Biomedical subjects

Charis Eng

Publications and source records attributed to Charis Eng.

99 records · Page 6Linked to original sources

PubMed2002

Protean PTEN: form and function.

Germline mutations distributed across the PTEN tumor-suppressor gene have been found to result in a wide spectrum of phenotypic features. Originally shown to be a major susceptibility gene for both Cowden syndrome (CS), which is characterized by multiple hamartomas and an increased risk of breast, thyroid, and endometrial cancers, and Bannayan-Riley-Ruvalcaba syndrome, which is characterized by lipomatosis, macrocephaly, and speckled penis, the PTEN hamartoma tumor syndrome spectrum has broadened to include Proteus syndrome and Proteus-like syndromes. Exon 5, which encodes the core motif, is a hotspot for mutations likely due to the biology of the protein. PTEN is a major lipid 3-phosphatase, which signals down the PI3 kinase/AKT pro-apoptotic pathway. Furthermore, PTEN is a protein phosphatase, with the ability to dephosphorylate both serine and threonine residues. The protein-phosphatase activity has also been shown to regulate various cell-survival pathways, such as the mitogen-activated kinase (MAPK) pathway. Although it is well established that PTEN's lipid-phosphatase activity, via the PI3K/AKT pathway, mediates growth suppression, there is accumulating evidence that the protein-phosphatase/MAPK pathway is equally important in the mediation of growth arrest and other crucial cellular functions.

Animals↗

PubMed2002

Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic microsatellite unstable tumors.

Germline PTEN mutations cause Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR), two hamartoma-tumor syndromes with an increased risk of breast, thyroid and endometrial cancers. Somatic genetic and epigenetic inactivation of PTEN is involved in as high as 93% of sporadic endometrial carcinomas (EC), irrespective of microsatellite status, and can occur in the earliest precancers. EC is the most frequent extra-colonic cancer in patients with hereditary non-polyposis colon cancer syndrome (HNPCC), characterized by germline mutations in the mismatch repair (MMR) genes and by microsatellite instability (MSI) in component tumors. To determine whether PTEN is involved in the pathogenesis of EC arising in HNPCC cases, and whether PTEN inactivation precedes MMR deficiency, we obtained 41 ECs from 29 MLH1 or MSH2 mutation positive HNPCC families and subjected them to PTEN expression and mutation analysis. Immunohistochemical analysis revealed 68% (28/41) of the HNPCC-related ECs with absent or weak PTEN expression. The remaining 27% (11/41) of tumors had normal expression and 5% (2/41) with mixed populations showing weak/absent as well as normal expression. Mutation analysis of 20 aberrant PTEN-expressing tumors revealed that 17 (85%) harbored 18 somatic PTEN mutations. All mutations were frameshift, 10 (56%) of which involved the 6(A) tracts in exon 7 or 8. These results suggest that PTEN plays a significant pathogenic role in both HNPCC and sporadic endometrial carcinogenesis, unlike the scenarios for colorectal cancer. Furthermore, we have shown that somatic PTEN mutation, especially frameshift, is a consequence of profound MMR deficiency in HNPCC-related ECs. In contrast, among 60 previously reported MSI+ sporadic ECs with 70 somatic mutations in PTEN, 39 (56%) were frameshift, of which only eight (21%) were affecting the 6(A) tracts in exon 7 or 8 (P = 0.01), suggesting that PTEN mutations may precede MMR deficiency.

Carcinoma↗

PubMed2002

Silencing of the PTEN tumor-suppressor gene in anaplastic thyroid cancer.

Germline mutations in the tumor-suppressor gene PTEN (MMAC1, TEP1) are found in Cowden syndrome, which predisposes to hamartomas, breast cancer, trichilemmomas, and thyroid tumors of follicular epithelium. PTEN has also been found to be somatically deleted, mutated, and/or silenced in various sporadically occurring cancers such as glioblastoma, breast cancer, kidney cancer, malignant melanoma, and endometrial cancer. Loss or reduction of PTEN protein expression as well as inappropriate subcellular compartmentalization is seen in non-medullary thyroid cancers. However, although allelic loss of the PTEN locus in 10q23.3 is frequently seen, this is not coupled with mutations in the PTEN gene. To approach further the frequency and mechanism behind PTEN silencing, we screened a panel of 87 sporadic thyroid tumors for PTEN mRNA expression, including 14 anaplastic carcinomas, 37 follicular carcinomas, 21 atypical adenomas, and 15 ordinary adenomas. Complete loss of PTEN mRNA expression was evident in six of the tumors, including four anaplastic carcinomas, one widely invasive carcinoma, and one ordinary adenoma. The transcriptional silencing of PTEN was significantly associated with the anaplastic subtype, suggesting that PTEN is involved in the carcinogenesis of highly malignant or late-stage thyroid cancers, whereas this particular mechanism appears to be of minor importance in differentiated follicular thyroid tumors. No association was observed between the expression, loss of heterozygosity, and mutation status in the 33 cases in which these parameters were compared. This indicates that PTEN silencing is a result of a wide variety of epigenetic and/or structural silencing mechanisms rather than a consequence of structural biallelic inactivation of the classical type. Furthermore, the high rate of alterations in the 10q23 region might indicate the presence of an as-yet unknown tumor-suppressor gene with an important role in the development of thyroid tumors.

