Cytogenetic analysis of short-term cultures from seven pulmonary hamartomas revealed an abnormal ... more Cytogenetic analysis of short-term cultures from seven pulmonary hamartomas revealed an abnormal karyotype in six of them. The most characteristic aberration was an exchange of material between 6p21 and 14q24, found in three tumours. Abnormalities of either 6p or 14q were seen in another two hamartomas. Other regions that were rearranged more than once were 12q (three times) and 17p (twice), sometimes in exchange with 6p or 14q and giving rise to complex derivative chromosomes. Only one tumour had aberrations that did not involve 6p, 12q, 14q, or 17p. These resultstogether with the data on three previously reported pulmonary hamartomas, two of which also had t(6;14)-show that recombinations between 6p2l and 14q24 are common, and hence probably pathogenetically important. The data support the view that these tumours are genuine neoplasms rather than developmental anomalies. The coexistence of a common 14q24 breakpoint in uterine leiomyomas and pulmonary hamartomas indicates that a gene important in the genesis of both tumours exists in this band. ml-' selenious acid, 5.35 jig ml-' linoleic acid, 1.25 mg ml-' bovine serum albumin, and 6.25 jig ml-' transferrin. After 3 days, the cultures were exposed to Colcemid (0.01 jig ml-') for 6 h and harvested by hypotonic treatment in 0.05 M KCI and repeated fixations in methanol: acetic acid (3:1). The slides from all cases were incubated overnight at 6O°C, treated for 4 h in 2 x SSC at 60°C and then G-banded with Wright's stain. The subsequent chromosome analysis followed the recommendations of the ISCN (1991).
The issue of whether multiple, ipsilateral or bilateral, breast carcinomas represent multiple pri... more The issue of whether multiple, ipsilateral or bilateral, breast carcinomas represent multiple primary tumours or dissemination of a single carcinomatous process has been difficult to resolve, especially for individual patients. We have addressed the problem by comparative genomic hybridisation analysis of 26 tumours from 12 breast cancer patients with multiple ipsilateral and/or bilateral carcinoma lesions. Genomic imbalances were detected in 25 of the 26 (96%) tumours. Using the genomic imbalances detected in these 26 lesions as well as those previously found by us in an independent series of 35 unifocal breast carcinomas, we compared a probabilistic model for likelihood of independence with unsupervised hierarchical clustering methodologies to determine the clonal relatedness of multiple tumours in breast cancer patients. We conclude that CGH analysis of multiple breast carcinomas followed by unsupervised hierarchical clustering of the genomic imbalances is more reliable than previous criteria to determine the tumours' clonal relationship in individual patients, that most ipsilateral breast carcinomas arise through intramammary spreading of a single breast cancer, and that most patients with bilateral breast carcinomas have two different diseases.
S_ry Cytogenetic analysis was performed on short-term cell cultures of two foci (A and B) from ea... more S_ry Cytogenetic analysis was performed on short-term cell cultures of two foci (A and B) from each of three multifocal breast carcinomas. In case I, four clones (three related and one unrelated) were detected in sample A. In sample B, two of the three related clones and the unrelated cone seen in A were found, as was also a third subclone showing a pattern of clonal evolution slightly different from that detected in A. In ca Case H A multifocal tumour was detected in the right breast of a 68-year-old woman. The A focus measured 23 mm in diameter, the B focus 15 mm. The histopathological examination revealed a tubuloductal carcinoma in A and a ductal carcinoma in situ with areas of severe epithelial hyperplasia in B. The two foci were separated by 0.5 cm of grossly normal breast tissue. There were no lymph node or distant metastases.
