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A Role for LKB1 Gene in Human Cancer Beyond the Peutz–Jeghers Syndrome

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A Role for LKB1 Gene in Human Cancer Beyond the Peutz–Jeghers Syndrome Oncogene (2007) 26, 7825–7832 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW A role for LKB1 gene in human cancer beyond the Peutz–Jeghers syndrome M Sanchez-Cespedes Molecular Pathology Programme, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro, Madrid, Spain Germline LKB1 mutations are responsible for Peutz– development, LKB1 expression becomes more pro- Jeghers syndrome (PJS). Tumors at several locations nounced in heart, esophagus, pancreas, kidney, colon, frequently arise in these patients, confirming that LKB1 is lung, small intestine and stomach (Luukko et al., 1999; linked to cancer predisposition and is therefore a bona fide Rowan et al., 2000). In adult tissues, levels of LKB1 tumor-suppressor gene. In humans, the LKB1 gene is protein are high in most epithelia, in the follicles and located in the short arm of chromosome 19, which is corpus luteum of the ovary, and the seminiferous tubules frequently deleted in many tumors of sporadic origin. of the testis, in myocytes from skeletal muscle and in glia However, LKB1 alterations in tumors other than those of cells (Rowan et al., 2000; Conde et al., 2007; Figure 1a). PJSare rarely reported. Notably, this is not the case for non-small-cell lung cancer, where nearly half of the tumors harbor somatic and homozygous inactivating mutations in LKB1. The present review considers the LKB1 and Peutz–Jeghers syndrome frequency and pattern of LKB1 gene mutations in LKB1 sporadic cancers of various origins, and the role of the Germline mutations of cause the autosomal encoded protein in cancer development. dominant Peutz–Jeghers syndrome (PJS) (OMIM et al et al Oncogene (2007) 26, 7825–7832; doi:10.1038/sj.onc.1210594; 175200) (Hemminki ., 1998; Jenne ., 1998). published online 18 June 2007 The type and pattern of these mutations have been extensively reviewed elsewhere (Alessi et al., 2006; Keywords: LKB1; lung cancer; Peutz-Jeghers syndrome; Launonen, 2005). Individuals with PJS typically exhibit tumor suppressor gene mucocutaneous melanin pigmentation and suffer from hamartomatous polyps in the gastrointestinal tract (Jeghers et al., 1949; Giardiello et al., 2000). However, among the most important associated health-related concerns is the increased risk of cancer development Characteristics of the LKB1 gene and encoded protein: (Giardiello et al., 2000). Gastrointestinal tumors are the patterns of LKB1 expression in human tissues most commonly diagnosed malignancies in PJS patients, but the risk of developing cancer from other origins is The LKB1 gene, also known as STK11, maps to the also significantly higher (Figure 1b) (Giardiello et al., chromosomal region 19p13.3, which is frequently lost in 2000; Hearle et al., 2006a). To some extent, the pattern several types of cancer. The gene spans 23 kb and is made of tumor susceptibility in PJS patients recapitulates the up of nine coding exons and a final noncoding exon. expression of LKB1 in normal adult and embryonic B LKB1 encodes for an mRNA of 2.4kb transcribed in a tissues. For example, gonadal cell types that derive from telomere-to-centromere direction and for a protein of the coelomic epithelium (sex cords) or mesenchymal 433 amino acids and approximately 48 kDa (Hemminki cells of the embryonic gonads include granulosa cells et al., 1998). The protein, which has serine–threonine and theca cells, which have very high levels of LKB1 kinase activity, possesses a nuclear localization signal in protein (Conde et al., 2007). Interestingly, a type of the N-terminal noncatalytic region (residues 38–43) and ovarian cancer arising from these cell types, the ovarian a kinase domain (residues 49–309) (Alessi et al., 2006). sex cord tumors with annular tubules, which occurs Although LKB1 protein expression is mainly cytoplas- rarely in the general population, is present at higher mic, it can also be localized in the nucleus. frequencies in women with PJS. Likewise, the level of LKB1 is widely expressed in embryonic and adult LKB1 immunostaining is moderately high in cells from tissues although at different levels. Early mouse the breast, epithelia from the small intestine, colon and embryos (E7–11) have highly ubiquitous expression in pancreatic islets from human adult normal tissue, and all embryonic and extra-embryonic tissues. During very high in the small intestine and stomach of human embryos. Tumors from these origins are the commonest Correspondence: Dr M Sanchez-Cespedes, Molecular Pathology types in PJS (Figure 1b). Programme, Spanish National Cancer Centre (CNIO), Melchor Most studies of PJS patients have reported that only Fernandez Almagro 3, Madrid 28029, Spain. E-mail: [email protected] about half of the individuals carry LKB1 germline Received 17 March 2007; revised 14May 2007; accepted 14May 2007; mutations, which suggested that other tumor-suppressor published