Neuropathology and Applied NeurobiologyVolume 34, Issue 5 p. 564-568 Choroid plexus carcinoma: a new case associated with a novel TP53 germ line mutation F. Becherini, F. Becherini Pathological Anatomy Section, Surgery Department,Search for more papers by this authorM. Castagna, M. Castagna Pathological Anatomy Section, Surgery Department,Search for more papers by this authorA. Iannelli, A. Iannelli Neuroscience Department,Search for more papers by this authorC. Favre, C. Favre Paediatric Haematogy and Oncology Department,Search for more papers by this authorA. Abbruzzese, A. Abbruzzese Neuroradiology Unit andSearch for more papers by this authorM. A. Caligo, M. A. Caligo Molecular Pathology Section, Division of Surgical, Molecular and Ultrastructural Pathology, Oncology Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, ItalySearch for more papers by this authorG. Bertacca, G. Bertacca Molecular Pathology Section, Division of Surgical, Molecular and Ultrastructural Pathology, Oncology Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, ItalySearch for more papers by this authorR. Pingitore, R. Pingitore Molecular Pathology Section, Division of Surgical, Molecular and Ultrastructural Pathology, Oncology Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, ItalySearch for more papers by this authorG. Bevilacqua, G. Bevilacqua Pathological Anatomy Section, Surgery Department,Search for more papers by this authorA. O. Cavazzana, A. O. Cavazzana Molecular Pathology Section, Division of Surgical, Molecular and Ultrastructural Pathology, Oncology Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, ItalySearch for more papers by this author F. Becherini, F. Becherini Pathological Anatomy Section, Surgery Department,Search for more papers by this authorM. Castagna, M. Castagna Pathological Anatomy Section, Surgery Department,Search for more papers by this authorA. Iannelli, A. Iannelli Neuroscience Department,Search for more papers by this authorC. Favre, C. Favre Paediatric Haematogy and Oncology Department,Search for more papers by this authorA. Abbruzzese, A. Abbruzzese Neuroradiology Unit andSearch for more papers by this authorM. A. Caligo, M. A. Caligo Molecular Pathology Section, Division of Surgical, Molecular and Ultrastructural Pathology, Oncology Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, ItalySearch for more papers by this authorG. Bertacca, G. Bertacca Molecular Pathology Section, Division of Surgical, Molecular and Ultrastructural Pathology, Oncology Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, ItalySearch for more papers by this authorR. Pingitore, R. Pingitore Molecular Pathology Section, Division of Surgical, Molecular and Ultrastructural Pathology, Oncology Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, ItalySearch for more papers by this authorG. Bevilacqua, G. Bevilacqua Pathological Anatomy Section, Surgery Department,Search for more papers by this authorA. O. Cavazzana, A. O. Cavazzana Molecular Pathology Section, Division of Surgical, Molecular and Ultrastructural Pathology, Oncology Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, ItalySearch for more papers by this author First published: 29 September 2008 https://doi.org/10.1111/j.1365-2990.2007.00934.xCitations: 5Read the full textAboutRelatedInformationPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessClose modalShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Citation StatementsbetaSmart citations by scite.ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by Wiley Online Library if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.SupportingSupporting0MentioningMentioning1ContrastingContrasting0Explore this article's citation statements on scite.aipowered by Volume34, Issue5October 2008Pages 564-568 Citation StatementsbetaSmart citations by scite.ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by Wiley Online Library if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.SupportingSupporting0MentioningMentioning1ContrastingContrasting0Explore this article's citation statements on scite.aipowered by RelatedInformation RecommendedAssociation of the highly prevalent TP53 R337H mutation with pediatric choroid plexus carcinoma and osteosarcoma in Southeast BrazilAna Luiza Seidinger BSc, Maria José Mastellaro MD, Fernanda Paschoal Fortes BSc, Juliana Godoy Assumpção PhD, Izilda Aparecida Cardinalli PhD, Mônica Aparecida Ganazza MSc, Raul Correa Ribeiro MD, Silvia Regina Brandalise PhD, Simone dos Santos Aguiar PhD, José Andrés Yunes PhD, CancerNovel SDHD germ-line mutations in pheochromocytoma patientsC. Neumayer, A. Moritz, R. Asari, A. Weinhäusel, T. Hölzenbein, G. Kretschmer, B. Niederle, O. A. Haas, European Journal of Clinical InvestigationA novel de novo germ-line V292M mutation in the extracellular region of RET in a patient with phaeochromocytoma and medullary thyroid carcinoma: functional characterizationMaria D. Castellone, Antonella Verrienti, Deva Magendra Rao, Marialuisa Sponziello, Dora Fabbro, Magesh Muthu, Cosimo Durante, Marianna Maranghi, Giuseppe Damante, Stefano Pizzolitto, Giuseppe Costante, Diego Russo, Massimo Santoro, Sebastiano Filetti, Clinical EndocrinologyA Novel Somatic Mutation in the RET Proto‐oncogene in Familial Medullary Thyroid Carcinoma with a Germline Codon 768 MutationAkira Miyauchi, Shin-ichi Egawa, Hitoyasu Futami, Kanji Kuma, Takao Obara, Ken Yamaguchi, Japanese Journal of Cancer ResearchChoroid Plexus Papilloma and CarcinomaDerek R. Johnson, Julie E. Hammack, Textbook of Uncommon Cancer, [1]

