Rowan A, Bataille V, MacKie R, Healy E, Bicknell D, Bodmer W, Tomlinson I
Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, London, UK.
J Invest Dermatol. 1999 Apr;112(4):509-11. doi: 10.1046/j.1523-1747.1999.00551.x.
Germline mutations in the LKB1/STK11 gene cause characteristic hamartomas and freckling to develop in patients with Peutz-Jeghers syndrome (PJS). The hamartomas arise as a result of somatic "second hits" at LKB1/STK11 and therefore contain a neoplastic element. The origin of the pigmented lesions in PJS is unknown and difficult to test, as these are hardly ever biopsied. PJS patients are at increased risk of benign and malignant tumors, particularly of the colon, breast, pancreas, testis, and ovary, although the increased risk for any one of these sites may be quite modest. Somatic LKB1/STK11 mutations have been found, albeit at a low frequency, in sporadic tumors of the colon, stomach, ovary, and testis. Although PJS patients are not known to have an excess of skin tumors, if the freckles of PJS patients are actually small, benign tumors, LKB1/STK11 mutations must provide these lesions with a selective advantage, and similar mutations might also give a selective advantage to related malignant tumors, such as melanomas. We have therefore screened 16 melanoma cell lines, 15 primary melanomas, and 19 metastases for LKB1/STK11 mutations. Two LKB1/STK11 mutations were found: a missense change (Y49D) accompanied by allele loss in a cell line; and a missense change (G135R), without a detected mutation in the other allele, in a primary tumor. Both these mutations are highly likely to be pathogenic. Novel polymorphisms, including an unusual heptanucleotide repeat, were also found in introns 2 and 3. LKB1/STK11 mutations occur in a significant minority of tumors of several sites, including malignant melanomas.
LKB1/STK11基因的种系突变会导致黑斑息肉综合征（PJS）患者出现特征性错构瘤和雀斑。错构瘤是由于LKB1/STK11发生体细胞“二次打击”而产生的，因此包含肿瘤成分。PJS中色素沉着病变的起源尚不清楚且难以检测，因为这些病变几乎从未进行过活检。PJS患者患良性和恶性肿瘤的风险增加，尤其是结肠、乳腺、胰腺、睾丸和卵巢的肿瘤，尽管这些部位中任何一个部位风险增加的幅度可能都不大。在结肠、胃、卵巢和睾丸的散发性肿瘤中，虽发现了体细胞LKB1/STK11突变，但频率较低。尽管已知PJS患者没有过多的皮肤肿瘤，但如果PJS患者的雀斑实际上是小的良性肿瘤，那么LKB1/STK11突变必定为这些病变提供了选择性优势，类似的突变也可能给相关恶性肿瘤（如黑色素瘤）带来选择性优势。因此，我们对16个黑色素瘤细胞系、15个原发性黑色素瘤和19个转移瘤进行了LKB1/STK11突变筛查。发现了两个LKB1/STK11突变：一个错义改变（Y49D），伴有一个细胞系中的等位基因缺失；以及一个原发性肿瘤中的错义改变（G135R），另一个等位基因未检测到突变。这两个突变极有可能具有致病性。在第2和第3内含子中还发现了新的多态性，包括一个不寻常的七核苷酸重复序列。LKB1/STK11突变在包括恶性黑色素瘤在内的多个部位的肿瘤中占少数。
