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PubMed1992

Clonal p53 mutation in primary cervical cancer: association with human-papillomavirus-negative tumours.

Analyses of cancer cell lines and of anal cancers suggest an inverse correlation between infection with human papillomavirus (HPV) and somatic mutation of the p53 tumour-suppressor gene. We have investigated this association in primary cervical tumours. Tumour-tissue samples from 28 women with primary cancer of the cervix were analysed for presence of HPV sequences and for somatic mutations of the p53 gene. Southern blot analysis and the polymerase chain reaction (PCR) showed that 25 of the tumours contained HPV sequences; 20 were HPV16 positive and 5 HPV18 positive. 17 tumours subjected to restriction fragment length polymorphism analysis for the short arm of chromosome 17 showed no evidence of allelic deletion. Sequencing of the entire coding region of the p53 gene by asymmetric PCR detected heterozygous point mutations in only 3 HPV-negative tumours. By contrast, in 21 HPV-positive cancers the p53 sequence was wild-type throughout. Our data indicate that loss of wild-type p53 function is important in the pathology of cervical cancer and that in the absence of an HPV-encoded gene product that mediates loss of p53 function, somatic mutation of the gene is required. This pattern of p53 mutation may partly explain the apparently worse prognosis of HPV-negative cervical cancers.

Adenocarcinoma↗

PubMed2004

Autoimmune lymphoproliferative syndrome with somatic Fas mutations.

BACKGROUND: Impaired Fas-induced apoptosis of lymphocytes in vitro is a principal feature of the autoimmune lymphoproliferative syndrome (ALPS). We studied six children with ALPS whose lymphocytes had normal sensitivity to Fas-induced apoptosis in vitro. METHODS: Susceptibility to Fas-mediated apoptosis and the Fas gene were analyzed in purified subgroups of T cells and other mononuclear cells from six patients with ALPS type III. RESULTS: Heterozygous dominant Fas mutations were detected in the polyclonal double-negative T cells from all six patients. In two patients, these mutations were found in a fraction of CD4+ and CD8+ T cells, monocytes, and CD34+ hematopoietic precursors, but not in hair or mucosal epithelial cells. CONCLUSIONS: Somatic heterozygous mutations of Fas can cause a sporadic form of ALPS by allowing lymphoid precursors to resist the normal process of cell death.

Adolescent↗

PubMed1998

Right ventricular outflow tract tachycardia due to a somatic cell mutation in G protein subunitalphai2.

Idiopathic ventricular tachycardia is a generic term that describes the various forms of ventricular arrhythmias that occur in patients without structural heart disease and in the absence of the long QT syndrome. Many of these tachycardias are focal in origin, localize to the right ventricular outflow tract (RVOT), terminate in response to beta blockers, verapamil, vagal maneuvers, and adenosine, and are thought to result from cAMP-mediated triggered activity. DNA was prepared from biopsy samples obtained from myocardial tissue from a patient with adenosine-insensitive idiopathic ventricular tachycardia arising from the RVOT. Genomic sequences of the inhibitory G protein Galphai2 were determined after amplification by PCR and subcloning. A point mutation (F200L) in the GTP binding domain of the inhibitory G protein Galphai2 was identified in a biopsy sample from the arrhythmogenic focus. This mutation was shown to increase intracellular cAMP concentration and inhibit suppression of cAMP by adenosine. No mutations were detected in Galphai2 sequences from myocardial tissue sampled from regions remote from the origin of tachycardia, or from peripheral lymphocytes. These findings suggest that somatic cell mutations in the cAMP-dependent signal transduction pathway occurring during myocardial development may be responsible for some forms of idiopathic ventricular tachycardia.

Amino Acid Sequence↗

PubMed1990

New approaches for biological monitoring of radiation workers.

Methods for measuring somatic mutation and chromosome aberration in humans are currently advancing and provide important new opportunities for biologic dosimetry of nuclear workers. Methods to test somatic mutation in four human genes (hprt, hla-a, glycophorin A, and beta globin) are reviewed briefly and evaluated for their applicability to biological radiation dosimetry of nuclear workers. Two somatic mutation tests can be currently recommended: an HPRT method applied to recently exposed workers and the glycophorin A method applied to workers exposed over their working lifetime. A new method of chromosome analysis using DNA hybridization with chromosome-specific gene libraries allows one to paint single or multiple chromosome pairs in standard metaphase preparations. This method is ideal for rapid and reliable detection of reciprocal translocations, the key lesion for the evaluation of long-term radiation exposure. Both mutational and aberrational approaches should be fostered in the expectation that they will complement other forms of dosimetry and will improve our ability to clarify whether or not significant health effects are dosimetrically related.

