An alternative route for multistep tumorigenesis in a novel case of hereditary renal cell cancer and a t(2;3)(q35;q21) chromosome translocation

Through allele-segregation and loss-of-heterozygosity analyses, we demonstrated loss of the translocation-derivative chromosome 3 in five independent renal cell tumors of the clear-cell type, obtained from three members of a family in which a constitutional t(2;3)(q35;q21) was encountered. In addition, analysis of the von Hippel-Lindau gene, VHL, revealed distinct insertion, deletion, and substitution mutations in four of the five tumors tested. On the basis of these results, we conclude that, in this familial case, an alternative route for renal cell carcinoma development is implied. In contrast to the first hit in the generally accepted two-hit tumor-suppressor model proposed by Knudson, the familial translocation in this case may act as a primary oncogenic event leading to (nondisjunctional) loss of the der(3) chromosome harboring the VHL tumor-suppressor gene. The risk of developing renal cell cancer may be correlated directly with the extent of somatic (kidney) mosaicism resulting from this loss.     

Differential expression of the retinoblastoma gene family members pRb/p105, p107, and pRb2/p130 in lung cancer

The Rb (retinoblastoma) gene family is composed of three members: the RB gene (one of the best-studied tumor suppressor genes) and two related genes, p107 and pRb2/p130. These three proteins share many structural and functional features and play a fundamental role in growth control. Using immunocytochemical techniques, we evaluated a variety of lung tumor specimens for the expression of this family of proteins and compared protein expression with the histological grading of the tumors and with the expression of the proliferating cell nuclear antigen. These Rb family members displayed distinctive patterns when compared and contrasted using different parameters. The highest percentage of undetectable levels in all of the specimens examined and the tightest inverse correlation (P) with the histological grading and with proliferating cell nuclear antigen expression in the most aggressive tumor types were found for pRb2/p130, which may suggest an important role for this protein in the pathogenesis and progression of lung cancer.     

Cytokine levels in cystic renal masses associated with renal cell carcinoma

PURPOSE: We compared cytokine levels in fluid from renal cysts with and without renal cell carcinoma. MATERIALS AND METHODS: Fluid was aspirated from 18 renal cysts without (benign) and 21 with renal cell carcinoma (malignant). Serum from patients with renal cell carcinoma and healthy controls was collected and cytokines were measured by enzyme-linked immunosorbent assay. RESULTS: Interleukin-6 (IL-6) and basic fibroblast growth factor concentrations were higher in malignant than benign cysts or serum (p <0.006). Epidermal growth factor levels were significantly higher in malignant cysts and serum than in benign cysts (p <0.01). IL-6 levels in malignant cysts positively correlated with the erythrocyte sedimentation rate (R=0.80) and C-reactive protein (R=0.86), and they were higher in grade 3 than in grade 2 tumors. Basic fibroblast growth factor levels were significantly higher in malignant cysts associated with hypervascular than hypovascular tumors (p=0.029). CONCLUSIONS: Cytokine levels in aspirated fluid may help to identify malignant renal cysts and indicate the characteristics of coexisting tumors.     

Prevalence, morphology and biology of renal cell carcinoma in von Hippel-Lindau disease compared to sporadic renal cell carcinoma

PURPOSE: Renal cell carcinoma occurs as a sporadic tumor but may be part of the autosomal dominant von Hippel-Lindau disease, characterized by retinal and central nervous system hemangioblastoma, pheochromocytoma, pancreatic cysts and renal cell carcinoma. We determine the prevalence of von Hippel-Lindau disease in a series of unselected renal cell carcinoma cases by molecular genetic analysis, and compare sporadic to von Hippel-Lindau renal cell carcinoma with respect to morphology and biology. MATERIALS AND METHODS: We established registers comprising 63 subjects with von Hippel-Lindau renal cell carcinoma, belonging to 30 distinct families (register A), and 460 unselected patients operated on for renal cell carcinoma in an 11-year period (register B). Molecular genetic analysis of the von Hippel-Lindau gene was performed for living patients of register A, representing 80% of von Hippel-Lindau families, and register B, 62% living patients, to identify von Hippel-Lindau germline mutations. In addition, register B was evaluated by a questionnaire (95% response) for familial occurrence of von Hippel-Lindau disease. RESULTS: The prevalence of von Hippel-Lindau renal cell carcinoma was 1.6% in 189 consenting unselected renal cell carcinoma patients. Risk factors for occult germline von Hippel-Lindau gene mutations in register B included familial renal cell carcinoma in 3 of 3 patients (100%), multifocal or bilateral renal cell carcinoma in 1 of 10 (10%) and age younger than 50 years at diagnosis in 1 of 33 (3%). Compared to sporadic von Hippel-Lindau renal cell carcinoma was characterized by an occurrence 25 years earlier, association with renal cysts, multifocal and bilateral tumors, cystic organization and low grade histology, and a better 10-year survival (p < 0.001 each). In von Hippel-Lindau disease metastases occurred only in tumors larger than 7 cm. CONCLUSIONS: von Hippel-Lindau differs from sporadic renal cell carcinoma in morphology and biology. Our data provide arguments for planning surgery for von Hippel-Lindau renal cell carcinoma and should stimulate future investigations.     

