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1.
J Eur Acad Dermatol Venereol ; 32(6): 956-961, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29080310

ABSTRACT

BACKGROUND: Melanoma is rare in the first two decades of life. Trends in incidence differ across countries. OBJECTIVE: To describe incidence and relative survival of children and adolescents with melanoma in the Netherlands for children (0 through 11 years) and adolescents (12 through 19 years) separately. We hypothesized that adolescent melanoma increased in contrast to childhood melanoma, possibly due to a difference in cancer biology and sun exposure patterns. METHODS: Data on all patients of 0-19 years diagnosed between 1989 and 2013 with histologically confirmed cutaneous invasive melanoma were retrieved from the Netherlands Cancer Registry (NCR). Incidence trends were analysed with Joinpoint regression. Relative survival analysis was performed. RESULTS: Between 1989 and 2013, 80 children and 544 adolescents with melanoma were registered in the NCR. Median age at diagnosis was 17 years (IQR 15-18); the female-to-male ratio was 1.7 : 1 Statistically significant incidence trends were found in the older age group (12-19 years): an increasing incidence since 1991 [annual percentage change (APC) 3.2%, 95%CI 1.3-5.1] followed by a decrease from 2005 to 2013 (APC -4.9%, 95%CI -9.6-0.0). No incidence trends for childhood melanoma were observed (APC 0.3%, 95% CI -3.0-3.8). Relative survival at 1, 5 and 10 years was 98% (95% CI 97-99), 94% (95% CI 92-96) and 90% (95% CI 87-92), respectively. Survival was worse in males and higher Breslow thickness. CONCLUSIONS: Melanoma is very rare under the age of 12 with stable incidence rates. In comparison with childhood melanoma, melanomas in adolescents are more common with a decreasing trend in the past decade. Male sex and increasing Breslow thickness are associated with worse survival in paediatric melanoma patients.


Subject(s)
Melanoma/epidemiology , Skin Neoplasms/epidemiology , Adolescent , Adult , Child , Child, Preschool , Cohort Studies , Female , Humans , Incidence , Infant , Infant, Newborn , Male , Melanoma/physiopathology , Netherlands/epidemiology , Skin Neoplasms/physiopathology , Survival Rate
2.
Ned Tijdschr Geneeskd ; 161: D1687, 2017.
Article in Dutch | MEDLINE | ID: mdl-29219794

ABSTRACT

A 44-year-old woman was referred with a brown-red papule on the back. Histopathologic examination showed a melanocytic BAP1-associated intradermal tumour. A germline mutation in the BAP1 gene confirmed a diagnosis of BAP1 tumour predisposition syndrome. This syndrome is associated with various tumour types. Early diagnosis is essential for counselling and screening.


Subject(s)
Germ-Line Mutation , Skin Neoplasms/diagnosis , Skin Neoplasms/genetics , Tumor Suppressor Proteins , Ubiquitin Thiolesterase , Adult , Female , Genetic Predisposition to Disease , Humans
3.
Surg Pathol Clin ; 10(2): 281-298, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28477881

ABSTRACT

Spitz tumors are melanocytic neoplasms hallmarked by large cell size, lack of high-grade atypia, and a regular architecture. Most are nonpigmented or poorly pigmented. Malignant potential ranges from absent (Spitz nevus), to fully present (spitzoid melanoma), with a further, ill-defined group of Spitz tumors with limited metastatic potential. Microscopic evaluation may prove inconclusive in some instances, resulting in a verdict of Spitz tumor of uncertain malignant potential (STUMP). STUMP is, therefore, not an entity, and should not be equated with Spitz tumors with limited metastatic potential. Novel diagnostic techniques are yielding promising results, and further evaluation is ongoing.


