Risk of cancer among patients with cutaneous basal cell carcinoma

A population-based cohort of 37,674 patients diagnosed during the period 1978-1991 and registered in the Danish Cancer Registry with basal cell carcinoma of the skin (BCC) were followed for the occurrence of new malignancies. BCC patients experienced significantly increased cancer incidence rates compared with the general Danish population. The elevated cancer risk was not restricted to new cutaneous malignancies. Cancers at various sites, including lip, salivary glands, larynx, lung, breast, kidney and non-Hodgkin lymphoma occurred in significant excess. Patients diagnosed with BCC before the age of 60 years were at higher risk of developing new malignancies than patients diagnosed with BCC at an older age. This age association pertained particularly to breast cancer, testicular cancer and non-Hodgkin lymphoma.     

AIDS-related malignancies

In the US over one million persons are currently infected with the HIV, over half a million have had AIDS, and over 300,000 have died from AIDS. Worldwide, it is estimated that more than 17 million people are currently infected with HIV, and over 1,200,000 cases of AIDS have been reported to the World Health Organization. By some estimates, up to 40% of patients with AIDS will ultimately develop some form of cancer. Non-Hodgkin's lymphoma, Kaposi's sarcoma and invasive cervical cancer have a higher incidence in persons with HIV infection and all three are AIDS-defining illnesses. In addition, several reports suggest that a number of other malignancies may occur at an increased incidence in persons with HIV infection, including squamous-cell carcinoma of the head, neck and anus, plasmacytoma, melanoma, small-cell lung cancer, basal-cell cancer, and germ-cell tumours. Clinicians should become familiar with HIV-related malignancies as their incidence is expected to further increase as more effective therapies for HIV and associated opportunistic infections allow patients to live longer in an advanced state of immunodeficiency. In the current article, we will review the clinical and therapeutic aspects of the most common AIDS-related malignancies including non-Hodgkin's and Hodgkin's lymphomas, Kaposi's sarcoma and anogenital epithelial neoplasias.     

Cytogenetic analysis of 52 colorectal carcinomas--non-random aberration pattern and correlation with pathologic parameters

Cytogenetic analysis of short-term cultures from 52 colorectal carcinomas revealed a normal karyotype in 13 and clonal chromosome aberrations in 39 tumors. In the abnormal group, 13 tumors had simple numerical changes only, whereas 26 had at least one structural rearrangement with or without concomitant numerical changes. The most common numerical abnormalities were, in order of decreasing frequency, +7, -18, -Y, +8, +13 and -14. The most common structural rearrangements affected, again in order of decreasing frequency, chromosomes 8, 1, 6, 7, 17, 3, 11, 13, 14, 16, 2 and 10. The chromosome bands most frequently involved in the structural changes were 8q10, 17p11, 11q13, 8p11, 6q21, 7p15, 7q36, 12q13, 13q10, and 16q13. The most frequent genomic imbalances brought about by the structural rearrangements were losses from chromosome arms 8p, 1p, 6q, 17p, 7p, and 16q, as well as gains of 7q, 8q, 13q, and 11q. A statistically significant (p < 0.05) correlation between the karyotypic pattern and tumor grade was found, with the poorly differentiated carcinomas generally having more massive chromosomal abnormalities.     

Importance of sliding screw position in trochanteric fracture. 4 cases of secondary cervical fracture

Random chromosome abnormality is an important issue in clinical cytogenetics, especially in cancer cytogenetics. The significance of random abnormalities needs to be well defined. In the present study, ten patients with malignant hematologic disorders were analyzed by classical cytogenetic techniques and fluorescence in situ hybridization (FISH) procedures. Cytogenetic studies showed all ten patients to have a single cell with trisomy, i.e., +8, +8 (5 cases), +12, +15, +18, +20, and +21, respectively. FISH necessitated revision of the cytogenetic diagnosis and confirmed the clonality of these "random" abnormalities.     

Chromosome studies in "preleukemia". III. Myelofibrosis

Cytogenetic studies were done on 18 patients with myelofibrosis or the closely related syndrome, undifferentiated myeloproliferative disorder (MPD). Clones of cells with chromosome abnormalities were demonstrated in the blood of eight individuals, including two with a history of radiation therapy and two with "acute myelofibrosis". Trisomy 8 was present in the latter two patients, but otherwise, there was no consistent cytogenetic pattern or correlation with specific hematologic findings. Sixteen of these patients have been followed for more than 1 year or until death; none has progressed to leukemia. The results indicate that chromosome abnormalities are relatively common in this disorder, but as with polycythemia vera, and unlike some other "preleukemic" states, the aberrant clones in myelofibrosis do not appear to indicate that clinical leukemia is imminent.     

