Somatic deletion mapping on chromosome 10 and sequence analysis of PTEN/MMAC1 point to the 10q25-26 region as the primary target in low-grade and high-grade gliomas

The 10q25-26 region between the dinucleotide markers D10S587 and D10S216 is deleted in glioblastomas and, as we have recently shown, in low-grade oligodendrogliomas. We further refined somatic mapping on 10q23-tel and simultaneously assessed the role of the candidate tumor suppressor gene PTEN/MMAC1 in glial neoplasms by sequence analysis of eight low-grade and 24 high-grade gliomas. These tumors were selected for partial or complete loss of chromosome 10 based on deletion mapping with increased microsatellite marker density at 10q23-tel. Three out of eight (38%) low-grade and 3/24 (13%) high-grade gliomas exclusively target 10q25-26. We did not find a tumor only targeting 10q23.3, and most tumors (23/32, 72%) showed large deletions on 10q including both regions. The sequence analysis of PTEN/MMAC1 revealed nucleotide alterations in 1/8 (12.5%) low-grade gliomas in a tumor with LOH at l0q21-qtel and in 5/21 (24%) high-grade gliomas displaying LOH that always included 10q23-26. Our refined mapping data point to the 10q25-26 region as the primary target on 10q, an area that also harbors the DMBT1 candidate tumor suppressor gene. The fact that we find hemizygous deletions at 10q25-qtel in low-grade astrocytomas and oligodendrogliomas - two histologically distinct entities of gliomas - suggests the existence of a putative suppressor gene involved early in glial tumorigenesis.     

Spontaneous expression of the chromosome fragile site at 10q23 in leiomyoma

A case is reported of a patient who had a respiratory arrest on a high dependency ward in a High Security Hospital with an unusual presentation. The patient had head and upper abdominal petechial haemorrhages with extensive conjunctival haemorrhaging. A considered antecedent for this potentially life-threatening presentation was strangulation. Analysis of all the available clinical information supports the hypothesis that he had a single tonic-clonic seizure with a focal-motor onset. This constitutes an unusual consequence of a partial seizure with secondary generalization.     

Basal cell carcinomas of the auricular region: a study of 23 cases

Basal cell carcinomas (BCCs) of the auricular region are not frequently reported, especially in the Japanese literature. Predisposing conditions such as sun exposure or frostbite are possibly involved in their development. In this study, we report our cases of auricular BCCs, discussing the obtained results, the possible significance of predisposing conditions, and the correlation with the histologic subtypes involved. Among 1094 patients with BCCs, auricular tumors were observed in 23 patients (2.1%), 4 women and 19 men. All of them were present on the external sun-exposed auricular side. Histologic patterns were nodular and micronodular (13 cases) and infiltrative (10 cases). No differences were observed between sexes. The relative degree of elastosis was higher in men than in women. Frostbite was recorded in 4 cases. The ear is an anatomical region that is heavily exposed to sun-light and equally prone to frostbite. Our data showed that all the lesions were located on the auricular region more or less exposed to sunlight. There was a recorded previous history of predisposing factors in most cases, and the high degree of elastosis suggests the involvement of these predisposing factors. Moreover, the high prevalence of infiltrative subtypes observed in our survey suggests a possible correlation between some histologic subtypes, sun-exposure, and frostbite. The differences between the relatively high number of auricular BCCs reported in the literature in contrast with the Japanese observations suggest the involvement of social or local conditions.     

Mapping of primary congenital lymphedema to the 5q35.3 region

Primary lymphedema is a chronic tissue swelling, most frequently of the lower limbs, resulting from deficient lymphatic drainage. The variability of the affected phenotype, incomplete penetrance, lack of large families, and possible genetic heterogeneity have hampered the identification of causative genes until now. We carried out a genomewide search, using a four-generation North American family with dominantly inherited primary congenital lymphedema (PCL), otherwise known as "Milroy disease," or "hereditary lymphedema type I" (MIM 153100). Linkage to markers from the 5q35.3 region in this and four additional, British families was established. A minimum of 79 directly scorable haplotypes (37 affected) in five families conspicuously segregated with the most telomeric region of 5q35.3, thus suggesting a major locus for PCL in this vicinity. No recombination was observed with D5S408 (Z = 10.03) and D5S2006 (Z = 8.46) with a combined multipoint score of 16.55. While D5S2073 and WIAF-2213 defined the upper centromeric boundary, no recombinants were obtained for the last telomeric marker of D5S2006. Four unaffected subjects were identified as gene carriers and provided an estimated penetrance ratio of.84 for this condition. A few of the positionally mapped genes in the 5q35 region that may potentially be involved in the etiology of this condition are CANX, FGFR4, HK3, and hnRPH1.     