Subject(s)
Melanoma/pathology , Skin Neoplasms/pathology , Diagnosis, Differential , Humans , Nevus, Epithelioid and Spindle Cell
4.
Ned Tijdschr Geneeskd ; 161: D1030, 2017.
Article in Dutch | MEDLINE | ID: mdl-28537538

ABSTRACT

OBJECTIVE: In the Netherlands the incidence of melanomas in situ and thin invasive melanomas is rising more quickly than that of thicker melanomas. Our aim was to gain insight into this increase and to test the hypothesis that it is attributable to over-diagnosis. METHOD: We analysed data taken from the Netherlands Cancer Registry on all primary melanomas diagnosed between 1994 and 2010. We assessed trends in European standardised rates (ESR) using joinpoint analysis, and expressed these trends as estimated annual percentage change (EAPC). Thin melanomas were subdivided into four subgroups. RESULTS: Between 1994 and 2010, 34 156 persons were diagnosed with melanoma in situ or thin invasive melanoma. The incidence of melanoma in situ doubled during this period, with an acceleration in incidence in men from 2004, and in women from 2007. In men the ESR of thin melanoma doubled, whereby the thinnest category (< 0.25 mm) rose more quickly, but not significant compared to the other Breslow thicknesses ≤ 1 mm. In women, the ESR of thin melanomas nearly doubled, with the exception of the thinnest melanoma. CONCLUSION: Between 1994 and 2010, the incidence of melanomas increased steadily. In part, this was a real rise as a result of increased exposure to ultraviolet rays. However, from 2006 the incidence of melanomas in situ and thin invasive melanomas in men has risen comparatively more quickly. This could point to over-diagnosis, but also to increased awareness, early detection, a diagnostic shift from benign to malignant lesions and changes in the Dutch health care system.

5.
Br J Dermatol ; 167(6): 1321-30, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22759226

ABSTRACT

BACKGROUND: Patients with melanoma are at increased risk of developing a subsequent melanoma. OBJECTIVES: To estimate the risks of developing a second primary in situ or invasive cutaneous melanoma after a first melanoma, between 1989 and 2008. METHODS: Patients were followed until diagnosis of a second melanoma, date of death or end of study. Cumulative risks, standardized incidence ratio (SIR, observed second melanomas divided by background age-, calendar- and sex-specific incidence rates of melanoma, as recorded in the Netherlands Cancer Registry) and absolute excess risk (AER, observed minus expected per 10 000 person-years) of second melanomas were calculated. RESULTS: In total, 10 765 patients with in situ melanoma and 46 700 with invasive melanoma were included. The cumulative risks of a second invasive melanoma after a first in situ or invasive melanoma at 20 years of follow-up were 6·2% and 5·0%, respectively. The relative risk of developing any melanoma (in situ or invasive) after any first melanoma (measured as SIR) varied from 12·4-fold [invasive after invasive melanoma; 95% confidence interval (CI) = 11·6-13·2] to 26·4-fold (in situ after in situ melanoma; 95% CI = 22·6-30·7) increase compared with the general population. SIRs and AERs remained elevated up to 20 years after the first melanoma. CONCLUSIONS: This study shows significantly increased long-term risks (both relative and absolute) of developing a second invasive melanoma after a first melanoma (invasive and in situ), and might serve as a basis for follow-up guidelines.


Subject(s)
Melanoma/epidemiology , Neoplasms, Second Primary/epidemiology , Skin Neoplasms/epidemiology , Cohort Studies , Female , Follow-Up Studies , Humans , Male , Melanoma/etiology , Melanoma/mortality , Middle Aged , Neoplasms, Second Primary/etiology , Neoplasms, Second Primary/mortality , Netherlands/epidemiology , Risk Factors , Skin Neoplasms/etiology , Skin Neoplasms/mortality
7.
Eur Respir J ; 34(2): 371-9, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19282344