Chromosome Aberrations↗

PubMed2006

Mutational analysis of the kinase domain of MYLK2 gene in common human cancers.

Genetic alterations of the genes encoding protein kinases have been implicated in the development of human cancers. Myosin light chain kinase 2, skeletal muscle (MYLK2) encodes a calcium/calmodulin-dependent serine/threonine kinase. In a recent study, MYLK2 gene was somatically mutated in colorectal carcinomas. The aim of this study was to explore the possibility that other common human carcinomas besides colorectal carcinomas harbored MYLK2 mutations in the kinase domain. We analyzed exons 6 and 7 eccoding the kinase domain of MYLK2 for somatic mutations in 60 gastric, 104 colorectal, 79 non-small cell lung, and 54 breast cancers using a polymerase chain reaction (PCR)-based single-strand conformation polymorphism (SSCP). We found one MYLK2 mutation in lung adenocarcinomas, but not in other cancers. The MYLK2 mutation detected was a missense mutation that would substitute an amino acid (E374D) However, there was no somatic mutation of the MYLK2 gene. These data suggest that the kinase domain of MYLK2 is rarely mutated in common human carcinomas and that it does not play a dominant role in cancer pathogenesis.

Adult↗

PubMed2007

Clonality and prognostic implications of p53 and epidermal growth factor receptor somatic aberrations in multiple primary lung cancers.

PURPOSE: For treatment decision and prognostic applications, we evaluated p53/epidermal growth factor receptor (EGFR) somatic aberrations in multiple primary lung cancers to differentiate multifocal tumors from intrapulmonary metastasis. EXPERIMENTAL DESIGN: Fifty-eight multiple primary lung cancers of 1,037 patients in a 10-year period were identified to investigate somatic mutations and altered expression of p53 and EGFR for clonality assessment. Genomic DNA was extracted from microdissected cells of paraffin-embedded multiple primary lung cancer tissues. Overexpression and somatic mutations in exons of p53 (exons 5-8) and tyrosine kinase domain of EGFR (exons 18-22) were examined by immunohistochemical staining and DNA sequencing, respectively. RESULTS: High frequency of somatic mutations in p53 (33 of 58, 56.9%) and/or EGFR (44 of 58, 75.9%) resulted in high discrimination rate of tumor clonality (50 of 58, 86.2%) of multiple primary lung cancers. Twenty-two cases (37.9%) were assessed as having the same clonality and 28 cases (48.3%) were determined as having different clonality, which further supported the carcinogenic theory of field cancerization. Notably, the occurrence of lymph node metastasis was more commonly observed in tumors with the same clonality (P = 0.045) and was associated with poor patient 5-year survival rate (P = 0.001). However, no correlation was found between tumor clonality and patient survival (P = 0.630). The EGFR somatic aberrations in 58 multiple primary lung cancers, including vascular invasion associated with EGFR overexpression (P = 0.012) and mutation (P = 0.025), further suggested the potential benefits of target therapy of inoperable multiple primary lung cancers. CONCLUSIONS: Our results suggest that analysis of somatic alterations in p53 and EGFR can significantly improve the clonality assessment and impact management of multiple primary lung cancer patients.

DNA Mutational Analysis↗

PubMed2005

High frequency of somatic mitochondrial DNA mutations in human thyroid carcinomas and complex I respiratory defect in thyroid cancer cell lines.