Allelic imbalance study of 16q in human primary breast carcinomas using microsatellite markers

The high incidence of allelic imbalance on the long arm of chromosome 16 in breast cancer suggests its involvement in the development and progression of the tumor. Several loss of heterozygosity (LOH) studies have led to the assignment of commonly deleted regions on 16q where tumor suppressor genes may be located. The most recurrent LOH regions have been 16q22.1 and 16q22.4-qter. The aim of this study was to gain further insight into the occurrence of one or multiple "smallest regions of overlap" on 16q in a new series of breast carcinomas. Hence, a detailed allelic imbalance map was constructed for 46 sporadic breast carcinomas, using 11 polymorphic microsatellite markers located on chromosome 16. Allelic imbalance of one or more markers on 16q was shown by 30 of the 46 tumors (65%). Among these 30 carcinomas, LOH on the long arm of chromosome 16 was detected at all informative loci in 19 (41%); 13 of them showed allelic imbalance on the long but not on the short arm, with the occurrence of variable "breakpoints" in the pericentromeric region. The partial allelic imbalance in 11 tumors involved either the 16q22.1-qter LOH region or interstitial LOH regions. A commonly deleted region was found between D16S421 and D16S289 on 16q22.1 in 29 of the 30 tumors. The present data argue in favor of an important involvement of a tumor suppressor gene mapping to 16q22.1 in the genesis or progression of breast cancer.     

Undiagnosed microinvasive carcinomas of the prostate

Quality assurance is becoming increasingly important in all aspects of health care, but a growing workload in recent years may delay the introduction of new quality assurance procedures. In 1994-95, in order to evaluate the standard of quality in executing routine histopathological procedures, a total of 1,135 prostatic specimens representing all surgical material taken from the prostate during 1974-75 were reviewed. The patients were followed up for to 20 years by comparing with the files of The Norwegian Cancer Registry. Only a few registration errors were found. Microscopic examination in 1994-95 revealed 311 carcinomas, 83 of which were not recorded in 1974-75. 73 of the patients had not received treatment. The histology reports revealed suspected malignancy, with irregular or atypical epithelium, or both, in 42% of the 83 carcinomas not reported in 1994-95, whereas for 45 carcinomas the histology reports did not describe changes suggestive of malignancy. Only 3% of the patients not treated died of prostate cancer during the follow-up time, compared with 78 (54%) cancer deaths in the group that had received treatment. Most undiagnosed cancers were well differentiated and in the pT1a category. It is important that the clinician is aware of the fairly benign outcome of these borderline tumors in order to avoid overtreatment.     

P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase

Protein tyrosine phosphatases (PTPs) have long been thought to play a role in tumor suppression due to their ability to antagonize the growth promoting protein tyrosine kinases. Recently, a candidate tumor suppressor from 10q23, termed P-TEN, was isolated, and sequence homology was demonstrated with members of the PTP family, as well as the cytoskeletal protein tensin. Here we show that recombinant P-TEN dephosphorylated protein and peptide substrates phosphorylated on serine, threonine, and tyrosine residues, indicating that P-TEN is a dual-specificity phosphatase. In addition, P-TEN exhibited a high degree of substrate specificity, showing selectivity for extremely acidic substrates in vitro. Furthermore, we demonstrate that mutations in P-TEN, identified from primary tumors, tumor cells lines, and a patient with Bannayan-Zonana syndrome, resulted in the ablation of phosphatase activity, demonstrating that enzymatic activity of P-TEN is necessary for its ability to function as a tumor suppressor.     

