Chromosomal evolution and tumor progression in a myxoid liposarcoma

A myxoid liposarcoma showed macroscopic, histologic, and cytogenetic heterogeneity. In one of three myxoid nodules and in the surrounding lipoma-like tumor tissue, the translocation t(12;16)(q13;p11), known to be specific for myxoid liposarcoma, was found as the sole chromosomal abnormality. In the other two nodules, additional rearrangements involving chromosomes 1, 12, and 16 were found. These aberrations were probably secondary to the primary t(12;16), and are cytogenetic evidence of clonal evolution. The complex chromosome aberrations were present in those tumor parts that had more malignant histology, indicating that the acquisition of secondary chromosomal aberrations parallels the histologic manifestations of tumor progression.     

Complex karyotypic anomalies in a bizarre leiomyoma of the uterus

Cytogenetic investigation of short-term cultures from a bizarre leiomyoma of the uterus, a tumor type not hitherto karyotypically characterized, revealed two abnormal clones with multiple complex rearrangements. Three-fourths of the aberrant cells were hypodiploid with the composite karyotype 38–44, XX,?6,?7,?10,?11,+20,?22, r(1), der(2) (:2p23→cen→2q13::1q21→1qter), der(2)t(2;9)(p21;q13), t(5;?)(q35;?), t(5;?),(q35;?), + der(5)t(5;15)(q11;q15), der(8)t(8;11)(q24;q13), t(15;?)(p12;?), der(16)t(12;16)(q13;p13),+r,+mar. The remaining abnormal mitoses were hypotetraploid, with chromosome numbers ranging from 74 to 86. These massively rearranged cells showed the same markers that were found in the hypodiploid clone, but in duplicate, indicating that this clone had arisen through polyploidization of hypodiploid cells. Flow cytometry revealed a DNA index of 1.03.     

Reduction in alkaline sphingomyelinase in colorectal tumorigenesis is not related to the APC gene mutation

BACKGROUND AND AIMS. The sphingomyelin pathway is an important intracellular mechanism in regulating cell growth. The first step in this pathway is catalysed by sphingomyelinases. Alkaline sphingomyelinase is specifically located in the intestinal tract. Markedly reduced alkaline sphingomyelinase activities have been found in sporadic colorectal tumours and in familial adenomatous polyposis adenomas. Since the adenomatous polyposis coli (APC) gene is mutated in about 80% of sporadic colorectal tumors, and familial adenomatous polyposis is the consequence of a germline mutation of the same gene, we examined whether low alkaline sphingomyelinase activity is linked to APC gene mutations. PATIENTS AND METHODS. Both germline and sporadic adenomatous polyposis coli gene mutations were studied. Alkaline, neutral, and acid sphingomyelinase activities were measured in the intestinal mucosa and content of multiple intestinal neoplasia mice, a murine model of familial adenomatous polyposis and compared to control mice. Alkaline sphingomyelinase activity was also measured in 11 human rectal tumors with APC gene mutation and compared with 9 control tumors without mutation. RESULTS. Alkaline, neutral, and acid sphingomyelinase activities were present in the small intestine and colon in both mice types with no differences in hydrolytic capacity or distribution pattern. In sporadic rectal tumors similar alkaline sphingomyelinase activities were identified in tumors with somatic APC gene mutations as in samples without mutations. In the tumors without detectable APC mutations beta-catenin was analyzed, but no mutation was detected. CONCLUSION. Alkaline sphingomyelinase is not directly linked to adenomatous polyposis coli gene mutations.     

Experiences from treatment-predictive KRAS testing; high mutation frequency in rectal cancers from females and concurrent mutations in the same tumor

Background  

KRAS mutations represent key alterations in colorectal cancer development and lead to constitutive EGFR signaling. Since EGFR inhibition represents a therapeutic strategy in advanced colorectal cancer, KRAS mutation analysis has quickly been introduced as a treatment-predictive test.     

High frequency of microsatellite instability and loss of mismatch-repair protein expression in patients with double primary tumors of the endometrium and colorectum