Significant progress has been made to elucidate the molecular mechanisms that determine thyroid tumor development and progression. However, most investigations have mainly focused on the genetic alterations of nuclear DNA. The potential role of mitochondrial DNA (mtDNA) mutations in thyroid tumorigenesis is not well defined. In the present study, we investigated the frequency of mtDNA mutations in 24 thyroid tumor specimens (19 primary papillary thyroid carcinomas (PTC), one follicular thyroid carcinoma, and four multinodular hyperplasias) and four thyroid cancer cell lines by sequencing the entire coding regions of mitochondrial genome. Among the 19 PTC samples tested, seven (36.8%) had somatic mutations. Somatic mtDNA mutations were also detected in one of four multinodular hyperplasias examined. All the thyroid tumor cell lines carried sequence variations that change amino acid and have not been reported previously as normal sequence variants. Flow cytometry analysis of mitochondria respiratory function in the thyroid tumor cell lines revealed a severe defect in mitochondrial complex I activity. The majority of the mutations was involved in genes located in the complex I of the mitochondrial genome. The mutations were either A --> G or C --> T transitions, often resulting in a change of a moderately or highly conserved amino acid of their corresponding protein. These data suggest that mtDNA mutations may play an important role in the thyroid tumorigenesis. Given that mtDNA mutation is present in the benign multinodular hyperplasia, it might be involved in the early stage of tumor development.

Carcinoma↗

PubMed1991

Somatic hypermutation of immunoglobulin kappa may depend on sequences 3' of C kappa and occurs on passenger transgenes.

We have compared the pattern of somatic mutation in different immunoglobulin kappa transgenes and suggest that an element(s) located between 1 kb and 9 kb 3' of C kappa is necessary for somatic hypermutation of the antibody V gene. The sequences of transgenic and endogenous Ig V regions were determined in antigen-specific B cell hybridomas specific for 2-phenyloxazolone from independent lines of hyperimmunized transgenic mice. We analysed somatic mutation of the transgene both in hybridomas in which the transgenic kappa chain contributes to the antigen combining site as well as in hybridomas in which the transgene is a passenger with the expressed antibody being composed of endogenously-encoded heavy and light chains. In both cases, nucleotide changes in the transgene are correctly targeted to the V region and are absent from the C region. They accumulate at a similar rate to that in the endogenous Ig genes within the same cell and we find that, irrespective of whether or not the transgene kappa is directly selected by antigen, somatic mutation occurs at a similar rate and involves only single base substitutions. Furthermore, the pattern of mutations in passenger transgenes gives information about the intrinsic sequence specificities of the somatic hypermutation mechanism.

Amino Acid Sequence↗

PubMed2004

Intronic polymorphism (1541-1542delGT) of the constitutive heat shock protein 70 gene has functional significance and shows evidence of association with lung cancer risk.

Somatic mutations of 11q23.3-linked constitutive heat shock protein 70 gene (HSPA8 alias HSC70) are detected by others in breast carcinomas. To examine whether intragenic, somatic mutations of HSPA8 occur in lung carcinomas, we sequenced its exons 2-8, with adjacent intronic sequences, in a series of DNA samples from non-small-cell lung cancers (NSCLC). Twenty-one polymorphisms were detected, but no somatic mutation. However, we observed an association between the HSC70 1541-1542delGT genotype and the immunohistochemical staining pattern of HSC70 protein. Tumors with weak (+) HSC70 protein staining were more frequent in the carriers of the polymorphic 1541-1542delGT allele than in the homozygotes of the major allele (20% vs. 6%, P=0.05 by Fisher's exact test). This statistically significant association prompted us to test the polymorphism functionally. The method we developed for the functional evaluation of intronic sequence alterations showed that the HSPA8 intron 2 with the deleted GT dinucleotide was associated with noticeable (approximately 20%) and statistically significant (P=0.005) reduction of the reporter gene activity. Our case-control analysis showed that the 1541-1542delGT heterozygous genotype was associated with significantly decreased risk for lung cancer (crude odds ratio (OR)=0.44; 95% confidence interval (CI): 0.23-0.84). To the best of our knowledge, this is the first report on the association between a polymorphism of a gene coding for the chaperone protein and lung cancer risk. Moreover, the simple method reported here, based on the dual-luciferase reporter assay system, can be useful for testing functional significance of polymorphisms located in introns of other genes.

Alleles↗

PubMed2001

Non-hyperfunctioning nodules from multinodular goiters: a minor role in pathogenesis for somatic activating mutations in the TSH-receptor and Gsalpha subunit genes.