Fluorescence in situ hybridization analyses of hematologic malignancies reveal frequent cytogenetically unrecognized 12p rearrangements

Thirty-two hematologic malignancies--nine with cytogenetically identified 12p abnormalities and 23 with whole or partial losses of chromosome 12--were selected for fluorescence in situ hybridization (FISH) investigations of 12p. These analyses revealed structural 12p changes, such as translocations, deletions, insertions, inversions and amplification, in 20 cases. ETV6 rearrangements were detected in three acute leukemias. One acute undifferentiated leukemia had t(4;12)(q12;p13) as the sole anomaly. The second case, an acute myeloid leukemia (AML), displayed complex abnormalities involving, among others, chromosomes 9 and 12. The third case, also an AML, had an insertion of the distal part of ETV6 into chromosome arm 11q and into multiple ring chromosomes, which also contained chromosome 11 material, resulting in an amplification of a possible fusion gene. The fusion partners in these cases remain to be identified. Thirty-one additional breakpoints on 12p could be characterized in detail. The majority of these breaks were shown to result in interchromosomal rearrangements, possibly indicating the location of hitherto unrecognized genes of importance in the pathogenesis of hematologic malignancies. The FISH analyses disclosed terminal or interstitial 12p deletions in 18 cases. Seven myeloid malignancies showed deletions restricted to a region, including ETV6 and CDKN1B, which has been reported to be frequently lost in leukemias. In four cases, the deletions involved both these genes, whereas two AML displayed loss of CDKN1B but not ETV6, supporting previously reported findings indicating a region of deletion not including this gene. However, one myelodysplastic syndrome lacked one copy of ETV6 but not CDKN1B. Hence, we suggest a minimal region of deletion on 12p located between the ETV6 and CDKN1B genes.     

Loss of heterozygosity on the long arm of human chromosome 7 in sporadic renal cell carcinomas

Cytogenetic and molecular analysis of DNA sequences with highly polymorphic microsatellite markers have implicated allele loss in several chromosomal regions including 3p, 6p, 6q, 8p, 9p, 9q, 11p and 14q in the pathogenesis of sporadic renal cell carcinomas (RCCs). Deletions involving the long arm of chromosome 7 have not been described in RCCs although they have been seen in several other tumor types. However, there have been no detailed analysis of loss of heterozygosity (LOH) of 7q sequences in sporadic RCCs. We therefore studied LOH for DNA sequences on 7q with 10 highly polymorphic markers in 92 matched normal/tumor samples representing sporadic RCCs including papillary, nonpapillary, and oncocytomas in order to determine whether allelic loss could be detected in a tumor type with no visible 7q rearrangements at the cytogenetic level. We found chromosome 7q allele loss in 59 of 92 cases (64%) involving one, two, or more microsatellite markers. The most common allele loss included loci D7S522 (24%) and D7S649 (30%) at 7q31.1-31.2, a region that contains one of the common fragile sites, FRA7G. By comparative multiplex PCR analysis, we detected a homozygous deletion of one marker in the 7q 31.1-31.2 region in one tumor, RC21. These results support the idea that a tumor suppressor gene in 7q31 is involved in the pathogenesis of sporadic renal cell carcinomas.     

Mechanisms explaining the onset, course and spontaneous resolution of gouty arthritis

Cytogenetic analysis of short-term cultures from three untreated and one recurrent ependymoma revealed clonal aberrations in three of the four tumors. A posterior fossa ependymoma from a 3-year-old male patient showed trisomy 11 as the sole clonal chromosome aberration. A recurrent spinal ependymoma from a 35-year-old male showed hypertriploid clones with abnormalities involving chromosomes 1p11,7q21, and 10p13. A 62-year-old male patient with a cerebellar ependymoma showed a hypodiploid stem-cell line with clonal structural aberrations of both the long and short arms of chromosome 1, an interstitial deletion of 2q, trisomy 7, and monosomy for chromosomes 11, 13, and 16. A 3-year-old female patient with posterior fossa ependymoma showed a normal 46,XX karyotype. Chromosome 1 aberrations appear to be the most consistent finding in this small series of tumors, with the net loss or rearrangement of chromosome 1 pter-->p22 material from two of the four tumors. These findings, in addition to a previously published case [1], suggest a possible role for genes on the short arm of chromosome 1 in the cytogenetic evaluation of ependymomas.     