ABSTRACT

Systemic sclerosis-associated pulmonary arterial hypertension (SScPAH) has a worse prognosis and response to pulmonary arterial hypertension (PAH) therapy than idiopathic PAH (IPAH). These differences have not yet been explained. Knowledge concerning histological pulmonary vasculopathy in SScPAH is limited in contrast to IPAH. Therefore, we explored patterns of vasculopathy in SScPAH compared with IPAH. Parameters of vasculopathy were assessed from lung tissue of eight PAH patients with limited cutaneous systemic sclerosis and 11 IPAH patients. Lung tissue was obtained at autopsy (n = 15), explantation (n = 3) and biopsy (n = 1). Pulmonary arterial/arteriolar intimal fibrosis was identified in all SScPAH patients and in three IPAH patients (p = 0.003). Fibrosis of pulmonary veins/venules was found in all SScPAH patients and in three IPAH patients (p = 0.003). In four SScPAH patients, fibrosis of veins/venules was focal and associated with capillary congestion as in pulmonary veno-occlusive disease (PVOD). Of the IPAH patients, 10 had unequivocal evidence of plexogenic arteriopathy compared with none of the SScPAH patients (p = 0.001). SScPAH is characterised by small vessel intimal fibrosis, which is associated with a PVOD-like pattern in some cases. This might explain its different clinical behaviour from IPAH. Small vessel intimal fibrosis may provide clues to elucidation of differences in pathogenetic mechanisms between the groups.


Subject(s)
Hypertension, Pulmonary/complications , Pulmonary Veno-Occlusive Disease/complications , Scleroderma, Systemic/complications , Skin Diseases/complications , Adult , Autopsy , Biopsy , Female , Fibrosis , Humans , Hypertension, Pulmonary/physiopathology , Lung/physiopathology , Male , Middle Aged , Pulmonary Artery/physiopathology , Pulmonary Veno-Occlusive Disease/physiopathology , Scleroderma, Systemic/physiopathology , Skin Diseases/physiopathology
8.
Anticancer Res ; 28(4C): 2297-302, 2008.
Article in English | MEDLINE | ID: mdl-18751409

ABSTRACT

BACKGROUND: The biochemical marker serum S-100B has been proven to reflect the stage of melanoma and to be useful for disease monitoring and prediction of survival, mainly in stage IV disease. For stage III melanoma, limited data are available and its predictive value for relapse is unknown. Serum S-100B was evaluated prospectively for monitoring response and its predictive value for relapse and overall survival in stage IIIB/C melanoma patients. PATIENTS AND METHODS: Treatment consisted of one cycle of neoadjuvant and adjuvant chemo(immuno)therapy, around surgery. S-100B was measured at enrollment and prior to and following surgery. The levels of S-100B in serum were compared to the pattern and intensity of the expression of S-100B in the melanoma tissue. RESULTS: Some patients with normal initial S-100B values (n=18) showed responses (3 complete remission and 2 partial remission), in contrast to patients with elevated S-100B values. Distant relapse within one year was found in 11/23 (48%) patients with increased S-100B versus 2/18 (11%) patients with a normal value (p=0.01). Overall survival was decreased in patients with increased S-100B compared to those with normal S-100B (p=0.02). Correlations between the pattern and intensity of S-100B expression in the tumor specimen and the value of serum the S-100B did not reach statistical significance. CONCLUSION: Serum S-100B is a valuable biomarker for the evaluation of response to treatment and prediction of early distant relapse and survival in stage IIIB/C melanoma. The marginal correlation between serum S-100B values and expression of S-100B in the tumor specimens needs further study.


Subject(s)
Biomarkers, Tumor/blood , Melanoma/blood , Nerve Growth Factors/blood , S100 Proteins/blood , Biomarkers, Tumor/biosynthesis , Chemotherapy, Adjuvant , Humans , Immunohistochemistry , Immunotherapy , Lymph Nodes/metabolism , Melanoma/metabolism , Melanoma/pathology , Melanoma/therapy , Neoadjuvant Therapy , Neoplasm Staging , Nerve Growth Factors/biosynthesis , S100 Calcium Binding Protein beta Subunit , S100 Proteins/biosynthesis
10.
Oncogene ; 27(7): 877-95, 2008 Feb 07.
Article in English | MEDLINE | ID: mdl-17724477

ABSTRACT

Of the RAF family of protein kinases, BRAF is the only member to be frequently activated by mutation in cancer. A single amino acid substitution (V600E) accounts for the vast majority and results in constitutive activation of BRAF kinase function. Its expression is required to maintain the proliferative and oncogenic characteristics of BRAF(E600)-expressing human tumour cells. Although BRAF(E600) acts as an oncogene in the context of additional genetic lesions, in primary cells it appears to be associated rather with transient stimulation of proliferation. Eventually, BRAF(E600) signalling triggers cell cycle arrest with the hallmarks of cellular senescence, as is illustrated by several recent studies in cultured cells, animal models and benign human lesions. In this review, we will discuss recent advances in our understanding of the role of BRAF(E600) in benign and malignant human tumours and the implications for therapeutic intervention.