Short-term cultures from 20 pancreatic tumours, three endocrine and 17 exocrine, were cytogenetic... more Short-term cultures from 20 pancreatic tumours, three endocrine and 17 exocrine, were cytogenetically analysed. All three endocrine tumours had a normal chromosome complement. Clonal chromosome aberrations were detected in 13 of the 17 exocrine tumours: simple karyotypic changes were found in five carcinomas and numerous numerical and/or structural changes in eight. When the present findings and those previously reported by our group were viewed in conjunction, the most common numerical imbalances among the 22 karyotypically abnormal pancreatic carcinomas thus available for evaluation turned out to be, in order of falling frequency,-18,-Y, + 20, + 7, + 11 and-12. Imbalances brought about by structural changes most frequently affected chromosomes I (losses in lp but especially gains of lq), 8 (in particular 8q gains but also 8p losses), and 17 (mostly 17q gain but also loss of 17p). Chromosomal bands lp32, 1q1O, 6q21, 7p22, 8p2l, 8ql 1, 14pl 1, l5q10-1 1, and 17qll were the most common breakpoint sites affected by the structural rearrangements. Abnormal karyotypes were detected more frequently in poorly differentiated and anaplastic carcinomas than in moderately and well differentiated tumours.
Thirty tumorous lesions from seven patients with colorectal cancer were short-term cultured and c... more Thirty tumorous lesions from seven patients with colorectal cancer were short-term cultured and cytogenetically analysed: 16 nonadenomatous polyps, six adenomas, seven carcinomas, including one in polyp, and one lymph node metastasis. Clonal chromosome aberrations were found in 20 samples in 100% of the carcinomas, in 100% of the adenomas and in 37.5% of the non-adenomatous polyps, i.e. all ten lesions with a normal karyotype were histologically diagnosed as hyperplastic polyps. Although adenomas and carcinomas shared several karyotypic features, two chromosome aberrations, der(8;17)(q10;q10) and-14, were found in carcinomas but not in adenomas, indicating that they might be specifically associated with carcinoma development in the large bowel mucosa. The karyotypic similarity seen between the malignant and benign tumours in the same patient, and also sometimes among non-malignant polyps in the same case, indicates that these microscopically distinct lesions may be part of a single neoplastic clonal expansion.
Malignant ovarian germ cell tumors (OGCTs) include immature teratomas (ITs), dysgerminomas (DGs),... more Malignant ovarian germ cell tumors (OGCTs) include immature teratomas (ITs), dysgerminomas (DGs), endodermal sinus tumors (ESTs), choriocarcinomas, and embryonal carcinomas. Knowledge about the genetic changes associated with malignant OGCT development is sparse. We therefore analyzed 25 OGCTs (12 DGs, 4 ESTs, and 9 ITs) for gains and losses by comparative genomic hybridization. In total, more gains than losses were observed, and the number of alterations ranged from 0-20 per tumor. The average number of changes among DGs, ESTs, and ITs was 10, 6, and 1.4, respectively. The most common changes in DGs were gains from chromosome arms 1p (33%), 6p (33%), 12p (67%), 12q (75%), 15q (42%), 20q (50%), 21q (67%), and 22q (58%); gains of the whole of chromosomes 7 (42%), 8 (42%), 17 (42%), and 19 (50%); and losses from 13q (58%). Two of three DGs with a gonadoblastoma component showed gains of 3p21 and loss of 5p, whereas none of the nine pure DGs had these changes, suggesting that they migh...
The reciprocal translocation t(9;16)(q22;p13) was identified in three short-term cultured basal c... more The reciprocal translocation t(9;16)(q22;p13) was identified in three short-term cultured basal cell carcinomas (BCCs). The t(9;16) was the sole anomaly in one clone in two tumors and was accompanied by a second change that also affected the long arm of chromosome 9 in the third. In addition, other cytogenetically unrelated abnormal clones were also found in all three BCCs. The identification of t(9;16)(q22;p13) as a primary chromosomal abnormality in a subset of BCCs (we found it in 3 of 22 tumors) is especially intriguing against the background that the PTCH gene, which when mutated in the germ line presumably gives rise to the autosomal dominant basal cell nevus or Gorlin's syndrome, maps to chromosome band 9q22. None of the genes rearranged in the BCC-specific t(9;16)(q22;p13) translocation have been identified, but we hypothesize that the translocation represents the cytogenetic corollary of a tumorigenic recombination of PTCH with an as yet unknown gene in 16p13. If so, th...