Adenoma↗

PubMed2002

Novel germline CDH1 mutations in hereditary diffuse gastric cancer families.

Hereditary diffuse gastric cancer (HDGC) is a recently defined cancer syndrome caused by inactivating, heterozygous germline mutations in the gene for the cell-to-cell adhesion protein E-cadherin (CDH1). Here, we describe the search for CDH1 mutations in 10 newly identified gastric cancer families. Seven of 10 families met the clinical criteria for HDGC. Germline mutations were identified in four of these seven families and one family that was borderline for the clinical criteria. Of the mutations identified in the five new families, four were previously unreported and consisted of two frameshift and two donor splice site mutations. One splice site mutation occurred at the 100% conserved +1 position. The second splice site mutation occurred at the +5 position and was shown to lead to abnormal splicing. Additional CDH1 variants detected include the heterozygous -160 C-->A promoter polymorphism, which has previously been reported to be associated with decreased CDH1 transcription. We, however, found this polymorphism to be common in a control population, suggesting that a major role for this polymorphism in gastric cancer susceptibility is unlikely.

Adult↗

PubMed2002

PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers.

PTEN on 10q23.3 encodes a dual-specificity phosphatase that negatively regulates the phosphoinositol-3-kinase/Akt pathway and mediates cell-cycle arrest and apoptosis. Germline PTEN mutations cause Cowden syndrome and a range of several different hamartoma-tumor syndromes. Hereditary nonpolyposis colon cancer (HNPCC) syndrome is characterized by germline mutations in the mismatch repair (MMR) genes and by microsatellite instability (MSI) in component tumors. Although both colorectal carcinoma and endometrial carcinoma are the most frequent component cancers in HNPCC, only endometrial cancer has been shown to be a minor component of Cowden syndrome. We have demonstrated that somatic inactivation of PTEN is involved in both sporadic endometrial cancers and HNPCC-related endometrial cancers but with different mutational spectra and different relationships to MSI. In the current study, we sought to determine the relationship of PTEN mutation, 10q23 loss of heterozygosity, PTEN expression, and MSI status in colorectal cancers (CRCs). Among 11 HNPCC CRCs, 32 MSI+ sporadic cancers, and 39 MSI- tumors, loss of heterozygosity at 10q23.3 was found in 0%, 8%, and 19%, respectively. Somatic mutations were found in 18% (2 of 11) of the HNPCC CRCs and 13% (4 of 32) of the MSI+ sporadic tumors, but not in MSI- cancers (P = 0.015). All somatic mutations occurred in the two 6(A) coding mononucleotide tracts in PTEN, suggestive of the etiological role of the deficient MMR. Immunohistochemical analysis revealed 31% (14 of 45) of the HNPCC CRCs and 41% (9 of 22) of the MSI+ sporadic tumors with absent or depressed PTEN expression. Approximately 17% (4 of 23) of the MSI- CRCs had decreased PTEN expression, and no MSI- tumor had complete loss of PTEN expression. Among the five HNPCC or MSI+ sporadic CRCs carrying frameshift somatic mutations with immunohistochemistry data, three had lost all PTEN expression, one showed weak PTEN expression levels, and one had mixed tumor cell populations with weak and moderate expression levels. These results suggest that PTEN frameshift mutations in HNPCC and sporadic MSI+ tumors are a consequence of mismatch repair deficiency. Further, hemizygous deletions in MSI- CRCs lead to loss or reduction of PTEN protein levels and contribute to tumor progression. Finally, our data also suggest that epigenetic inactivation of PTEN, including differential subcellular compartmentalization, occurs in CRCs.

Base Pair Mismatch↗

PubMed2002

A 39-bp deletion polymorphism in PTEN in African American individuals: implications for molecular diagnostic testing.

Germline mutations in the PTEN/MMAC1/TEP1 tumor suppressor gene cause Cowden syndrome (CS), a hereditary hamartoma-tumor syndrome with an increased risk of breast, thyroid, and endometrial cancers, and seemingly unrelated developmental disorders, such as Bannayan-Riley-Ruvalcaba (BRR) syndrome, Proteus, and Proteus-like syndromes. Data to date suggest that irrespective of the clinical presentation, the identification of a PTEN mutation should trigger medical management which includes cancer surveillance. Clinic-based molecular diagnostic testing for germline PTEN mutations has been available for at least 2 years. This study reports on the finding of a previously unobserved heterozygous alteration (IVS7-15-->53del39) found in an African American individual who had features of CS. Further investigation revealed that 12 of 42 (28.6%) African American controls, but not individuals of Caucasian or Japanese origin, also carried this heterozygous 39-bp deletion in PTEN. Due to its location immediately upstream of the splicing site of exon 8, this polymorphism could be mistaken for a deleterious mutation in the PTEN.