Decreased levels of soluble amyloid beta-protein precursor are associated with Alzheimer''s disease in concordant and discordant monozygous twin pairs

Cytogenetic analysis of four specimens (biopsy, definitive surgical, and two separately occurring lung metastases) of a dedifferentiated chondrosarcoma with a rhabdomyosarcomatous component revealed clonal karyotypic abnormalities in each. Anomalies seen in all specimens included a structurally aberrant chromosome 17 and extra copies of chromosomes 5, 7, 12, and 20. The derivation of the chromosomally abnormal cells was determined by a combined immunocytochemical/cytogenetic approach that allowed simultaneous assessment of cytogenetic aberrations and immunophenotypic features of individual cells. S-100 protein and desmin antibodies were used to evaluate the chondrosarcomatous and rhabdomyosarcomatous components, respectively. A chromosome 7-specific centromeric probe was used for determination of aneuploidy. In both specimens obtained from the primary lesion, S-100 protein and desmin-positive and -negative aneuploid cells were observed. These findings: 1) suggest that both the chondrocytic and rhabdomyoblastic cells arose from the same abnormal clone, 2) support the theory of a common primitive mesenchymal cell progenitor with the ability to differentiate or express features of more than one line of mesenchymal differentiation, and 3) indicate that the term dedifferentiated may be an inaccurate designation for this neoplasm.     

Multistep carcinogenesis of breast cancer and tumour heterogeneity

Breast cancer emerges by a multistep process which can be broadly equated to transformation of normal cells via the steps of hyperplasia, premalignant change and in situ carcinoma. The elucidation of molecular interdependencies, which lead to development of primary breast cancer, its progression, and its formation of metastases is the main focus for new strategies targetted at prevention and treatment. Cytogenetic and molecular genetic analysis of breast cancer samples demonstrates that tumour development involves the accumulation of various genetic alterations including amplification of oncogenes and mutation or loss of tumour suppressor genes. Amplification of certain oncogenes with concomitant overexpression of the oncoprotein seems to be specific for certain histological types. Loss of normal tumour suppressor protein function can occur through sequential gene mutation events (somatic alteration) or through a single mutational event of a remaining normal copy, when a germline mutation is present. The second event is usually chromosome loss, mitotic recombination, or partial chromosome deletion. Chromosome loci 16q and 17p harbour tumour suppressor genes, which seem to be pathognomonic for the development or progression of a specific histological subtype. There are an overwhelming number of abnormalities that have been identified at the molecular level which fit the model of multistep carcinogenesis of breast cancer. When the functions of all of these genes are known and how they participate in malignant progression, we will have the tools for a more rational approach to diagnosis, prevention and treatment. This review deals only with the factors that are involved in the conversion of a normal breast cell into a malignant cell rather than those required for invasion and metastases. A key critical long-term step in the molecular analysis of breast cancer will be to link the specific molecular damage with the effects of environmental carcinogens.     

Cytogenetical findings of recurrent meningiomas. A study of 10 tumors

Cytogenetic analyses of 10 cases of recurrent meningiomas growing in culture between 1-10 days are reported, of which seven showed benign morphology, one atypical, and two, malignant features. Normal karyotypes with nonclonal alterations were found in three cases, one case with only monosomy 22, and complex karyotypes in the remaining six. Four cases were hypodiploid, one pseudodiploid, and one hyperdiploid. The chromosomes most often involved in structural rearrangements were 1, 7, and 14 and the losses were chromosomes 7, 10, 14, 15, 18, and 22. Ring chromosome, dicentrics, double minutes, and association between satellites were found in one case. These complex karyotypes with hypodiploidy, structural rearrangements, and other markers in recurrent meningiomas may indicate aggressive tumor characteristics.     

A chromosome 14q11/TCR alpha/delta specific yeast artificial chromosome improves the detection rate and characterization of chromosome abnormalities in T-lymphoproliferative disorders

The rate of detection of chromosome abnormalities in T-cell proliferations is lower than that observed in B-cell malignancies. The former frequently involve the TCR alpha/delta locus at chromosome band 14q11. We have identified a YAC encompassing 70% of the TCR alpha/delta locus, which has been used as a fluorescence in situ hybridization probe to detect chromosome rearrangements involving 14q11, both at metaphase and within interphase nuclei, in patients with a variety of T-lymphoproliferative disorders. Its use allowed detection of previously unsuspected TCR alpha/delta rearrangements in 4/13 (30%) immature T-lineage acute leukemias, including two t(10;14) and 2 minor inversion 14s. It also clarified interpretation of complex chromosome 14 abnormalities in mature T-cell proliferations (T-prolymphocytic leukemia and ataxia telangiectasia). Use of this probe will aid the detection and characterization of abnormalities involving the TCR alpha/delta locus, particularly in cases with normal or complex karyotypes and in those proliferations for which mitoses are difficult to obtain.     