BACKGROUND: Patients with the familial syndrome hereditary nonpolyposis colorectal carcinoma (HNPCC) exhibit an increased risk for several tumor types, of which the greatest lifetime risk is for colorectal and endometrial carcinoma. HNPCC is caused by a germline mutation in one of several identified mismatch repair (MMR) genes and typically presents with microsatellite instability (MSI) and frequent loss of MMR protein expression in the tumor tissue. The objective of this study was to estimate the proportion of double primary tumors of the endometrium and colorectum that displays tumor characteristics suggestive of MMR deficiency. METHODS: The authors used the southern Sweden regional population-based Cancer Registry to identify women who developed double primary tumors of the endometrium and colorectum. Of the 256 women who were diagnosed with carcinoma at both of these sites during the period 1958-1998, 39 women had developed their first tumor before age 50 years. The authors successfully retrieved 67 tumors from 36 of these patients and analyzed them for MSI and immunohistochemical expression of the MMR genes, MLH1, MSH2, and MSH6. RESULTS: The MSI status of the 67 tumors was high MSI in 37 tumors, low MSI in 13 tumors, and microsatellite stable (MSS) in 17 tumors. Immunohistochemical loss of MMR protein expression was correlated with MSI status and was demonstrated in 29 high MSI tumors, in 1 low MSI tumor, and in 1 MSS tumor. A concordant loss of the same MMR protein in both tumors was found in 12 of 27 patients. CONCLUSIONS : The authors demonstrated a high frequency of MSI (75%) in tumors from women with endometrial and colorectal carcinoma who had their first tumor diagnosed before age 50 years and observed concordant immunohistochemical loss of MMR protein expression, suggestive of a possible underlying germline mutation, in 12 of 27 patients (44%). They concluded that double primary malignancies of the colorectum and endometrium at a young age should make the clinician suspect HNPCC.     

Dissecting karyotypic patterns in colorectal tumors: two distinct but overlapping pathways in the adenoma-carcinoma transition

More than 500 colorectal tumors with clonal chromosomal abnormalities have been reported. Although the pattern of aberrations is nonrandom, no specific primary or secondary karyotypic abnormality has been identified. Also, the chronological order in which the aberrations appear during disease progression is not well known. One reason why our understanding of the cytogenetic evolution is unclear is the high degree of karyotypic complexity seen in these tumors. To overcome some of these difficulties we have previously used several statistical methods that allow identification and interpretation of karyotypic pathways as well as establishment of a temporal order of appearance of the imbalances. These methods were applied on 531 colorectal tumor karyotypes. By using a resampling strategy, 1p-, +7, 7q-, and +12p were identified as early events. Two major and two minor cytogenetic pathways were identified by means of principal component analysis. The two major pathways were initiated with 1p- and +7, and the minor pathways were initiated with +12p and 7q-. The +7/+12p tumors were found to be hyperdiploid, whereas those with 1p-/7q- were pseudodiploid. We also show that the adenoma-carcinoma transition in the 1p- pathway is strongly linked to karyoytypic evolution, whereas the +7 pathway is not, and that the cytogenetic pathways are separated at both early and late stages.     

Intratumor versus intertumor heterogeneity in gene expression profiles of soft-tissue sarcomas

Soft-tissue sarcomas (STSs) constitute more than 30 histologic entities. In addition, within each entity, tumors are often heterogeneous in macroscopic features, genetic alterations, microscopic appearance, and clinical course. Therefore, there has been concern about whether a single tumor sample can provide a gene expression profile representative of the entire tumor. We used 27-k cDNA microarray slides to assess the importance of intratumor versus intertumor heterogeneity of the gene expression profiles of 2 morphologically heterogeneous STSs. Multiple pieces of tumor (8 and 10 pieces) were obtained from a myxoid variant of malignant fibrous histiocytoma (MFH) and a leiomyosarcoma (LMS), respectively, and the expression patterns were compared with single tumor samples from 20 MFHs and 16 LMSs. Hierarchical clustering analysis of the expression profiles showed that samples from the same tumor clustered together. The average intratumor distance was considerably shorter than the average intertumor distance in both LMS and MFH. In addition, tumor subclusters that distinguished different macroscopic parts of the tumor could be discerned. We concluded that intratumor variability exists but that accurate gene expression profiling also could be obtained using single samples from a large STS.     

Changing clinical presentation of angiosarcomas after breast cancer: from late tumors in edematous arms to earlier tumors on the thoracic wall

Angiosarcoma is a rare complication of breast cancer treatment. In order to define predictors, clinical presentation, and outcome, we characterized a population-based 50-year cohort of angiosarcomas after breast cancer. Clinical data were collected from all females with previous breast cancer who developed angiosarcomas/lymphangiosarcomas on the thoracic wall/upper extremity between 1958 and 2008 in the Southern Swedish health care region. In total, 31 angiosarcomas developed at a median age of 71 years. The patients formed two distinct groups; 14 females treated for breast cancer with radical mastectomy and radiotherapy 1949–1988 developed angiosarcomas in edematous arms (Stewart–Treves syndrome) after median 11 years, and 17 females treated by segmental resection, anti-hormonal treatment and radiotherapy 1980–2005 developed angiosarcomas in the irradiated field on the thoracic wall after median 7.3 years. The clinical presentations were heterogeneous and included hematoma-like lesions, multiple bluish-reddish nodules, and asymptomatic lumps. The overall 5-year survival was 16%. In this population-based cohort, the early angiosarcomas developed in edematous arms after radical mastectomies, whereas more recent cases occurred after a shorter time period in the irradiated fields following breast conserving surgery. We conclude that the clinical presentation of angiosarcomas has changed, parallel with altered treatment principles for breast cancer.