The aim of the present study was to test the polymerase chain reaction (PCR) as a tool to identify human papillomavirus (HPV) in routine cytological samples scraped from the uterine cervix. Moreover, attention has been focused on the correlation between HPV types and early intraepithelial lesions. The study involved 586 women who had undergone conventional Pap test. Analysis of HPV infection was performed by PCR and HPV typing by dot blot. In a group of 78 cases histologically diagnosed as high-grade squamous intraepithelial lesions (HSILs), the cytological diagnosis was correct in 92.3% and the HPV test was positive in 89.8% of cases; combined positivity at Pap and/or HPV tests raised this figure to 99.0%. In a group of 67 cases histologically diagnosed as low-grade squamous intraepithelial lesions (LSILs), the cytological diagnosis was correct in 73.1% and the PCR-based HPV test was positive in 64.2%; combined positivity at Pap and/or HPV tests raised this figure to 91.0%. This study confirms the limitations of screening programs based on Pap test only. Our results suggest, in fact, that adding the HPV test to primary screening could increase the yield of preinvasive cervical lesions.

Introduction: Pancreatic ductal carcinoma (PDC) is extremely rare before age 40 years. The aim of this study was to evaluate the clinical, pathological and molecular features of this tumor in patients aged < 40. Materials and Methods: Two hundred and ninety three pancreatic ductal carcinomas were collected from 1976 to 2004 at our Institution. Six specimens from patients (3 males and 3 females) with a mean age of 36 years (range: 32–39) were included in the study. Familial history of pancreatic cancer was excluded by the anamnestic analysis. The mutation analysis of BRCA2 gene on frozen samples from 2 patients is under way. The tumor grade and stage were assessed according to the WHO and pTNM classification. Molecular analysis included the study of K-ras and p53 mutations on laser microdissected tumor paraffined samples. The expression of p53, EGF-R, E-cadherin, beta-catenin, and microsatellite instability (MLH1, MSH2) was performed by immunohistochemistry. Results: Pathological status was similar to that occurring in elderly patients. No mutations of k-ras were found at codon 12 in 3/3 cases and at codon 61 in 5/5 cases. Some samples were not amplifiable due to degradation of nucleic acids. p53 mutations were detected in 3/6 patients (50%). p53 over-expression was evidenced in 4/6 cases (67%). EGF-R expression on the tumor cell membrane was present in 3/6 cases (50%). E-cadherin at cell membrane was found in 3/6 cases (50%). Abnormal accumulation in the cytoplasm and nucleus of beta-catenin, was observed in 5/6 cases (83%). All cases presented nuclear staining with both antibodies against MLH1 and MSH2. Conclusions: Sporadic pancreatic ductal carcinoma in young patients is extremely rare and shows similar pathological and biological aspects with respect to the olders. The frequent stabilization of beta-catenin in the cytoplasm and nucleus could suggest an high transactivation activity. Even if the detection of k-ras mutations is incomplete, these data seem to show a reduced rate of k-ras mutations in young patients.