Numerical chromosomal aberrations in transition-zone carcinomas of the prostate

PURPOSE: Prostatic carcinomas arising in the transition zone (TZ) are thought to differ from the more frequent cancers of the peripheral zone (PZ) with regard to morphology and biologic behavior. It is unclear, however, whether the differences are reflected in genetic alterations. MATERIALS AND METHODS: We assessed numerical aberrations of chromosomes 7, 8, 10, 17, and X with interphase cytogenetics in 10 radical-prostatectomy specimens containing exclusively TZ cancers larger than 0.5 cm.3 and in 10 additional specimens containing both TZ and PZ cancers larger than 0.5 cm.3 each. RESULTS: Of the 20 TZ carcinomas, 9 were completely disomic, 5 were at least focally tetrasomic but not aneusomic, and 6 were focally aneusomic. Ploidy correlated well with tumor volume (p = 0.0083), grade (p = 0.0064) and surgical margins (p = 0.0141) but not with preoperative prostate-specific antigen. A strong correlation was observed between the presence of low grade tumor (Gleason grade 4 or 5) and a nondiploid chromosomal status (p = 0.0001). In 10 cases there were also foci of PZ cancer larger than 0.5 cm.3, of which 4 were disomic, 3 were tetrasomic at the most, and 3 were aneusomic. The mean tumor volumes of disomic and aneusomic cancers differed significantly between TZ and PZ carcinomas (p = 0.0336 and 0.0476, respectively). CONCLUSIONS: Numerical chromosomal instability parallels tumor progression in TZ carcinomas of the prostate. However, our results indicate that PZ and TZ cancers differ in that the latter can reach larger volumes before histological dedifferentiation and aneusomy occur.     

Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN

The chromosomal region 10q23-24 is frequently deleted in a number of tumour types, including prostate adenocarcinoma and glioma. A candidate tumour-suppressor gene at 10q23.3, designated PTENor MMAC1, with putative actin-binding and tyrosine phosphatase domains has recently been described. Mutations in PTEN have been identified in cell lines derived from gliomas, melanomas and prostate tumours and from a number of tumour specimens derived from glial, breast, endometrial and kidney tissue. Germline mutations in PTEN appear to be responsible for Cowden disease. We identified five PTEN mutations in 37 primary prostatic tumours analysed and found that 70% of tumours showed loss or alteration of at least one PTEN allele, supporting the evidence for PTEN involvement in prostate tumour progression. We raised antisera to a peptide from PTEN and showed that reactivity occurs in numerous small cytoplasmic organelles and that the protein is commonly expressed in a variety of cell types. Northern blot analysis revealed multiple RNA species; some arise as a result of alternative polyadenylation sites, but others may be due to alternative splicing.     

Recommendations for the reporting of resected prostate carcinomas

The Association of Directors of Anatomic and Surgical Pathology has developed recommendations for the surgical pathology reporting of common malignant tumors. The recommendations for resected prostate carcinomas are reported herein.     

Frequent inactivation of PTEN in prostate cancer cell lines and xenografts

Loss of chromosome 10q is a frequently observed genetic defect in prostate cancer. Recently, the PTEN/MMAC1 tumor suppressor gene was identified and mapped to chromosome 10q23.3. We studied PTEN structure and expression in 4 in vitro cell lines and 11 in vivo xenografts derived from six primary and nine metastatic human prostate cancers. DNA samples were allelotyped for eight polymorphic markers within and surrounding the PTEN gene. Additionally, the nine PTEN exons were tested for deletions. In five samples (PC3, PC133, PCEW, PC295, and PC324), homozygous deletions of the PTEN gene or parts of the gene were detected. PC295 contained a small homozygous deletion encompassing PTEN exon 5. In two DNAs (PC82 and PC346), nonsense mutations were found, and in two (LNCaP and PC374), frame-shift mutations were found. Missense mutations were not detected. PTEN mRNA expression was clearly observed in all cell lines and xenografts without large homozygous deletions, showing that PTEN down-regulation is not an important mechanism of PTEN inactivation. The high frequency (60%) of PTEN mutations and deletions indicates a significant role of this tumor suppressor gene in the pathogenesis of prostate cancer.     

The t(10;11)(p12;q23) translocation in acute leukaemia: a cytogenetic and clinical study of 20 patients. European 11q23 Workshop participants

The clinical, haematological and cytogenetic data for 20 patients with an acquired abnormality of 11q23 and 10p have been reviewed at this workshop. Patients predominantly presented with de novo AML M5a and the most common cytogenetic finding was an inversion of part of the long arm of chromosome 11 followed by a translocation between 11q and 10p. Band p12 represented the most common breakpoint on chromosome 10. The t(10;11) subgroup defined a subset of younger 11q23 patients, the majority of whom achieve a first complete remission despite the differing treatment regimens.     