Clinicopathological study of incidental renal cell carcinoma

BACKGROUND: The objective of this study is to evaluate the clinicopathological features of incidental renal cell carcinoma, compared with non-incidental carcinoma. METHODS: Between July 1st, 1984 and June 30, 1994, 87 renal cell carcinoma patients were treated at our hospital; 56 had non-incidental renal cell carcinoma and 31 had incidental carcinoma. The clinicopathological features were examined. RESULTS: The incidence of incidental cancer ranges from 0 to 66%, and the incidence has increased in recent years. The median value of maximal tumor size was 4.0cm (1.5 approximately 8.0cm) for incidental cancer, and 8.0cm (3.0 approximately 16cm) for incidental cancer, and 8.0cm (3.0 approximately 16cm) for non-incidental cancer, i.e., the incidental cancer was significantly smaller than the non-incidental one (p < 0.001). The pathological stage of the resected non-incidental renal cell carcinoma (n = 47) was pT1, pT2, pT3 and pT4 in 0, 23, 21 and 3 patients, respectively. For the resected incidental renal cell carcinoma (n = 31) 3, 26, 2 and 0 patients showed pathological stages pT1, pT2, pT3 and pT4, respectively; the pathological stage of incidental renal cell carcinoma was significantly lower than that of non-incidental carcinoma (p < 0.001). Eighteen and 29 resected non-incidental renal cell carcinoma were grades 1 and 2, respectively, whereas 17 and 14 resected incidental renal cell carcinomas were in grades 1 and 2, respectively. Vascular invasion by tumor cells was shown in 31 (66.0%) and 8 (25.8%) patients with non-incidental and incidental renal cell carcinomas, respectively; the incidence of vascular invasion in incidental cancer being significantly lower than in non-incidental cancer (p < 0.001). The performance status and general condition in patients with incidental renal cell carcinoma were superior to those in patients with the non-incidental cancer. The 1, 3 and 5-year survival rate of all 87 renal cell carcinoma patients was 81, 62 and 57%, respectively. These rates for patients with non-incidental renal cell carcinoma were 72, 48 and 41%, respectively, and those for incidental cancer patients were 100%. The survival of patients with incidental renal cell carcinoma was significantly better than that of non-incidental carcinoma patients (p < 0.005). CONCLUSION: Our results suggest that the detection of incidental renal cell carcinoma will increase, and that the prognosis for renal cell carcinoma will improve. However, even in incidental renal cell carcinoma, careful long-term follow up may be necessary, since some tumors are comparatively large and exhibit vascular invasion.     

The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8

The 3;8 chromosomal translocation, t(3;8)(p14.2;q24.1), was described in a family with classical features of hereditary renal cell carcinoma. Previous studies demonstrated that the 3p14.2 breakpoint interrupts the fragile histidine triad gene (FHIT) in its 5' noncoding region. However, evidence that FHIT is causally related to renal or other malignancies is controversial. We now show that the 8q24.1 breakpoint region encodes a 664-aa multiple membrane spanning protein, TRC8, with similarity to the hereditary basal cell carcinoma/segment polarity gene, patched. This similarity involves two regions of patched, the putative sterol-sensing domain and the second extracellular loop that participates in the binding of sonic hedgehog. In the 3;8 translocation, TRC8 is fused to FHIT and is disrupted within the sterol-sensing domain. In contrast, the FHIT coding region is maintained and expressed. In a series of sporadic renal carcinomas, an acquired TRC8 mutation was identified. By analogy to patched, TRC8 might function as a signaling receptor and other pathway members, to be defined, are mutation candidates in malignant diseases involving the kidney and thyroid.     