Subject(s)
Neoplasms/metabolism , Proto-Oncogene Proteins B-raf/physiology , Animals , Cell Proliferation , Humans , Neoplasms/therapy , Signal Transduction
12.
Br J Dermatol ; 155(1): 182-5, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16792771

ABSTRACT

BACKGROUND: Familial cylindromatosis is a rare genetic disorder, giving rise to neoplasms of the skin appendages. We have recently shown that loss of the cylindromatosis tumour suppressor gene leads to activation of NF-kappaB, a transcription factor having antiapoptotic activity. This provides a possible explanation for the deregulated growth of cylindromas. In cell-based assays, salicylate can prevent NF-kappaB activation caused by loss of the cylindromatosis gene, suggesting that salicylic acid application might be a potential treatment for cylindromatosis. OBJECTIVES: To assess the effectiveness of topical application of salicylic acid on familial cylindromas. METHODS: Cylindromas in five patients from four different cylindromatosis families were treated with twice daily and then once daily topical salicylic acid. Clinical response was determined by serial tumour measurements. RESULTS: In total 17 cylindromas in five patients were studied: 12 target lesions and five control lesions. The median size of the cylindromas was 1.0 cm (range, 0.6-2.8 cm). Two of the 12 cylindromas showed a complete remission. Another eight lesions showed some response, but not sufficient to qualify as partial remission. The control lesions remained stable or increased in size. CONCLUSIONS: Salicylic acid is a well-tolerated and potential new treatment for cylindromatosis.


Subject(s)
Carcinoma, Adenoid Cystic/drug therapy , Carcinoma, Skin Appendage/drug therapy , Keratolytic Agents/administration & dosage , Neoplastic Syndromes, Hereditary/drug therapy , Salicylic Acid/administration & dosage , Administration, Topical , Carcinoma, Adenoid Cystic/genetics , Carcinoma, Adenoid Cystic/metabolism , Carcinoma, Skin Appendage/genetics , Carcinoma, Skin Appendage/metabolism , Female , Follow-Up Studies , Genes, Tumor Suppressor , Humans , I-kappa B Kinase/metabolism , Keratolytic Agents/therapeutic use , NF-kappa B/metabolism , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/metabolism , Pilot Projects , Remission Induction , Salicylic Acid/therapeutic use
13.
Ned Tijdschr Geneeskd ; 149(33): 1852-8, 2005 Aug 13.
Article in Dutch | MEDLINE | ID: mdl-16128184

ABSTRACT

A melanocytic lesion was removed from each of three patients: 2 men aged 37 and 65 and 1 woman aged 45. The preferred diagnosis was 'Spitz naevus'. Subsequently, all three developed regional (sub)cutaneous and/or lymph node metastases, indicating that the lesions were melanomas. The histopathological distinction between Spitz naevus and melanoma is often very difficult. Classical Spitz naevi can be diagnosed correctly only if the entire lesion is available for histological examination. Incompletely removed lesions should be re-excised for further examination. Some melanomas resemble Spitz naevi, but can be recognised on the basis of well-defined histological indicators of malignancy. Some melanocytic lesions, however, cannot be categorised with confidence as being either benign (Spitz naevus) or malignant (spitzoid melanoma). Thus, a group of lesions with inconclusive histology remains and has been designated as 'atypical Spitz tumour' or 'Spitz tumour of uncertain malignant potential'. Generally, such lesions are best treated as melanomas.