Constitutive activation of the cAMP pathway stimulates thyrocyte proliferation. Gain-of-function mutations in Gsalpha protein have already been identified in thyroid nodules which have lost the ability to trap iodine. In contrast, most of the studies failed to detect somatic activating mutations in the thyrotropin receptor (TSH-R) in non-hyperfunctioning thyroid tumors. The aim of this study was to screen for mutations TSH-R exon 10, encoding the whole intracytoplasmic area involved in signal transduction, and Gsalpha exons 8 and 9, containing the two hot-spot codons 201 and 227, in a subset of non-hyperfunctioning nodules from multinodular goiter. Identified by matching ultrasonography and scintiscan, 22 eufunctioning (normal 99Tc uptake) and 15 nonfunctioning (decreased 99Tc uptake) nodules from 27 non-toxic multinodular goiters were isolated. After DNA extraction, TSH-R exon 10 was analyzed by direct sequencing of the PCR products and Gsalpha exons 8 and 9 by Denaturing Gradient Gel Electrophoresis. No mutation of TSH-R or Gsalpha was detected in the 37 nodules analyzed. This absence of mutation, despite the use of two sensitive screening methods associated with the analysis of the TSH-R whole intracytoplasmic area and Gsalpha two hot-spot codons, suggests that TSH-R and Gsalpha play a minor role in the pathogenesis of non-toxic nodules from multinodular goiters.

Codon↗

PubMed2005

Comparative genomic hybridization and mutation analyses of sporadic schwannomas.

Schwannomas of the vestibular nerve are the striking characteristics of neurofibromatosis type 2 (NF2), an autosomal dominant hereditary disease. The NF2 gene on 22q12 has been isolated as the gene responsible for NF2. Previous studies have reported that 60% of sporadic schwannomas showed inactivation of the NF2 gene, but genetic alterations of remaining 40% tumors remain elusive. Moreover, detailed genetic alterations of this tumor remain an open question. In this study, we analyzed genomic alterations in 17 sporadic schwannomas using comparative genomic hybridization (CGH). Loss of chromosome 22q, including the NF2 locus, was the only notable abnormality (5/17, 29%). Further, we performed fluorescence in situ hybridization analysis with a genomic BAC clone harboring the NF2 gene and found that the 5 tumors with loss detected by CGH as well as three cases without such a detectable loss by CGH, or a total, 8/17 (47%), showed loss of the NF2 locus. Mutation search by PCR-SSCP followed by direct sequencing revealed that 71% (12/17) of the tumors had one or two mutations in the NF2 gene. Our analyses disclosed that 14 (82%) of 17 tumors had structural alteration of NF2; among these 14 cases, 9 (64%) had two inactivating mutations in the NF2 gene, either a somatic mutation in one allele coupled with loss of the other allele or two independent somatic mutations. Our present results suggested that (i) most of the sporadic schwannomas have two-hit mutations in the NF2 gene, and (ii) NF2 is the only major causative gene in the genesis of schwannomas that is activated or inactivated by copy number alterations.

Adult↗

PubMed1988

Genetics of the phosphocholine-specific antibody response to Streptococcus pneumoniae. Germ-line but not mutated T15 antibodies are dominantly selected.

The role that somatic mutations play in the phosphocholine-specific, antibody response to Streptococcus pneumoniae was examined by studying sets of hybridomas from different individual mice. As expected most of the cell lines were from the T15 anti-phosphocholine family and were not encoded by the v1 gene of the T15 VH family and V kappa 22. A minority of antibodies were from the M603 (v1/V kappa 8) and M511 (v1/V kappa 24) families. Three additional antibodies were encoded by the v11 gene of the T15 family; two were paired with a V lambda and the other with a V kappa 1 gene. In vitro binding studies showed that T15- and M603-like antibodies had the highest affinity for S. pneumoniae. Complete sequencing of the VH and VL mRNA from 25 of the hybridomas revealed somatic mutations in 11 of the antibodies. A total of 17 independently derived T15 positive cell lines were studied in detail, six of these were mutated. These mutations were scattered throughout the V regions and the replacement to silent ratio was typical of that for framework regions. Statistical evaluation of the placement of mutations showed that there was a slight but significantly decreased frequency of mutations in complementarity determining regions. Comparisons of mutated and unmutated T15-related antibodies showed that mutations caused a decrease in binding to S. pneumoniae in every case. These results argue that the optimal specificity for this molecular form of phosphocholine is encoded in the germline and that Ag-driven events favor selection of B cells expressing these germ-line encoded antibodies.

Amino Acid Sequence↗

PubMed2001

Mutation analysis of C-KIT in patients with myelodysplastic syndromes without mastocytosis and cases of systemic mastocytosis.

