Genetic analysis of the LKB1/STK11 gene in hepatocellular carcinomas

Kim, C.J.; Cho, Y.G.; Park, J.Y.; Kim, T.Y.; Lee, J.H.; Kim, H.S.; Lee, J.W.; Song, Young Woo; Nam, Soon Woo; Lee, S.H.; Yoo, Nam Jin; Lee, J.Y.; Park, W.S.

doi:10.1016/s0959-8049(03)00659-2

Cited by 54 publications

(31 citation statements)

References 25 publications

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“…Only seven of the mutations are identical to the reported LKB1 germline mutations. The mononucleotide repeat (C6 repeat, c.837-c.842) seems to be also a somatic mutational hotspot including three cases of a 1-bp deletion and three cases of 1-bp substitution (c.842C4T) [Nishioka et al, 1999;Kim et al, 2004;Dong et al, 1998;Nakagawa et al, 1999].…”

Section: Lkb1 Somatic Mutationsmentioning

confidence: 99%

Mutations in the humanLKB1/STK11gene

Launonen

2005

Hum. Mutat.

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Communicated by Richard WoosterThe human LKB gene (official HUGO symbol, STK11) encodes a serine/threonine protein kinase that is defective in patients with Peutz-Jeghers syndrome (PJS). PJS is an autosomal dominantly inherited syndrome characterized by hamartomatous polyposis of the gastrointestinal tract and mucocutaneous pigmentation. To date, 145 different germline LKB1 mutations have been reported. The majority of the mutations lead to a truncated protein product. One mutational hotspot has been observed. A 1-bp deletion and a 1-bp insertion at the mononucleotide repeat (C6 repeat, c.837-c.842) between the codons 279-281 have been found in six and seven unrelated PJS families, respectively. However, these mutations account only for approximately 7% of all mutations identified in the PJS families (13/193). A review of the literature provides a total of 40 different somatic LKB1 mutations in 41 sporadic tumors and seven cancer cell lines. Mutations occur particularly in lung and colorectal cancer. Most of the somatic LKB1 mutations result in truncation of the protein. A mutational hotspot seems to be a C6 repeat accounting for 12.5% of all somatic mutations (6/48). These results are concordant with the germline mutation spectrum. However, the proportion of the missense mutations seems to be higher among the somatic mutations (45%) than among the germline mutations (21%), and only seven of the mutations are exactly the same in both of the mutation types. Hum Mutat 26(4), [291][292][293][294][295][296][297] 2005.

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Section: Lkb1 Somatic Mutationsmentioning

confidence: 99%

Mutations in the humanLKB1/STK11gene

Launonen

2005

Hum. Mutat.

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“…In those mutations, STK11 mutations were critical, since 75% of those mutations were frameshift variants and missense variants. A previous genetic analysis of the STK11 gene demonstrated that this mutation may serve a role in tumor progression in a subset of HCC, protecting from p53-dependent apoptosis (29). Huang et al (30) identified that decreased expression of STK11 is associated with poor prognosis.…”

Section: Tp53 Ctnnb1 Smarcb1 ----------------------------------------mentioning

confidence: 99%

Targeted sequencing of cancer‑associated genes in hepatocellular carcinoma using next‑generation sequencing

et al. 2017

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Abstract. Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Although the clinical success rate for the treatment of early-stage HCC has improved, the prognosis of advanced HCC remains poor owing to the high recurrence rate and the refractory nature of HCC for various anticancer drugs. A better understanding of the pathogenesis of HCC is therefore critically needed in order to treat HCC, including its genetic alterations. Next-generation sequencing (NGS) has provided an unbiased platform to systematically identify gene mutations and reveal the pathogenesis of various cancers. In the present study, a total of 118 samples (59 liver tissues including cancer and adjacent normal tissues) were sequenced using the AmpliSeq Hotspot Cancer Panel (version 2). The most common somatic mutations identified were tumor protein 53 (TP53; 35.6%) and β-catenin 1 (CTNNB1; 30.5%), and the most frequent variants of those genes were missense variants. In addition, somatic mutations including those in genes encoding colony-stimulating factor 1 receptor (5.1%), epidermal growth factor receptor (6.8%), RET proto-oncogene (3.4%), Erb-B2 receptor tyrosine kinase 4 (ERBB4; 1.7%) and serine/threonine kinase 11 (STK11, also known as liver kinase B1; 6.8%) were also identified at a low frequency in patients with HCC. A frameshift variant in STK11, a splice acceptor variant in TP53, a splice region variant in ERBB4 and a stop-gained variant in TP53 were also specifically determined. The most abundant alteration was a C:G>T:A transition (50%) and other transversions, i.e., C:G>G:C (19.6%), T:A>C:G (19.6%), C:G>A:T (12.5%), T:A>G:C (12.5%) and T:A>A:T (5.4%). This spectrum pattern differs from that in other solid tumors. TP53 mutations in the tumors at advanced stages were significantly more frequent compared with those in early-stage tumors. Additionally, age (<70 vs. ≥70 years) was significantly associated with CTNNB1 mutations. Using NGS, a number of novel gene mutations were identified in HCC, including established mutations and disproved mutations. The results of the present study offer new insight and improved understanding of the etiology and the development of HCC.

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“…Somatic LKB1 mutations are also common in cervical cancer, found in about 20% of cases [48]. In addition, LKB1 mutations have been observed in melanomas and cancers of the pancreas, liver, breast and endometrium, although at reduced frequency [49][50][51][52][53]. Reduced or missing expression of Lkb1 has been reported in a range of cancers, including endometrial, pancreatic and breast cancer [49,[54][55][56].…”

Section: (A) Lkb1 In Hereditary and Sporadic Tumoursmentioning

confidence: 99%

Breaking the epithelial polarity barrier in cancer: the strange case of LKB1/PAR-4

Partanen

Tervonen

Klefström

2013

Phil. Trans. R. Soc. B

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The PAR clan of polarity regulating genes was initially discovered in a genetic screen searching for genes involved in asymmetric cell divisions in the Caenorhabditis elegans embryo. Today, investigations in worms, flies and mammals have established PAR proteins as conserved and fundamental regulators of animal cell polarization in a broad range of biological phenomena requiring cellular asymmetries. The human homologue of invertebrate PAR-4, a serine–threonine kinase LKB1/STK11, has caught attention as a gene behind Peutz–Jeghers polyposis syndrome and as a bona fide tumour suppressor gene commonly mutated in sporadic cancer. LKB1 functions as a master regulator of AMP-activated protein kinase (AMPK) and 12 other kinases referred to as the AMPK-related kinases, including four human homologues of PAR-1. The role of LKB1 as part of the energy sensing LKB1-AMPK module has been intensively studied, whereas the polarity function of LKB1, in the context of homoeostasis or cancer, has gained less attention. Here, we focus on the PAR-4 identity of LKB1, discussing the weight of evidence indicating a role for LKB1 in regulation of cell polarity and epithelial integrity across species and highlight recent investigations providing new insight into the old question: does the PAR-4 identity of LKB1 matter in cancer?

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Genetic analysis of the LKB1/STK11 gene in hepatocellular carcinomas

Cited by 54 publications

References 25 publications

Mutations in the humanLKB1/STK11gene

Mutations in the humanLKB1/STK11gene

Targeted sequencing of cancer‑associated genes in hepatocellular carcinoma using next‑generation sequencing

Breaking the epithelial polarity barrier in cancer: the strange case of LKB1/PAR-4

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