In B-cell chronic lymphocytic leukaemia chromosome 17 abnormalities and not trisomy 12 are the single most important cytogenetic abnormalities for the prognosis: a cytogenetic and immunophenotypic study of 480 unselected newly diagnosed patients

Of 560 consecutive, newly diagnosed untreated patients with B CLL submitted for chromosome study, G-banded karyotypes could be obtained in 480 cases (86%). Of these, 345 (72%) had normal karyotypes and 135 (28%) had clonal chromosome abnormalities: trisomy 12 (+12) was found in 40 cases, 20 as +12 alone (+12single), 20 as +12 with additional abnormalities (+12complex). Other frequent findings included abnormalities of 14q, chromosome 17, 13q and 6q. The immunophenotype was typical for CLL in 358 patients (CD5+, Slg(weak), mainly FMC7-) and atypical for CLL in 122 patients (25%) (CD5-, or Slg(strong) or FMC7+). Chromosome abnormalities were found significantly more often in patients with atypical (48%) than in patients with typical CLL phenotype (22%) (P < 0.00005). Also +12complex, 14q+, del6q, and abnormalities of chromosome 17 were significantly more frequent in patients with atypical CLL phenotype, whereas +12single was found equally often in patients with typical and atypical CLL phenotype. The cytomorphology of most of the +12 patients was that of classical CLL irrespective of phenotype. In univariate survival analysis the following cytogenetic findings were significantly correlated to a poor prognosis: chromosome 17 abnormalities, 14q+, an abnormal karyotype, +12complex, more than one cytogenetic event, and the relative number of abnormal mitoses. In multivariate survival analysis chromosome 17 abnormalities were the only cytogenetic findings with independent prognostic value irrespective of immunophenotype. We conclude that in patients with typical CLL immunophenotype, chromosome abnormalities are somewhat less frequent at the time of diagnosis than hitherto believed. +12single is compatible with classical CLL, and has no prognostic influence whereas chromosome 17 abnormalities signify a poor prognosis. In patients with an atypical CLL immunophenotype, chromosome abnormalities including +12complex, 14q+, del 6q and chromosome 17 are found in about 50% of the patients, and in particular chromosome 17 abnormalities suggest a poor prognosis.     

Diode laser cyclophotocoagulation: histopathology in two cases of clinical failure

We report an unusual case of a 55 year old Japanese woman with a seminoma but relatively normal menses. The patient was a phenotypic female with late onset menarche (18 years of age), who was amenorrhoeic for the first year, followed by menses of one to three days' slight flow with dysmenorrhoea, but an otherwise normal menstrual history. A typical seminoma was removed from the left adnexal region and an immature testis was identified separately as an associated right adnexal mass. Repeated karyotypic studies on peripheral blood lymphocyte cultures showed only 46,X,-Y,t(Y;15)(q12;p13). Cytogenetic examination of the patient's younger brother, who had fathered three healthy children, showed an identical karyotype. Mosaicism of 46,X,-Y,t(Y;15)(q12;p13)/45,X cell lines was found in skin samples from the patient's elbow and genital regions, although there were no clinical stigmata of Turner syndrome. An androgen receptor binding assay of cultured genital skin fibroblasts was negative. Molecular analysis using Southern blot hybridisation, PCR, and direct DNA sequencing showed that neither the patient nor her brother had a detectable deletion or other abnormalities of Y chromosome sequences, including the SRY (sex determining region of the Y chromosome) gene sequence. These findings suggest that Turner mosaicism of the 45,X cell line may have contributed to this atypical presentation in an XY female, although we cannot exclude abnormalities of other genes related to sex differentiation.     

Experiments on second intermediate fish host related cercarial transmission of the eyefluke Diplostomum spathaceum into rainbow trout (Oncorhynchus mykiss)

