority of PJS cases, the germline mutations in serine/threonine kinase STK11/LKB1 gene were found to be associated with disease. Here we report the results of a first mutational screen of STK11/LKB1 in PJS patients characterized in Slovak population. The first patient with unusual carcinoma of duodenum was a sporadic case and carried c.842delC change residing in a mutational C6 repeat hotspot. Neither the polyp nor the tumor of the patient displayed the loss of heterozygosity at the site of mutation suggesting different mechanism involved in the formation of polyp and tumor in this case. The second patient belonged to a three-generation family with typical PJS features but not cancers. Interestingly, the patient displayed concomitant occurrence of adenomatous and hamartomatous polyps. Molecular analysis revealed an IVS2+1A>G mutation that alters the second intron 5' splice site and was shown to lead to aberrant splicing mediated by the U12-dependent spliceosome. The same mutation was present in the 9 affected members of the family but in none of their normal relatives. We also observed novel c. IVS2+61G>A unclassified variant, and recurrent IVS2+24G>T and 3UTR+129C>T polymorphisms. Based on the achieved results, we could offer predictive genetic testing and counseling to other members of the patient's families.
黑斑息肉综合征（PJS）的特征是胃肠道存在多个错构瘤性息肉以及不同部位出现黏膜皮肤黑素细胞增多性病变。老年患者患小肠、胃、胰腺、结肠、食管、卵巢、睾丸、子宫、乳腺和肺癌的风险增加。在大多数PJS病例中，发现丝氨酸/苏氨酸激酶STK11/LKB1基因的种系突变与该病相关。在此，我们报告斯洛伐克人群中PJS患者STK11/LKB1首次突变筛查的结果。首例十二指肠罕见癌患者为散发病例，携带位于突变C6重复热点区域的c.842delC改变。该患者的息肉和肿瘤在突变位点均未显示杂合性缺失，提示此例中息肉和肿瘤形成涉及不同机制。第二名患者属于一个有典型PJS特征但无癌症的三代家族。有趣的是，该患者同时出现腺瘤性息肉和错构瘤性息肉。分子分析显示存在IVS2+1A>G突变，该突变改变了第二个内含子5'剪接位点，并导致由U12依赖性剪接体介导的异常剪接。该家族9名受累成员存在相同突变，但其正常亲属均无此突变。我们还观察到新的c.IVS2+61G>A未分类变异以及复发性IVS2+24G>T和3UTR+129C>T多态性。基于所取得的结果，我们可为患者家族的其他成员提供预测性基因检测和咨询服务。