Prognostic parameters of renal cell carcinoma. Clinicopathologic and DNA image cytometric analysis in 133 pT3a cases

In 133 cases of patients with renal cell carcinoma which infiltrated locally into the renal fatty tissue (stage pT3a, TNM classification of 1987), the prognostic potential of the following parameters was investigated: symptoms, patient's age at the time of operation, tumor size and localization, grade of malignancy, cell type, growth pattern, and prognostic score according to St?rkel et al. [Eur Urol 1990;18(suppl 2):36]. Additionally, automated image analysis DNA cytometry was performed on 110/133 carcinomas. After an average observation period of 3.6 years (maximum 10.1 years), 59 (44.4%) of the patients died of their tumors. The cause-specific 5- and 10-year survival rates were 51.3 and 29.1%, respectively. Statistically significant differences (p < 0.05) within the individual parameters were found only for the grade of malignancy and the corresponding prognostic score. Using DNA cytometry, 13 types of renal cell carcinoma were differentiated; 90% of the tumors contained aneuploid cells. Significant differences between these relative to prognosis did not exist. In the case of locally advanced renal cell carcinoma, the DNA histogram does not seem to be superior to conventional prognostic criteria.     

Expression of Fas in renal cell carcinoma

We have investigated whether the Fas-mediated cell death pathway is functional in renal cell carcinoma. The expression of Fas in surgical specimens and cell lines of renal cell carcinoma was examined. Fas expression was positive in six out of 18 tumors measured by flow cytometry and was prominent in advanced tumors. Three out of the six Fas-positive tumors had already metastasized at the time of surgery. A significant correlation was found between the tumor volume and the percentage of Fas-positive cells in a tumor (r = 0.70, P = 0.0007). Fas-positive tumors were larger than Fas-negative tumors [mean tumor volume (ml) +/- SD, Fas(+), 265.6 +/- 136.8; Fas(-), 65.8 +/- 80.9, P = 0.0012]. All human renal carcinoma cell lines tested (ACHN, Caki-1, SMKT-R-2, SMKT-R-3 and SMKT-R-4) expressed Fas abundantly, as Fas-positive cells accounted for > 50% in all cell lines by flow cytometry. Treatment with anti-Fas antibody caused apoptosis in Fas-positive renal cell carcinoma cell lines. However, the effectiveness of apoptosis induction in individual cell lines was not correlated with the level of Fas expressed. These data suggest that Fas targeting may be a therapeutic option for treatment of advanced renal cell carcinoma which is refractory to either chemotherapy or irradiation.     

Clinical study of incidentally diagnosed renal adenocarcinoma

OBJECTIVES: To determine the incidence of incidentally detected renal cell carcinoma and compare primary tumor size, clinical stage (TNM) and survival versus renal cell carcinoma with clinical manifestations. PATIENTS AND METHODS: 140 patients diagnosed as having renal cell carcinoma from 1986 to 1994 were retrospectively studied. Of these, 121 had undergone surgery. The statistical analyses were done using the ANOVA test and the Yates-adjusted chi 2 test for a significance value of p < 0.05. RESULTS/CONCLUSIONS: Incidentally detected renal cell carcinoma accounted for 40.7% of the cases. No differences were observed between both groups for age (p = 0.5), sex (p = 0.6), compromised side (p = 0.9), lymph node invasion (p = 0.1), distant metastasis (p = 0.01), multiple unsuspected tumors (p = 0.4) or survival (p = 0.8). The incidentally detected tumors, however, were smaller (p = 0.0002) and more frequently localized to the kidney (p = 0.0003).     

Familial leukoencephalopathy in bipolar disorder

OBJECTIVE: Imaging studies of patients with bipolar disorder demonstrate changes in deep white matter and subcortical gray nuclei that are seen as focal hyperintensities on T2-weighted magnetic resonance imaging (MRI). The objective of this study was to examine MRIs in a family with a strong history of bipolar disorder to look for possible MRI abnormalities in members with and without affective illness. METHOD: The authors obtained MRIs of 21 members of a family with a strong history of bipolar disorder. Eight of the family members studied had bipolar illness, one had symptoms of bipolar disorder but did not meet full DSM-III-R criteria, two had unipolar disorder, and 10 did not have bipolar disorder. RESULTS: Fifteen of the 21 family members had MRI findings, including six of 10 family members who had no affective disorder and all of those with bipolar disorder. Lesions of both white matter and subcortical gray nuclei were found. CONCLUSIONS: Although the clinical significance of these MRI findings is unknown, the high prevalence of MRI findings in both affected and unaffected family members suggests that MRI findings may potentially serve as a biological marker for bipolar disorder. Recent genetic studies have established a link between familial leukoencephalopathy and chromosome 19. If leukoencephalopathy appears to be related to bipolar disorder, it may allow clearer characterization of the genetics of the disorder.     