The int-6 gene, originally identified as a common integration site for the mouse mammary tumor virus (MMTV) in mouse mammary tumors, encodes the p48 component of the eukaryotic translation initiation factor-3 (eIF3-p48). Int-6/eIF3-p48 is expressed in all adult tissues which have been tested and early in embryonic development. Int-6/eIF3-p48 has been highly conserved throughout evolution and the deduced amino acid sequence of the human gene product is identical to the mouse protein. Viral insertions at the Int-6/eIF3-p48 locus in mouse mammary tumors result in production of chimeric Int-6/eIF3-p48/MMTV products that may act as dominant negative oncoproteins. Int-6/eIF3-p48 has also been identified as a human protein that binds to the human T-cell leukemia virus type I Tax oncoprotein. The role of Int-6/eIF3-p48 in human carcinogenesis is unknown at the present time. In this study we have examined Int-6/eIF3-p48 gene status and expression in two of the most common forms of cancer in humans, breast and lung tumors. Sixty-two breast carcinomas and 78 non-small cell lung carcinomas (NSCLC) were investigated. LOH at the Int-6/eIF3-p48 locus was observed in 5 (21%) of 24 informative breast tumors and 10 (29%) of 34 informative lung tumors. A reduced expression of Int-6/eIF3-p48 was seen in 23 (37%) of breast cancer samples and 24 (31%) of NSCLC samples. An association between Int-6/eIF3-p48 expression and LOH at the Int-6/eIF3-p48 locus was observed. Int-6/eIF3-p48 expression was not related to commonly used pathological parameters in breast cancer patients, while in NSCLC patients int-6/eIF3-p48 expression was mainly seen in adenocarcinomas (P<0.0001). In conclusion, our data show for the first time a decreased expression of Int-6/eIF3-p48 in a consistent portion of human breast and lung carcinomas, frequently associated with LOH at the Int-6/eIF3-p48 locus. Additional studies on larger series of tumor specimens with long-term follow-up are needed to determine whether Int-6/eIF3-p48 expression may represent a new prognostic or predictive marker.

Histological detection of axillary lymph node metastases is still the most valuable prognostic parameter for breast cancer, but about 30% of node-negative patients relapse within five years, suggesting that current methods are inadequate for identifying metastatic disease. More sensitive, PCR-based methods for the detection of metastatic cells are now available, enabling the amplification of cancer cell-specific mRNA messages by the RT-PCR assay. An ideal tumour marker, consistently expressed in tumour samples and not at all in normal lymph nodes, remains to be identified. The present study first investigated the expression of seven mRNA markers, CEA, CK19, c-Met, mammaglobin, MUC-1, beta1-->GalNAc-T and p97, selected on the basis of their previously reported specificity for breast cancer cells. Eighteen lymph nodes were examined from patients without tumours. Only mammaglobin mRNA and CEA mRNA were not expressed in normal nodes. All of the other markers showed a band of expression in 17%-55% of cases, indicating that they are not breast cancer-specific. CEA mRNA and mammaglobin mRNA expression could be detected in 15/20 (75%) and 19/20 (95%) primary breast carcinomas, respectively. The expression of mammaglobin mRNA and CEA mRNA was then compared in axillary lymph nodes from 248 consecutive breast cancer patients, 89 with histologically documented lymph node metastasis and 159 without histological evidence of metastatic disease. Ninety-seven per cent of the patients with histologically involved nodes showed expression of mammaglobin mRNA, whereas CEA mRNA was expressed in 79% of these cases. In the group of patients with histologically negative lymph nodes, 46 (29%) and 32 (20%) were found to be positive for mammaglobin and CEA expression, respectively, indicating the presence of metastases not detected by routine histological examination of one lymph node section. These results show that both mammaglobin RT-PCR and CEA RT-PCR are useful tools for the detection of breast cancer metastases in axillary lymph nodes. The detection sensitivity of the mammaglobin RT-PCR is far superior to that of the CEA RT-PCR, allowing the diagnosis of occult metastases in nearly one-third of cases.