Base Sequence↗

PubMed2002

Evaluation of germline sequence variants of GFRA1, GFRA2, and GFRA3 genes in a cohort of Spanish patients with sporadic medullary thyroid cancer.

The etiology of sporadic medullary thyroid carcinoma (sMTC) remains elusive. While germline gain-of-function mutations in the RET proto-oncogene cause hereditary MTC, somatic RET mutations have been described in a variable number of sMTC. So far, S836S of RET, is the only variant whose association with sMTC has been found in several European cohorts. Because RET variants seem to be associated with MTC, it is plausible that variants in genes encoding for RET coreceptors may play a role in the pathogenesis of sMTC. Recently, we described two possible low penetrance susceptibility alleles in the gene encoding RET coreceptor GFRalpha1, -193C > G and 537T > C, in a German series of sMTC. In this study, we have genotyped nine polymorphisms within GFRA1-3 genes for 51 Spanish sMTC, and 100 normal controls. Our results show that no statistical signification was found when Spanish sMTC patients were compared to controls. Taken together with the observations in the German sMTC series, the present findings suggest that GFRA1-193C > G and 537T > C could be in linkage disequilibrium with other loci responsible for the disease with a founder effect in Germany. Alternatively, the combined observations might also suggest that, if indeed the polymorphisms are functional, the effect is small.

Base Sequence↗

PubMed2002

Role of PTEN, a lipid phosphatase upstream effector of protein kinase B, in epithelial thyroid carcinogenesis.

Both benign and malignant thyroid disease are well-established components of Cowden syndrome (CS), an autosomal dominant disorder characterized by multiple hamartomas and breast cancer that may be considered a phakomatosis. The susceptibility gene for CS is PTEN, a tumor suppressor gene on 10q23.3 that encodes a lipid phosphatase that lies upstream of protein kinase B (Akt). Interestingly, Carney complex is also a phakomatosis where multiple endocrine neoplasias are prominent and thyroid cancer might be a rare component. One of its susceptibility genes is the regulatory subunit of protein kinase A. Over the course of the last four years, investigators have found the increasing clinical spectrum of syndromes characterized by germline loss-of-function PTEN mutation. In addition to CS, subsets of such disparate syndromes as Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and possibly VATER with hydrocephalus and megencephaly with autistic features have been found to have germline PTEN mutations. Paradoxically, somatic intragenic PTEN mutations were rare in uncultured primary epithelial thyroid tumors, although hemizygous deletion occurred in 10-20% of thyroid adenomas and carcinomas. However, with subsequent study, it was discovered that epigenetic silencing of PTEN and perhaps inappropriate subcellular compartmentalization were two novel mechanisms of PTEN inactivation pertinent in thyroid carcinogenesis. Ectopic expression studies in vitro have borne out the importance of PTEN in the pathogenesis of epithelial thyroid neoplasias.

Apoptosis↗

PubMed2002

The expanding role of PTEN in neoplasia: a molecule for all seasons? Commentary re: M. A. Davies, et al., Adenoviral-mediated expression of MMAC/PTEN inhibits proliferation and metastasis of human prostate cancer cells. Clin. Cancer Res., 8: 1904-1914, 2002.

Not since the discovery of p53 has another molecule received as much attention as PTEN. In the 5 years since the discovery of PTEN, encoding a dual specificity phosphatase tumor suppressor on 10q23, it has been shown to be a susceptibility gene for an inherited cancer syndrome, Cowden syndrome, and for several developmental disorders; it has been shown to play a prominent role in normal murine and human development; and it has been shown to be instrumental in cell cycle arrest, apoptosis, and/or possibly cell migration and cytoskeletal affairs. Initial work on cancer cell lines had suggested that PTEN caused every type of cancer because it was reported that a relatively high frequency of a variety of cancer cell lines, whether derived from solid tumors or hematological malignancies, had homozygous or compound heterozygous genetic alterations involving PTEN. Such data, together with the germ-line human and murine model data, suggested that PTEN mutations occurred "early" in sporadic tumorigenesis. However, subsequent painstaking work in noncultured primary tumors and in careful in vitro overexpression studies over the last 4 years demonstrated that the mechanism of PTEN inactivation can be varied and might be cell type dependent. Furthermore, apart from sporadic endometrial carcinoma, PTEN alteration in noncultured sporadic neoplasias likely occurs "late," promoting progression and metastasis. The article by Davies et al. (Clin Cancer Res., 8: 1904-1914, 2002) sheds light on all of these issues when they report on data that derive from a "triple threat" strategy, i.e., in vitro, in vivo, and ex vivo, to demonstrate that adenoviral infection of PTEN into PTEN-null PC3 prostate cancer cell lines results in decreased metastatic potential without significantly altering tumor size via the predominant mechanism of G(1) cell cycle arrest but not apoptosis.

Animals↗