online 18 June 2007 genes must be associated with the syndrome in the Role of LKB1 in sporadic tumors M Sanchez-Cespedes 7826 a LKB1 PROTEIN EXPRESSION b PEUTZ-JEGHERS-RELATED TUMORS (Luuko et al. 1999; Rowan et al. 2000 (Giardiello et al.et al. 2000; et al. 2002; Conde et al. 2007) Lim et al. 2004; Hearle et al. 2006a) ADULT TUMOR TYPE (increased cancer risk) HIGH Gastroesophageal (15) Cerebral cortex (neurons and glia) Breast (6) Ovary (follicles and corpus luteum) Small bowel (15) Salivary glands (serous acini) Skeletal muscle Colorectal (15) Testis (developing, mature spermatozoa) Pancreas (22-130) Tonsil (epithelia) Gynecological (8.5) Breast (6) Lung(4-9) MODERATE Breast Colon (surface epithelium) Endometrium (glandular epithelium) Heart Kidney (tubules) Pancreas (islets) Respiratory epithelia (except goblet cells) Small Intestine (villous epithelium) Thyroid (follicular cells) EMBRYO HIGH Small intestine Stomach MODERATE Colon Heart Kidney Lung Pancreas Esophagus Figure 1 LKB1 protein-expression profile in normal tissues and pattern of tumor susceptibility in PJS patients. (a) Levels of LKB1 protein immunostaining in adult and embryonic human normal tissues. (b) Tumor spectrum in patients with PJS. The increased risk of each type of tumor is cited in parentheses. PJS, Peutz–Jeghers syndrome. remaining patients (Wang et al., 1999a; Alhopuro et al., sporadic origin screened to date. When first identified as 2005). Several chromosomal regions were thought to the gene responsible for PJS, LKB1 was tested for contain a second PJS locus, such as 19q, but genes inactivating mutations in a variety of sporadic tumors. within these regions do not contain LKB1 mutations Although tumor-specific LKB1 alterations have been (Buchet-Poyau et al., 2002). More recently, the use of identified in many of these tumor types, their frequency specific technical approaches, such as multiplex ligation- is extremely low. Table 1 summarizes most of the LKB1 dependent probe amplification, which allows the identi- mutations found in sporadic cancer to date, including fication of large-scale gene deletions, has improved the cancer cell lines and primary tumors of various origins. detection of LKB1 alterations in PJS patients by up to The mutational screening method is also indicated. 80% (Hearle et al., 2006b; Volikos et al., 2006). Thus, LKB1 mutations are present in about 4% of pancreatic these results indicate that LKB1 is the main causal gene cancers (cell lines and primary tumors from xenografts), in PJS, lessening the probability of there being a second but no mutations have been reported in breast, color- PJS locus. ectal or gastric cancer. The exception is non-small-cell lung cancer (NSCLC), in which LKB1 inactivation is a common event (Sanchez-Cespedes et al., 2002; Carretero Is LKB1 involved in the carcinogenesis of sporadic et al., 2004; Matsumoto et al., 2007). These differences tumors? The example of lung cancer are puzzling because lung cancer risk is higher but is not among the commonest tumors that occur in PJS. Before As described above, PJS patients have an increased risk ruling out the LKB1 tumor-suppressor role in sporadic of several types of cancer. Unexpectedly, LKB1 is tumors other than in lung, the obstacles associated with infrequently mutated in most of the tumor types of the detection of mutations in tumors need to be Oncogene Role of LKB1 in sporadic tumors M Sanchez-Cespedes 7827 Table 1 Frequency of LKB1 mutations in primary tumors and cancer cell lines of sporadic origin Tumor type No of tumors % Mutationsa Methodb Reference Cancer cell lines Breast 17 0% Sequencing Bignell et al. (1998) 5 0% Sequencing Ikediobi et al. (2006) Colorectal 7 0% Sequencing Ikediobi et al. (2006) Gliomas 6 0% Sequencing Ikediobi et al. (2006) HNSCC 8 12.5% Sequencing Qiu et al. (2006) Lung Adenocarcinomas/LCC 11 54% Sequencing Carretero et al. (2004) 7 43% Sequencing Ikediobi et al. (2006) 38 42% Sequencing Matsumoto et al. (2007) Squamous cell carcinomas 11 27% Sequencing Matsumoto et al. (2007) Small-cell lung cancer 11 0% Sequencing Carretero et al. (2004) 19 5% Sequencing Matsumoto et al. (2007) Melanoma 6 0% SSCP Avizienyte et al. (1999) 35 6% DGGE Guldberg et al. (1999) 16 6% SSCP Rowan et al. (1999) 9 0% Sequencing Ikediobi et al. (2006) Myeloma 8 0% SSCP Avizienyte et al. (1999) Pancreas 11 0% Sequencing Su et al. (1999) Prostate 2 50% Sequencing Ikediobi et al. (2006) Ovary 7 0% Sequencing Ikediobi et al. (2006) Renal 8 0% Sequencing Ikediobi et al. (2006) Primary tumors Breast 62 0% Sequencing Bignell et al. (1998) Cervix Squamous cell carcinoma 18 0% SSCP Avizienyte et al. (1999) 15 0% SSCP Kuragaki et al. (2003) Adenocarcinoma 8 12.5% SSCP Avizienyte et al. (1999) 244%SSCP Kuragaki et al. (2003) MDA 11 55% SSCP Kuragaki et al. (2003) 8 0% Sequencing Connolly et al. (2000) Colorectal 33 0% SSCP Avizienyte et al. (1998) Gastric 8 0% SSCP Avizienyte et al. (1999) HNSCC 7 0% Sequencing Qiu et al. (2006) Liver 80 1% SSCP Kim et al. (2004) Lung Adenocarcinomas 12 8% SSCP Avizienyte et al.
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