DNA was analyzed from 57 sporadic gastrointestinal tumors (34 pancreatic cancers, 23 colon tumors) and cognate normal tissues to verify whether mutations at coding sequences were associated with microsatellite instability (MSI). Genomic instability was present in 41% (14/34) of pancreatic samples and in 26% (6/23) of colon cancers previously tested by six microsatellite markers. The tumors included 37 cases showing no MSI; 15 cases with MSI at only 1 locus and 5 cases with MSI at 2 or more loci. All the samples were screened for mutations in genes containing repeated tracts in their coding sequences (TGFbetaRII, IGFRII and bax) and in codon 12 of the K-ras oncogene. Furthermore, loss of heterozygosity (LOH) at NM23.H1 locus was tested, 17/34 (50%) pancreatic tumors and 6/23 (26%) colon cancers showed mutations in codon 12 of K-ras; allelic loss of NM23. H1 locus was found in 6/18 (33%) informative colon tumors and in no pancreatic cancers. The TGFbetaRII, IGFRII and bax genes were altered in 3 (13%), 1 (4%) and 3 (13%) out of 23 colon tumors respectively, but no mutation was detected in pancreatic cancers. Mutations in the repeated nucleotide stretches within the coding sequences of TGFbetaRII, IGFRII and bax genes were found only in colon tumors with a high unstable phenotype (more than 3 microsatellite loci altered).

Tumours developed in non-smoking patients represent about 10% of all lung neoplasms and show peculiar morphologic and genetic features. In a previous study, we found a constant association between p53 gene alterations and loss of heterozygosity (LOH) at the FHIT locus in a subset of non-smoking tumours (7 cases out of 35 analyzed), so we hypothesized that a genomic instability associated with p53 mutations could be the cause of FHIT LOH in these neoplasms. To test this hypothesis, in the same panel of tumours, we investigated the presence of LOH at 7 other microsatellite loci located on different chromosomes. Interestingly we found that all of the tumours with p53 alterations and LOH at the FHIT locus showed loss of heterozygosity at all of the informative tested loci. This association was statistically significant (p=0.0001). Our data indicate the presence of a generalized genomic instability in this subset of lung tumours. Since p53 alterations were mostly G:C --> A:T transitions and frameshift deletions, we are tempted to hypothesize that the genomic instability observed in non-smoking patients could be caused by particular p53 alterations. In fact, other kind of p53 mutations (G:C --> T:A transversions), frequently found in a series of 35 tumours of smokers used as control, were not associated with LOH at microsatellites loci. However, we cannot exclude that p53 alterations are a consequence and not the cause of the genomic instability. In this case, we have to admit that a gene(s), upstream of p53, is implicated in genome destabilisation in a subset of lung adenocarcinomas developed in non-smoking patients.