The proto-oncogene C-KIT encodes a tyrosine kinase receptor that is expressed on mast cells and haematopoietic stem cells and can show somatic mutations in patients with mastocytosis. Only scattered information is available about mutations in C-KIT in patients with other myeloid neoplasms. Moreover, the prevalence of mutations in C-KIT in bone marrow specimens of individuals with systemic mastocytosis is largely unknown. Using sequence analysis, we have screened cDNAs of the C-KIT domain encompassing codon 510-626 and codon 763-858 in bone marrow (BM) mononuclear cells (MNCs) of patients with myelodysplastic syndromes (n = 28) and patients with systemic mastocytosis (n = 12) for the presence of mutations. Furthermore, restriction fragment length polymorphism analysis was applied for identification of the C-KIT 2468A-->T and the C-KIT 1700T-->G mutation, as well as the C-KIT 1642A-->C polymorphism. All 11 patients with systemic indolent mastocytosis tested positive for C-KIT 2468A-->T. In contrast, no mutation was identified in the case of aggressive mastocytosis. Among patients with myelodysplastic syndromes, no patient showed a somatic mutation in C-KIT. The allele frequency for C-KIT 1642A-->C among the entire patient population was 0.038 and was 0.125 among age- and sex-matched healthy controls. Our data demonstrate that myelodysplastic syndromes without histological or cytological evidence of mastocytosis do not exhibit somatic mutations in exons 10, 11, 12, 16, 17 and 18 of C-KIT. In contrast, BM MNCs of patients with systemic indolent mastocytosis were all positive for C-KIT 2468A-->T and negative for additional mutations in these exons. The C-KIT 1642A-->C polymorphism is not associated with myelodysplastic syndrome or systemic mastocytosis.

Adult↗

PubMed1995

[Mutation of G proteins].

Guanine nucleotide-binding proteins (G proteins) function as transducers of information across the cell membrane by coupling receptors to effectors. A large number of G protein-linked receptors funnel extracellular signals as diverse as hormones, growth factors, neurotransmitters, and primary sensory stimuli through a set of G proteins to a small number of second-messenger systems. The G proteins act as molecular switches with an "on" and "off" state governed by a GTPase cycle. By virtue of its high affinity and specificity for guanine nucleotide binding and its intrinsic GTPase activity, the alpha-subunit of the G protein (G alpha) plays the critical role in regulation of the effectors by their corresponding G protein. Mutations of G alpha may result in either constitutive activation or loss of expression mutations. Given the variety of functions subserved by G protein-coupled signal transduction, it is not surprising that abnormalities in G protein-coupled pathways can lead to diseases with manifestations as dissimilar as blindness, hormone resistance, precocious puberty and neoplasia. For a given defect in a G protein-coupled pathway, the extent of the manifestations will also be determined by the cellular distribution of the affected component. Defects in components expressed exclusively in a single cell type will cause more a focal disorder than defects in a widely expressed component, particularly in germline mutations (e.g., Albright's hereditary osteodystrophy), whereas somatic mutations of genes encoding even an ubiquitously expressed component can cause focal disease when the somatic mutation itself is focal (e.g., McCune-Albright syndrome).

Child↗

PubMed2000

Crypt-restricted metallothionein immunopositivity in murine colon: validation of a model for studies of somatic stem cell mutation.

The ability to visualize the cellular effects of a somatic mutation is relevant to studies of cell kinetics and carcinogenesis. In the colon, mutagen administration leads to scattered crypt-restricted loss of activity of the X-linked enzyme glucose-6-phosphate dehydrogenase (G6PD); it has been shown that this is due to somatic mutation in the G6PD gene. Mutagen-induced crypt-restricted immunopositivity for metallothionein (MT) has been reported in one study in the mouse colon; if this is also due to somatic mutation, it provides a simple method for studying the phenomenon which could be carried out on paraffin sections. This study shows that, as in the G6PD model, the frequency of crypt-restricted immunopositivity for MT is very low in untreated animals, but increases proportionately with the dose of mutagen administered. There is a good overall correlation of a range of MT-positive crypt frequencies with those derived from studies using G6PD. As with the G6PD model, the MT-positive crypt phenotype evolves over time after mutagen administration; initially individual crypts include both positive and negative phenotype cells, but later almost all involved crypts are composed entirely of MT-positive cells. The frequency of MT-positive crypts stabilizes after a few weeks and remains at the same level 6 months later. All these observations are qualitatively identical to those found using the G6PD model and provide strong evidence that stable, crypt-restricted immunopositivity for MT results from a mutation affecting expression of the metallothionein gene in a colonic stem cell. This model will provide a useful tool to study factors influencing stem cell mutation frequency and cell kinetics in the colon.