Subject(s)
Melanoma/pathology , Nevus, Epithelioid and Spindle Cell/pathology , Skin Neoplasms/pathology , Adult , Aged , Diagnosis, Differential , Female , Humans , Immunohistochemistry , Male , Melanoma/diagnosis , Middle Aged , Nevus, Epithelioid and Spindle Cell/diagnosis , Skin Neoplasms/diagnosis
14.
Br J Plast Surg ; 57(8): 707-19, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15544766

ABSTRACT

INTRODUCTION: Congenital naevi (CN) vary greatly in size, macroscopic appearance and histology. There is a practical need to subdivide CN according to size, since size differences have a direct bearing on cosmetic and resultant psychological problems, and on therapeutic options, and probably on the chance of malignant transformation. In this review, we summarise the literature on size subgroupings of CN, with special focus on giant congenital naevi and their risk of malignant transformation. MATERIALS AND METHODS: A Medline literature search from 1966 to October 2002 was performed. Only English-language studies focusing on CN in association with melanoma were included. The final strategy consisted of textwords and medical subject heading (MeSH) terms on small, medium, large and giant congenital naevi combined with the textwords classification, histology and melanoma. Additional manual cross-referencing was performed. We excluded articles that dealt only with aspects of treatments. RESULTS: A wide variety of criteria for size subgrouping of CN has been put forward in the literature and precludes a direct comparison of reported data (Table 1). We identified 35 such articles in the world literature in which no less than seven different definitions of minimum size of a giant CN were employed. Histologically, it is difficult or even impossible to conclude that a naevus is congenital or acquired, especially in case of a small lesion, since the differences are not absolute (Table 2). Giant CN have an increased risk for malignant transformation, but the reported incidence rates have differed widely from one to 31% (Table 3). Reported melanoma incidence rates have derived from retro- and prospective studies, reviews and case reports, and compared with each other using different definitions. On top of this, patients in different age groups were reported, who were registered in different referral centers. CONCLUSION: To allow comparison of study results from different centers, it is essential that the size subclassification of CN is based on standard and generally accepted criteria. We recommend defining GCN as a CN covering one percent body surface area in face and neck and two percent elsewhere on the body. Based on a review of the world literature, we recommend prophylactic excision of all CN, in close communication with patient and family and individualising treatment accordingly.


Subject(s)
Nevus, Pigmented/classification , Skin Neoplasms/classification , Cell Transformation, Neoplastic , Humans , Infant, Newborn , Nevus, Pigmented/congenital , Nevus, Pigmented/pathology , Risk Factors , Skin Neoplasms/congenital , Skin Neoplasms/pathology
15.
J Cutan Pathol ; 31(5): 388-92, 2004 May.
Article in English | MEDLINE | ID: mdl-15059225

ABSTRACT

BACKGROUND: In three cases of chronic scrotal lymphedema, histological and immunohistochemical changes were observed that were strikingly similar to an exceedingly rare lesion reported previously under the name of acquired smooth-muscle hamartoma (ASMH) of the scrotum. The clinical context indicated that the cases were reactive rather than hamartomatous in nature. MATERIALS AND METHODS: The histological and immunohistochemical findings of the three cases were compared to macroscopically normal scrotal specimens obtained during sex reassignment surgery in seven male-to-female transsexuals. RESULTS: Compared to the seven controls, the three cases of chronic scrotal edema revealed a marked increase of dartos smooth-muscle tissue and of connective tissue of the scrotal skin and underlying soft tissues. Still, even the normal amount of scrotal smooth-muscle tissue may easily be misinterpreted as smooth-muscle hyperplasia. CONCLUSIONS: Chronic scrotal lymphedema may induce hyperplasia of the dartos muscle, resulting in a histological appearance previously described as ASMH. This indicates that ASMH may not always represent a later onset of abnormality similar to congenital smooth-muscle hamartoma but, rather, may constitute a histological simulator.