Patients with stage I non-small cell lung cancer (NSCLC) are typically treated with surgical resection alone. However, about one-third of such patients develop disease recurrence and die within 5 years after complete resection. The ability to predict recurrence could represent an important contribution to treatment planning. This study evaluates the presence of telomerase activity in tumor cells as a predictor of disease recurrence and cancer-related death after operation for stage I NSCLC patients. The activity of the telomerase enzyme was investigated by telomeric repeat amplification protocol (TRAP) in tumors and matching normal lung tissue samples obtained from 107 consecutive operable patients with pathological stage I NSCLC. Telomerase activity was detected in 66 (62%) of the 107 tumors examined and in none of the corresponding adjacent noncancerous lung tissue samples. Correlation with pathological parameters showed that telomerase activity was associated with histopathological grade (P = 0.0135) but not with tumor size or histological type. Univariate survival curves, estimated using the method of Kaplan and Meier, defined a significant association between telomerase activity and both disease-free survival (P = 0.0115) and overall survival (P = 0.0129). In multivariate analyses, performed by Cox's proportional hazards regression models, the presence of telomerase activity was the only strong predictor of disease-free survival (P = 0.0173) and overall survival (P = 0.0187). Our data indicate that telomerase activity can be an important prognostic factor that should be considered in future prospective trials of adjuvant therapy for high-risk stage I NSCLC patients.

Lung cancer is strictly associated with tobacco smoking. Tumours developed in non-smoking subjects account for less than 10% of all lung cancers and show peculiar histopathological features, being prevalently adenocarcinomas. A number of genetic data suggest that their biological behaviour may be different from that of lung tumours caused by smoking, however the number of cases investigated to date is too low to draw definitive conclusions. We have examined the status of p53 and K-ras genes and the presence of loss of heterozygosity (LOH) at the FHIT locus in a series of 35 lung adenocarcinomas that developed in subjects who had never smoked. Results were compared with those obtained in a series of 35 lung adenocarcinomas from heavy-smoking subjects. In the group of non-smoking subjects p53 mutations and LOH at the FHIT locus were present in seven (20%) cases, and the two alterations were constantly associated (P < 0.0001), whereas they were not related in the series of carcinomas caused by smoking. In tumours developed in heavy-smoking subjects, the frequency of LOH at the FHIT locus was significantly higher (P = 0.006) than in tumours from non-smoking subjects. The frequency of p53 mutations in adenocarcinomas caused by smoking was not different from that seen in non-smoking subjects. However, in the group of smoking subjects we observed mostly G:C --> T:A transversions, whereas frameshift mutations and G:C --> A:T transitions were more frequently found in tumours from non-smoking subjects. No point mutations of the K-ras gene at codon 12 were seen in subjects who had never smoked, whereas they were present (mostly G:C --> T:A transversions) in 34% of tumours caused by smoking (P = 0.002). Our data suggest that lung adenocarcinomas developed in subjects who had never smoked represent a distinct biological entity involving a co-alteration of the p53 gene and the FHIT locus in 20% of cases.

Bronchioloalveolar carcinoma (BAC) is a particular type of adenocarcinoma of the lung which accounts for up to 9 per cent of pulmonary malignancies. The aetiology and pathogenesis of this unique neoplastic disease are still unclear. Three histological subtypes of BAC have been recognized: mucinous, non-mucinous, and sclerosing. Of these, mucinous and sclerosing BAC have a worse prognosis than non-mucinous tumours. The different morphological patterns and clinical outcomes of the subtypes of BAC suggest differences in their biological behaviour. Previous reports have shown that the mucinous form of BAC is characterized by constant mutations at codon 12 of the K-ras gene, whereas the other two histotypes show a frequency of K-ras mutations which is not different from that observed in conventional lung adenocarcinomas. The present study of a series of 51 BACs, previously investigated for K-ras gene mutations, has evaluated the status of two other genes, p53 and FHIT, known to be frequently altered in non-small cell lung cancer. Loss of heterozygosity at microsatellite-containing loci located within the FHIT gene was observed in 22 (43 per cent) BACs. The distribution of FHIT gene abnormalities was not statistically different in the three histological subtypes. p53 mutations were present in 13 (32 per cent) non-mucinous/sclerosing BACs, while no mutations were seen in mucinous tumours (P = 0.039). Correlations with clinicopathological parameters showed that p53 mutations in BACs are associated with more aggressive tumours. No correlations were observed between FHIT or K-ras gene abnormalities and clinicopathological data. In conclusion, these results indicate that FHIT alterations are frequently involved in BAC tumourigenesis and that genetic changes in the p53 and K-ras genes can distinguish between different histotypes of BAC.