Animals↗

PubMed1981

Somatic mutation/neodifferentiation/selection and the origins of human cancers.

For some time, there has been a confusing and often frustrating difference of opinion amongst molecular pathologists and biologists regarding the relative involvement of somatic mutation vs. altered differentiation (neodifferentiation) in human carcinogenesis. This distinction, however, has led to opposing biological viewpoints which have a found alignment with opposing political viewpoints. While this distinction may have historical rationale, it has little biological basis, and it is possible to construct an integrative viewpoint which reconciles the "very different points of view and styles of argument" resulting from its use. The general evidence available suggests that most human epithelial cancers are caused by chemicals and radiations capable of inducing local mutations in regulatory sequences of genomic DNA, leading, perhaps through genetic transposition, to a mis-programming of natural genomic information expression. In this viewpoint, somatic mutation and altered differentiation are not mutually exclusive mechanisms as often implied, but, in all likelihood, are temporally related mechanisms; and human cancer thus becomes fundamentally a disease of cellular differentiation caused by somatic mutations.

Cell Differentiation↗

PubMed2006

PIK3CA mutations in head and neck squamous cell carcinoma.

PURPOSE: Recent studies have reported high frequencies of somatic mutations in the phosphoinositide-3-kinase catalytic alpha (PIK3CA) gene in several human solid tumors. Although gene amplifications of PIK3CA have been reported in head and neck squamous cell carcinoma (HNSCC), small mutation of the gene has not been evaluated in HNSCC previously. In this study, we examined the mutation frequency of PIK3CA in HNSCC. EXPERIMENTAL DESIGN: More than 75% of the somatic mutations of PIK3CA are clustered in the helical (exon 9) and kinase domains (exon 20). To investigate the possible role of PIK3CA in HNSCC tumorigenesis, exons 1, 4, 5, 6, 7, 9, and 20 of the gene were analyzed by direct genomic DNA sequencing in 38 HNSCC specimens. RESULTS: We identified four missense mutations in the seven exons of PIK3CA from 38 HNSCC specimens (11%). Three of the four mutations (i.e., H1047R, E542K, and E545K) have been previously reported as hotspot mutations. The remaining novel mutation, Y343C, is identified at exon 4 nucleotide 1028 A --> G. Three of the four mutations were shown to be somatic, whereas the fourth mutation (H1047R) was identified in a cell line. Interestingly, three of the four mutations identified were in pharyngeal cancer samples. CONCLUSIONS: These data provide evidence that oncogenic properties of PIK3CA contribute to the carcinogenesis of human head and neck cancers, especially in pharyngeal cancer. A specific kinase inhibitor to PIK3CA may potentially be an effective therapeutic reagent against HNSCC or pharyngeal cancer in particular.

Adult↗

PubMed2002

Duodenal cancer in a patient with Peutz-Jeghers syndrome: molecular analysis.

We experienced an unusual case of duodenal adenocarcinoma associated with Peutz-Jeghers syndrome (PJS). A 34-year-old woman was admitted to our hospital with abdominal pain. She had been diagnosed as having PJS at 21 years of age, based on the presence of mucocutaneous pigmentation of the lip and fingertips, and colonic hamartomatous polyps. Abdominal computed tomography revealed a tumor in the third portion of the duodenum extending into the pancreas head. As the tumor was pathologically determined to be adenocarcinoma at the time of surgery, pylorus-preserving pancreaticoduodenectomy was performed. We carried out molecular analyses of this patient to examine the pathway of carcinogenesis in PJS. The tumor did not show somatic mutation of the APC and K-ras genes, which is a critical step for the adenoma-carcinoma sequence in colon cancer. Importantly, a germline mutation of the STK11 gene was detected at codon 281 delC in exon 6. Moreover, the tumor showed loss of heterozygosity of the 19p marker near STK11 and somatic mutation of the p53 gene. These findings suggest that STK11 is a tumor suppressor gene regulating the development of hamartomas, and that somatic mutation of p53 subsequently promotes gastrointestinal cancer at a later stage in PJS.

AMP-Activated Protein Kinase Kinases↗