Subject(s)
Genital Diseases, Male/pathology , Hamartoma/pathology , Lymphedema/pathology , Muscle, Smooth/pathology , Scrotum/pathology , Adult , Antigens, CD34/metabolism , Case-Control Studies , Diagnosis, Differential , Genital Diseases, Male/metabolism , Humans , Lymphedema/metabolism , Male , Middle Aged
16.
J Pediatr Surg ; 37(9): 1258-62, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12194113

ABSTRACT

BACKGROUND/PURPOSE: Thyroid transcription factor-1 (TTF-1) was detected in human respiratory epithelial cells from 11 weeks of gestation. TTF-1 is involved in both lung morphogenesis and in the regulation of surfactant proteins. Recently, low expression of TTF-1 in the nitrofen rat model of congenital diaphragmatic hernia (CDH) was shown and restoration of this downregulation by antenatal glucocorticolds (CS) was reported. The aim of this study was to investigate the expression of TTF-1 as a marker of lung morphogenesis in normal human lung development and in age-matched controls of human lung specimen in hypoplastic lungs of human CDH and other forms of lung hypoplasia. METHODS: Immunohistochemistry by a monoclonal TTF-1 antibody was performed on paraffin sections of human fetal and neonatal lung tissues. The so-called developmental group (12 weeks' gestation to full term) included 47 lung specimens. The congenital hypoplasia group included 8 full-term CDH patients who died within 12 hours after birth, 3 full-term CDH patients who had antenatal CS therapy, and 4 full-term CDH patients after extracorporeal membrane oxygenation (ECMO) therapy. For comparison, 6 full-term born patients, who died of other forms of pulmonary hypoplasia, were used as comparative specimen. Immunohistochemical localization of TTF-1 was evaluated by light microscopy for 3 different areas of the airways including intrapulmonary bronchi, intermediate airways so-called terminal bronchioles, distal airways, and later sacculi and alveoli. RESULTS: Nuclear TTF-1 staining was observed in the progenitor cells of the developing bronchiolar cells early in the human lung developmental series. At full term, TTF-1 was expressed in both type II epithelial cells and in subsets of respiratory nonciliated bronchiolar epithelial cells in a pattern similar in all studied groups. No TTF-1 expression was detected at the level of the intrapulmonary bronchi. CONCLUSIONS: No difference in TTF-1 expression was observed in the developing early fetal and full-term neither in hypoplastic human lungs. This expression did not change with antenatal CS and postnatal ECMO treatment. Although TTF-1 appears to play an important role in lung morphogenesis, a pivotal role in human lung development is not likely.


Subject(s)
Fetus/metabolism , Hernias, Diaphragmatic, Congenital , Lung/embryology , Nuclear Proteins/metabolism , Transcription Factors/metabolism , Gene Expression , Hernia, Diaphragmatic/embryology , Hernia, Diaphragmatic/metabolism , Humans , Infant, Newborn , Lung/metabolism , Lung/pathology , Thyroid Nuclear Factor 1
18.
Br J Cancer ; 86(3): 342-5, 2002 Feb 01.
Article in English | MEDLINE | ID: mdl-11875695

ABSTRACT

UNLABELLED: Malignant pleural mesothelioma is a notoriously chemoresistant tumour. However, a recent single institution study showed an impressive activity of gemcitabine and cisplatin. Our aim is to investigate the efficacy and toxicity of a gemcitabine and cisplatin combination in selected and chemo-naive patients with histologically proven malignant pleural mesothelioma. METHOD: Gemcitabine 1250 mg m(-2) was administered on day 1 and day 8 and cisplatin 80 mg m(-2) was administered on day 1 in a 3-week cycle with a maximum of six cycles. Response and toxicity evaluations were performed according to WHO and NCIC-CTC criteria. Pathology and radiology were centrally reviewed. Results show that in 25 evaluable patients, four PR were observed (ORR 16%, 95% CI 1-31%). Responses of seven patients were unevaluable. No unexpected toxicity occurred. Time to progression was 6 months (5-7 months) with a median survival from registration of 9.6 months (95% CI 8-12 months). In conclusion this trial excludes with 90% power a response rate of greater than 30% in patients with malignant pleural mesothelioma using a combination of gemcitabine and cisplatin at the proposed dose and schedule.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Deoxycytidine/analogs & derivatives , Mesothelioma/drug therapy , Pleural Neoplasms/drug therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Deoxycytidine/administration & dosage , Female , Humans , Male , Mesothelioma/mortality , Mesothelioma/pathology , Middle Aged , Neoplasm Staging , Pleural Neoplasms/mortality , Pleural Neoplasms/pathology , Survival Rate , Gemcitabine
19.
Oncogene ; 20(45): 6551-8, 2001 Oct 04.
Article in English | MEDLINE | ID: mdl-11641780