The FHIT gene, recently cloned and mapped on chromosome 3p14.2, has frequently been found to be abnormal in several established cancer cell lines and primary tumours. As alterations of chromosome 3p are common events in ovarian cancers with breakpoint sites at 3p14.2, we decided to investigate the role of FHIT in human ovarian tumorigenesis. Fifty-four primary ovarian carcinomas were studied by reverse transcription of FHIT mRNA followed by polymerase chain reaction (PCR) amplification and sequencing of products. The same tumours and matched normal tissues were also investigated for loss of heterozygosity using three microsatellite markers located inside the gene. We found an abnormal transcript of the FHIT gene in two cases (4%) and allelic losses in eight cases (15%). Twelve (22%) of the 54 tumours investigated belonged to young patients with a family history of breast/ovarian cancer. In none of these cases was the FHITgene found to be altered. Our results indicate that FHITplays a role in a small proportion of ovarian carcinomas.

The status of the P16, gene was investigated by Southern blot, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP), and DNA sequencing analyses in 30 primary resected non-small cell lung carcinomas (NSCLCs) with metastatic involvement of thoracic lymph nodes and 33 NSCLCs without node metastases. Direct sequencing of tumour DNA samples scored positive by PCR-SSCP showed five somatic mutations of the P16 gene: four nonsense and one frameshift. The Southern blot analysis revealed the presence of a homozygous deletion of the P16 locus in one tumour. All of the sis NSCLCs with somatic aberrations of the P16 gene belonged to the series of tumours with metastatic diffusion to thoracic lymph nodes. In each of these six cases, the genetic aberration was seen in both the primary tumour and the node metastasis. No P16 alteration was found in tumours without metastatic lymph nodes. This difference was statistically significant (P=0.02). No correlation was present between P16 alterations and other clinicopathological parameters including age of patients, tumour size, histological type, and grade. In three tumours with genetic aberration of P16, there was a concomitant alteration of the p53 gene. Our results indicate that the P16 gene is infrequently mutated (10 per cent of the cases examined) in primary resected NSCLC. However, since P16 mutations were found only in metastatic tumours, they may be important events in late phases of tumour progression and could represent useful markers of tumour aggressiveness in NSCLC.

Detection of gene mutations by sensitive polymerase chain reaction (PCR)-based methods can allow to identify occult neo-plastic cells in a great excess of nonmalignant cells. These molecular approaches have an enormous potential in terms of early diagnosis, detection of occult micrometastases of solid tumors, and minimal residual disease in patients with hemato-poietic malignancies. Currently, the applications of such methods are limited, mainly because the high sensitivity required for the identification of rare mutated alleles can be achieved only in cases in which mutations occur in few specific codons of a gene or when the mutation is already known. No methods are available by which few alleles with unknown mutations in tumor genes can be recognized in a great excess of wild-type alleles. We have developed an extremely sensitive method, termed enriched single-strand conformational polymorphism (E-SSCP). which permits detection of a rare alleles with unknown mutations. The method is based on the observation that after a conventional SSCP analysis the vast majority of mutated bands migrate close to the wild-type bands. The area of the gel having the highest chance to hold mutated alleles is physically isolated and is used as a substrate for a second round of SSCP. Serially diluted DNA samples containing gene mutations demonstrated detection of 1 mutant/10 normal alleles. The E-SSCP assay was first applied to six sputum samples of patients affected by lung cancers with known p53 mutations showing in sputa the same mutations observed in tumors. The technique was then applied to eight cytologically negative sputum samples obtained from patients who later developed a clinically manifested lung carcinoma. In three cases, harboring a p53 mutation in tumor tissue, the E-SSCP analysis allowed the detection of the mutations in sputa months before clinical diagnosis. In conclusion, we have presented a general, highly sensitive technique for the detection of unknown mutations that may have several potential applications and may hold considerable promise for the early detection and study of cancer.