Cytogenetic analysis of short-term cultures from 15 cases of benign proliferative breast disease (PBD), 10 diffuse PBD and 5 papillomas, and 15 fibroadenomas of the breast revealed clonal chromosome abnormalities in 7 diffuse PBD lesions, 4 papillomas and 5 fibroadenomas. The remaining 14 cases had a normal female chromosome complement. Cytogenetically unrelated abnormal clones were seen in 4 fibroadenomas and 2 PBDs. A single abnormal clone was found in 9 PBDs and 1 fibroadenoma. Three clonal abnormalities were seen as recurrent changes in 6 cases, namely interstitial deletions of 3p with 3p 12-14 as the minimally common deleted segment (in 1 papilloma, 1 diffuse PBD with atypia and 1 mixed-pattern lesion with both papilloma and atypical diffuse PBD features), r(9)(p24q34) (in 1 diffuse PBD and 1 fibroadenoma), and del(1)(q12)(again in 1 diffuse PBD and 1 fibroadenoma). Intriguingly, 6 of the 16 abnormal cases had chromosome changes that have been seen repeatedly as primary abnormalities in breast carcinomas: der(16)t(1;16)(q10;p10), del(3)(p12p14), and del(1)(q12). We conclude that some of the chromosome anomalies frequently found in breast carcinomas are also present in PBD and fibroadenomas. These aberrations may be accepted as early, neoplasia-relevant mutations. However, they do not seem to be sufficient by themselves to unleash a malignant process.     

Human PEG1/MEST, an imprinted gene on chromosome 7

The mouse Peg1/Mest gene is an imprinted gene that is expressed particularly in mesodermal tissues in early embryonic stages. It was the most abundant imprinted gene among eight paternally expressed genes (Peg 1-8) isolated by a subtraction-hybridization method from a mouse embryonal cDNA library. It has been mapped to proximal mouse chromosome 6, maternal duplication of which causes early embryonic lethality. The human chromosomal region that shares syntenic homology with this is 7q21-qter, and human maternal uniparental disomy 7 (UPD 7) causes apparent growth deficiency and slight morphological abnormalities. Therefore, at least one paternally expressed imprinted gene seems to be present in this region. In this report, we demonstrate that human PEG1/MEST is an imprinted gene expressed from a paternal allele and located on chromosome 7q31-34, near D7S649. It is the first imprinted gene mapped to human chromosome 7 and a candidate for a gene responsible for primordial growth retardation including Silver-Russell syndrome (SRS).     

Identification of a consistent region of allelic loss on 1p32 in meningiomas: correlation with increased morbidity

Meningioma is a common tumor of the central nervous system. Deletions of the short arm of chromosome 1 (1p) are the second most commonly observed chromosomal abnormality in these tumors. Here, we analyzed tumor and normal DNAs from 157 meningioma patients using PCR-based polymorphic loci. Loss of heterozygosity (LOH) for at least one informative marker on 1p was observed in 54 cases (34%), whereas LOH on 1q occurred in only 9 cases (8%). High-resolution deletion mapping defined a consensus region of deletion flanked distally by D1S2713 and proximally by D1S2134, which spans 1.5 cM within 1p32. LOH in this region has also been observed in several other malignancies, suggesting the presence of a tumor suppressor gene or genes that are important for several types of cancer. Statistical analysis revealed that 1p LOH was associated with chromosome 22 deletions and with abnormalities of the NF2 gene in meningioma. In addition, unlike other clinical and molecular characteristics, only 1p LOH was shown to be significantly associated with recurrence-free survival.     

The cytogenetic disorders in the people who took part in the cleanup of the sequelae at the Chernobyl Atomic Electric Power Station and who lived continuously in areas with an unfavorable ecological situation

Cytogenetic disturbances are manifested now in persons who liquidated aftereffects of the Chernobyl disaster. The character and course of the disturbances depend on the ecological conditions of the region where liquidators live at present. Examination of a group of liquidators with nerve-psychopathologic disorders and accompanying somatic pathology has revealed the presence of cytogenetic disturbances, mainly of the chromosome aberration type. At the same time, in persons who live under conditions of high environment pollution with ejections of industrial enterprises, the number of chromatid aberrations increases, which may be a result of action of chemical mutagens. A tight correlation is revealed between the level of cytogenetic disorders in lymphocytes and expressivity of the secondary immunodeficiency. Elimination of lymphocytes with unstable chromosome aberration is delayed when ecological pollution of the biosphere reaches the high level.     

B-cell acute lymphoblastic leukemia with L1 morphology and coexistence of t(1;19) and t(14;18) chromosome translocations

We report a case of adult de novo acute lymphoblastic leukemia (ALL) with unique cytogenetic abnormalities and discrepant morphologic and immunologic features. Morphology was L1 by the French-American-British classification, but flow cytometry was consistent with a mature B-cell phenotype. Cytogenetic analysis showed numerous chromosome abnormalities nonspecific for lymphoid neoplasm except for t(1;19) and t(14;18). The former is characteristic of pre-B-ALL and the latter is characteristic of follicular lymphoma. This is the first report of these two translocations occurring concurrently in ALL.