Absence or reduction of Fhit expression in most clear cell renal carcinomas

The FHIT gene at human chromosome region 3p14.2 straddles the common fragile site, FRA3B, and numerous homozygous deletions in cancer cell lines and primary tumors. Also, the 3p14.2 chromosome breakpoint of the familial clear cell kidney carcinoma-associated translocation, t(3;8)(p14.2;q24), disrupts one FHIT allele between exons 3 and 4, fulfilling one criterion for a familial tumor suppressor gene: that one allele is constitutionally inactivated. Because the FHIT gene sustains biallelic intragenic deletions rather than mutations, there has not been evidence that the FHIT gene frequently plays a role in kidney cancer, although replacement of Fhit expression in a Fhit-negative renal carcinoma cell line suppressed tumor growth in nude mice. We have now assessed 41 clear cell renal carcinomas for expression of Fhit by immunohistochemistry. Normal renal tubule epithelial cells express Fhit uniformly and strongly, whereas 51% of the tumors are completely negative, 34% of tumors show a mixture of positive and negative cells, and 14% are uniformly positive, although usually less strongly positive than the normal epithelial cells. Most interestingly, there was a correlation between complete absence of Fhit and the G1 morphological grade and early clinical stage. Morphological grades G2 and G3 exhibited a mixture of positive and negative cells with a tendency for a higher fraction of negative cells in G3. Fhit inactivation is likely to be an early event in G1 tumors and may be associated with progression in G2 and G3 tumors.     

Rheumatic fever in the Kimberley region of Western Australia

BACKGROUND: Effusions in patients with renal cell carcinoma are rare; the clinicopathologic features of these patients have not been described fully. METHODS: All effusions from patients with renal cell carcinoma obtained between 1986 and 1997 at the study institution were reviewed. RESULTS: Twelve effusions from 9 patients were benign, and 8 effusions from 7 patients were malignant. Patients with sarcomatoid tumors presented early with benign effusions, and patients with papillary tumors presented later with malignant effusions. Patients with clear cell tumors were intermediate. The majority of patients who developed malignant effusions had tumors that were classified as T3 or higher (according to the American Joint Committee on Cancer) at the time of resection. Tumor cells had abundant clear to vacuolated cytoplasm, large nuclei, and prominent nucleoli. Cells from clear cell and papillary tumors could not be distinguished in effusion specimens unless papillae were present. At last follow-up 13 of 15 patients were dead of disease within 2 years of the onset of effusion (median 24 weeks; range, 1-93 weeks), including 7 of 9 patients with benign effusions. CONCLUSIONS: Malignant effusions due to renal cell carcinoma most commonly occur in patients with papillary and clear cell tumors. Malignant effusions from these two tumor types are difficult to distinguish unless papillae are present. Effusions associated with renal cell carcinoma confer a poor prognosis.     

Insulin and insulin-like growth factor I stimulate the proliferation of human ovarian theca-interstitial cells

PURPOSE: We analyzed familial renal oncocytoma to provide a foundation for studies aimed at defining genes involved in the pathogenesis of renal oncocytoma. MATERIALS AND METHODS: We describe 5 families with multiple members affected with renal oncocytoma. Tumors were analyzed pathologically, and affected and nonaffected members were screened clinically and genetically. RESULTS: We identified 12 affected male and 3 affected female (ratio 4:1) individuals in the 5 families. In affected family members renal oncocytomas were often multiple and bilateral. No metastatic disease was observed. Most renal oncocytomas were detected incidentally in asymptomatic individuals or during screening of asymptomatic members of renal oncocytoma families. One identical twin pair was affected with bilateral multiple renal oncocytomas. CONCLUSIONS: Renal oncocytoma may be inherited in some families.     