Analysis of the t(2;5) (p23;q35) translocation in CD30+ primary cutaneous lymphoproliferative disorders and Hodgkin''s disease

To observe the expression of p16, pRb, cdk4 and cyclinD1 in non-small cell lung cancers, 104 cases of resected lung cancers were collected, which included squamous cell carcinomas, adenocarcinomas and large cell carcinomas. Immunohistochemistry assay was carried out. The results showed that 67% of squamous cell carcinomas and 46% of adenocarcinomas expressed p16, 64% of squamous cell carcinomas and 85% of adenocarcinomas expressed pRb and 66% of cancers expressed p16 or pRb. About 70% of the tumors expressed cyclinD1. More than 90% of the tumors expressed cdk4 and there was an increased trend with decreasing differentiation of both squamous cell carcinomas and adenocarcinomas. Sixty-seven percent of the highly differentiated and 100% of the poorly differentiated squamous cell carcinomas expressed cdk4. The aberrant p16 and pRb gene product expression played a significant role in the development and histological subtype of lung cancers by conditioning the biological behavior of NSCLC. cdk4 was an important factor in histological differentiation.     

Hematological malignancies with a deletion of 11q23: cytogenetic and clinical aspects. European 11q23 Workshop participants

OBJECTIVE: Using receiver-operating characteristic (ROC) curves, we tried to determine the diagnostic threshold of amniotic fluid index (AFI) that will identify abnormal fetal size (birth weights under 2500 g or at least 4000 g) at 37 weeks or beyond. METHODS: We analyzed prospectively over 2 years all parturients with intact membranes and known AFI in early labor. Patients with the following conditions were excluded: pregestational or gestational diabetes, known anomalies, and preterm labor. Two ROC curves were constructed, and the areas (+/- standard error of the mean [SE]) under the curves were calculated. P < .05 was considered significant. RESULTS: Of the 1038 subjects meeting study criteria, 3.6% and 11.5% gave birth to infants who were small for gestational age (SGA) or macrosomic, respectively. Overall, 28.7% had oligohydramnios (AFI at most 5.0 cm) and 3.6% had hydramnios (AFI at least 24.0 cm). Small for gestational age was more common in patients with AFI at most 5.0 cm (6.4%) than in those with adequate fluid (AFI 5.1-23.9; 2.5%), or hydramnios (2.7%; P = .012). Macrosomic newborns were less likely to be born to women with oligohydramnios (7.7%) than to those with adequate amniotic fluid (13.1%) or hydramnios (13.5%). Areas under ROC curves are not significantly different from the area under the nondiagnostic line, indicating that AFI (0-34 cm) cannot differentiate between newborns under 2500 g and at or over 2500 g or under 4000 and at or more 4000 g. CONCLUSION: Intraparterium AFI appears to be a poor screening test to identify risk for delivery of SGA or macrosomic fetus.     

M-plasty in the treatment of carcinomas located on the interglabellar region

One of the main tasks of current cutaneous surgery is to completely eliminate the tumor while avoiding unnecessary normal tissue extirpation. This is especially important when removing facial tumors close to the external canthus, mouth angles and perialar regions. In all these areas we advise fusiform excision but with distal M-plasty in the nearest angle so as to avoid angle retraction. The same is true for mediofrontal tumors, as this often causes a drawing together of the eyebrows. We have reviewed all mediofrontal excisions carried out during the last six years. M-plasty following fusiform excision was always performed in the interglabellar area. The good results achieved allow us to recommend this technique in this location.     

Involvement of 10q22 in leiomyoma

Growth during infancy was analyzed using data from a study in which groups of infants were fed breast-milk or one of three formulas: Good Start, Isomil, or Similac. After adjustments for size at birth and parental stature, growth was within the normal range for all feeding groups and there were few significant differences in growth between those fed different formulas. There was, however, some evidence that Similac was associated with larger gains in weight and that those fed breast-milk or Isomil had lower weights at ages older than two months. Additionally, at six months, recumbent length tended to be smaller in the Isomil group of boys and in both the Isomil and Similac groups of girls and larger in the Good Start groups of boys and girls.