ABSTRACT

The onset of human lung cancer occurs through sequential mutations in oncogenes and tumor suppressor genes. Mutations in K-Ras play a prominent role in human non-small cell lung cancer. We have developed a mouse lung tumor model in which K-Ras can be sporadically activated through Cre-lox mediated somatic recombination. Adenoviral mediated delivery of Cre recombinase in lung epithelial cells gave rise to rapid onset of tumorigenesis, yielding pulmonary adenocarcinomas with 100% incidence after a short latency. The lung tumor lesions shared many features with human non-small cell lung cancer. Our data show that sporadic expression of the K-Ras oncogene is sufficient to elicit lung tumorigenesis. Therefore this model has many advantages over conventional transgenic models used thus far.


Subject(s)
Adenocarcinoma/etiology , Carcinoma, Non-Small-Cell Lung/etiology , Disease Models, Animal , Integrases/genetics , Lung Neoplasms/etiology , Oncogene Protein p21(ras)/genetics , Viral Proteins/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adenoviridae/genetics , Alleles , Animals , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Genes, Reporter , Genetic Vectors , Integrases/metabolism , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Mice, Transgenic , Oncogene Protein p21(ras)/biosynthesis , RNA, Neoplasm/biosynthesis , Recombination, Genetic , Viral Proteins/metabolism
20.
Nature ; 413(6851): 83-6, 2001 Sep 06.
Article in English | MEDLINE | ID: mdl-11544530

ABSTRACT

CDKN2A (INK4a/ARF) is frequently disrupted in various types of human cancer, and germline mutations of this locus can confer susceptibility to melanoma and other tumours. However, because CDKN2A encodes two distinct cell cycle inhibitory proteins, p16INK4a and p14ARF (p19Arf in mice), the mechanism of tumour suppression by CDKN2A has remained controversial. Genetic disruption of Cdkn2a(p19Arf) (hereafter Arf) alone predisposes mice to tumorigenesis, demonstrating that Arf is a tumour-suppressor gene in mice. We mutated mice specifically in Cdkn2a(p16Ink4a) (hereafter Ink4a). Here we demonstrate that these mice, designated Ink4a*/*, do not show a significant predisposition to spontaneous tumour formation within 17 months. Embryo fibroblasts derived from them proliferate normally, are mortal, and are not transformed by oncogenic HRAS. The very mild phenotype of the Ink4a*/* mice implies that the very strong phenotypes of the original Ink4a/ArfDelta2,3 mice were primarily or solely due to loss of Arf. However, Ink4a*/Delta2,3 mice that are deficient for Ink4a and heterozygous for Arf spontaneously develop a wide spectrum of tumours, including melanoma. Treatment of these mice with the carcinogen 7,12-dimethylbenzanthracene (DMBA) results in an increased incidence of melanoma, with frequent metastases. Our results show that, in the mouse, Ink4a is a tumour-suppressor gene that, when lost, can recapitulate the tumour predisposition seen in humans.


Subject(s)
Genes, p16 , Genetic Predisposition to Disease , Melanoma, Experimental/genetics , 9,10-Dimethyl-1,2-benzanthracene , Animals , Carcinogens , Cell Transformation, Neoplastic , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/physiology , Embryo, Mammalian/cytology , Female , Fibroblasts/physiology , Gene Deletion , Genes, ras , Humans , Male , Melanoma, Experimental/pathology , Melanoma, Experimental/secondary , Mice , Point Mutation , Proteins/genetics , Tumor Suppressor Protein p14ARF
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