Analysis of histological heterogeneity in renal cell carcinoma: tumor size-related histological change and its prognostic significance

BACKGROUND: It is well recognized that the histology of renal cell carcinoma (RCC) is often heterogeneous. It is also believed that the prognosis of patients with large tumors is generally poorer than those with small tumors. However, there has been no detailed study on changes in histological features of RCCs associated with tumor growth. This study was conducted to investigate whether there are any specific histological changes related to tumor size and to study the prognostic value of histological parameters in RCCs. METHODS: The presence or absence of each histological component (3 cell types and 5 histological architectures) was investigated in 110 RCCs. The tumor size-associated changes in the histological composition of the RCCs were evaluated, and the prognostic significance of the histological parameters was analyzed using univariate and multivariate analysis. RESULTS: The percentage of RCCs with multiple cell types increased with tumor size, whereas increases in multiplicity were not as prominent in the histological architectures. Several characteristic changes, however, were observed in both cell types and architectures. RCCs with a pure clear cell, pure alveolar pattern or cystic architectural pattern decreased, while those with granular or spindle/pleomorphic cell types, or papillary or solid architectural patterns increased with tumor size. A univariate analysis revealed that a clear cell type and an alveolar or cystic architectural pattern were associated with a better prognosis, while spindle/pleomorphic cells and a solid architecture pattern correlated with a poorer prognosis. Multivariate analysis of cell types and architectures showed, however, that only the presence of spindle/pleomorphic cell types and a solid architecture were independent prognostic variables. CONCLUSION: The histological composition of RCCs varied according to the size of the tumor. Sarcomatous components increased with tumor size and were independently associated with a poor prognosis. Further study is warranted to correlate specific genetic alterations with tumor growth-related histological changes in RCCs.     

Sarcomatoid renal carcinoma

OBJECTIVE: Sarcomatoid carcinoma of the kidney is a unique, uncommon variety of parenchymatous tumors and is considered to have a worse prognosis by stage than the other histological types. Our experience is reviewed and compared with the larger series reported in the literature. METHODS: Of 101 cases of renal carcinoma submitted to surgery at our department from January, 1990 to December, 1996, there were 4 cases of sarcomatoid carcinoma of the kidney. We compared our cases with the larger series (91 cases in total) reported in the literature for incidence, age, distribution according to sex, tumor size, location, form of presentation, stage and survival. RESULTS: Sarcomatoid renal carcinoma accounts for 1% to 6% of parenchymatous tumors of the kidney according to the different series. The mean age at presentation was 48 years (range 27-61) in our series; there was no prevalence according to sex or location; the renal capsule was not compromised in 3 out of the 4 cases; only one case showed regional lymph node involvement and no case showed distant metastasis at the time of diagnosis. Although these tumors are diagnosed in the advanced stages, two of our cases were incidentally discovered in the early stages (one died 13 months thereafter and the other is alive at 42 months). Patients that are alive and disease-free can only be found in the patient group with stage I or II tumor. All patients with tumor stage III and IV have died. This histological type has a worse prognosis. Most of the series report a mean survival of 5 months. CONCLUSIONS: Sarcomatoid renal carcinoma accounts for 1%-6% of all renal carcinomas. It can present at any age and has a very poor prognosis, with a mean survival of 6 months.     

Molecular pathogenesis and prognostic factors in testicular tumor

Aim of this review article was to critically analyse the recently described zytogenetic and molecular markers for testicular germ cell tumors with regard to their clinical utility. The isochromosome i(12p) represents the most common and characteristic cytogenetic finding which already appears in testicular carcinoma in situ. A number of proto-oncogenes (Cyclin D and PTHLH) as well as putative tumor suppressor genes are localized on 12p; however, their role in pathogenesis and prognosis of testicular germ cell tumors has not been defined yet. Clinical characteristics of patients with familial testicular germ cell tumors indicate a genetic background for the development of testicular tumors. Although a number of chromsomal loci encoding potential testicular tumor susceptibility genes have been identified, the genetic basis of testicular cancer pathogenesis is still unknown. With regard to molecular prognostic risk factors most of the reported data on proliferation markers, tumor suppressor genes, proteases and adhesion molecules have to be confirmed in prospective randomized trials prior to their widespread clinical use. Based on the available data on prospective studies percentage of embryonal carcinoma and vascular invasion appear to be the most significant prognosticators. Investigation and identification of those factors determining the aggressive biologic behavior of embryonal carcinoma compared to all other histological components appear to be most promising in research for prognosticators of metastatic disease. In conclusion, the increasing knowledge of molecular genetic events involved in pathogenesis and prognosis of testicular germ cell tumors will not only help to better understand development and progression of testicular cancer, but it also will define new approaches to classification and management of germ cell tumors.     

Progressive central and peripheral demyelinating disease of adult onset in a Norwegian family

OBJECTIVE: To describe the clinical features of a Norwegian family with a combined central and peripheral demyelinating disease. DESIGN: Multiple case report. SUBJECTS AND MATERIALS: Three generations of a Norwegian family. Medical records were available for all 9 members of the second generation and 5 affected members in the third generation. RESULTS: At least 5 members had clinical features, neuroimaging findings, and electrophysiologic signs indicating a chronic progressive disorder affecting both the central and peripheral nervous systems. The clinical symptoms developed between the ages of 30 and 70 years in affected family members, who gradually developed sensory loss, muscle deterioration, and distal weakness in all extremities, unsteady gait, and dysarthria. Five of 9 persons in the second generation had strokes and experienced mental deterioration. The initial stroke episodes were recognized between the ages of 54 and 68 years, and death occurred between the ages of 62 and 75 years. In 7 subjects, cerebrospinal fluid protein levels were increased, and in 5 agar gel electrophoresis indicated blood-brain barrier dysfunction. Seven family members had neuroimaging signs of a widespread white matter disorder. In 4 subjects, neurophysiological investigations indicated a polyneuropathy, and in 3 subjects, results from a sural nerve biopsy showed a demyelinating neuropathy. There was no evidence of co-inheritance with genetic markers of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (19p), PMP22 (17q), APP (21q), CMTX1 (Xq), or PLP (Xq). CONCLUSIONS: Progressive central and peripheral demyelinating disease seems to be a distinct type of hereditary adult-onset demyelinating disorder affecting both the peripheral and central nervous systems. Its exact nature remains unknown.     

Tumor-induced suppression of T lymphocyte proliferation coincides with inhibition of Jak3 expression and IL-2 receptor signaling: role of soluble products from human renal cell carcinomas

The proliferative capacity of T cells infiltrating human tumors is known to be impaired, possibly through their interaction with tumor. Here we demonstrate that soluble products derived from renal cell carcinoma (RCC-S) explants but not normal kidney can inhibit an IL-2-dependent signaling pathway that is critical to T cell proliferation. A major target of the immunosuppression was the IL-2R-associated protein tyrosine kinase, Janus kinase 3 (Jak3). RCC-S suppressed basal expression of Jak3 and its increase following stimulation with anti-CD3/IL-2. Jak3 was most sensitive to suppression by RCC-S; however, reduction in expression of p56(lck), p59(fyn), and ZAP-70 was observed in some experiments. Expression of other signaling elements linked to the IL-2R (Jak1) and the TCR (TCR-zeta, CD3-epsilon, and phospholipase C-gamma) were minimally affected. In naive T cells, RCC-S also partially blocked induction of IL-2R alpha-, beta- and gamma-chain expression when stimulating via the TCR/CD3 complex with anti-CD3 Ab. To determine whether RCC-S suppressed IL-2-dependent signaling, primed T cells were employed since RCC-S had no effect on IL-2R expression but did down-regulate Jak3 expression and, to a lesser degree, p56(lck) and p59(fyn). Reduction in Jak3 correlated with impaired IL-2-dependent proliferation and signal transduction. This included loss of Jak1 kinase tyrosine phosphorylation and no induction of the proto-oncogene, c-Myc. These findings suggest that soluble products from tumors may suppress T cell proliferation through a mechanism that involves down-regulation of Jak3 expression and inhibition of IL-2-dependent signaling pathways.     

Astrocytomas and choroid plexus tumors in two families with identical p53 germline mutations

Germline p53 mutations carry an increased risk of development of breast cancer, soft tissue and osteosarcomas, brain tumors, leukemia and adrenocortical carcinomas. Cerebral neoplasms are usually of astrocytic lineage and occur in 40% of affected families. This report presents clinical, neuropathological and molecular genetic data from 2 families in France with an identical p53 germline mutation in codon 248 (CGG->TGG; Arg->Trp) and a clustering of CNS tumors. The youngest patient in each family developed a malignant choroid plexus tumor while several young adults of both kindred succumbed to low-grade astrocytoma, anaplastic astrocytoma or glioblastoma. The only non-neural neoplasm was an adrenocortical carcinoma in a boy aged 4 years who developed an anaplastic choroid plexus papilloma 2 years later. Of 2 previously reported inherited choroid plexus tumors, 1 occurred in a family which also carried a germline mutation in codon 248. It remains to be shown whether this unusual pattern of CNS tumors is due to an organ-specific effect of this particular p53 mutation or whether it reflects the genetic background of the affected families.