Short-term cultures from 115 squamous cell carcinomas (SCC) of the head and neck were cytogenetic... more Short-term cultures from 115 squamous cell carcinomas (SCC) of the head and neck were cytogenetically investigated. Thirty-six of the tumors have been reported previously, whereas 79 are new cases. The material was divided into two series based on the medium used. The 80 tumors of series I were cultured in RPMI 1640 supplemented with fetal calf serum, glutamine, antibiotics, insulin, cholera toxin, and epidermal growth factor. The 35 tumors of series II were cultured in a chemically defined, serum-free medium with a low calcium concentration, MCDB 153, which stimulates epithelial growth while inhibiting fibroblasts. A total of 83 tumors with clonal karyotypic abnormalities were detected in the two series. Series II had a higher proportion of tumors with complex karyotypic changes than series I (43% versus 15%), a lower proportion of tumors with pseudo- or neardiploid clones characterized by simple rearrangements (3% versus 34%), and a lower frequency of unrelated clones (3% versus 2...
Cytogenetic analysis of short-term cultures from benign intestinal tumors revealed clonal chromos... more Cytogenetic analysis of short-term cultures from benign intestinal tumors revealed clonal chromosome aberrations in five colorectal adenomas, one adenoma of the papilla Vateri, and one hyperplastic polyp of the rectum. One adenoma had numerical aberrations only, but in all other tumors structural rearrangements were found that led to loss of genetic material from 1p. In three of the cases, the deletion was restricted to the 1p36 band; the rest had lost larger 1p segments. The rearrangement of chromosome 1 was the sole karyotypic anomaly in three adenomas, all with mild or moderate dysplasia, and in the hyperplastic polyp. Both adenomas that had additional aberrations beyond the 1p loss showed severe dysplasia. We conclude that cytogenetically detectable loss of genetic information from 1p36 is an early, seemingly primary, premalignant event in intestinal tumorigenesis. The fact that the adenomas with 1p- as the sole change showed only mild or moderate dysplasia and that the del(1p) ...
We report the finding of clonal chromosome abnormalities in short-term cultures from 44 squamous ... more We report the finding of clonal chromosome abnormalities in short-term cultures from 44 squamous cell carcinomas of the head and neck region. Eleven tumors had gain or loss of the Y chromosome, sometimes one clone with +Y and another with -Y, as the sole anomaly, whereas the remaining 33 all carried structural rearrangements and usually were cytogenetically complex with multiple aberrations. The chromosomal bands most frequently involved were, in decreasing order of frequency, 8p11-q11, 1p11-q11, 3p11-q11, 11q13, 13p11-q11, 1p13, 5p11-q11, 7p11-q11, 15p11-q11, and 14p11-q11. Almost one-half of the breakpoints were located in centromeric or juxtacentromeric bands. Recurrent aberrations included i(8q), i(5p), i(1q), del(3)(p11-12), del(5)(p11), t(1;1)(p13;q25), and der(14;15)(q10;q10). To see whether the karyotypic features of head and neck squamous cell carcinoma differ depending on exact tumor site, we added to the present series our previously published 23 karyotypically abnormal h...
In an attempt to quantify the nonrandomness of primary neoplasia-associated acquired chromosomal ... more In an attempt to quantify the nonrandomness of primary neoplasia-associated acquired chromosomal aberrations in humans, we have retrieved information from a computerized data base on the chromosomal abnormalities of 9069 human neoplasms. By restricting the survey to the 1985 cases with a solitary structural rearrangement, we attempted to limit the analysis to only those aberrations that were most likely to represent pathogenetically important, primary changes. The breakpoints of the primary abnormalities thus identified clustered to 71 bands. It furthermore turned out that 27 of the 41 oncogene sites known with reasonable precision (i.e., localized within one or two bands) coincide with bands consistently involved in neoplasia-associated rearrangements. These comparisons add to the evidence that acquired, cancer-associated chromosomal aberrations are nonrandom in distribution, that only a limited number of genomic sites are consistently involved in primary neoplasia-associated aberr...
Cytogenetic analysis of short-term cultures from 33 basal cell carcinomas (BCC), a type of neopla... more Cytogenetic analysis of short-term cultures from 33 basal cell carcinomas (BCC), a type of neoplasm for which no previous karyological data exist, revealed clonal chromosome aberrations, all of them different, in 8 tumors. In 2 cases, 2 cytogenetically unrelated clones were detected, suggesting a multicellular origin in at least a subset of BCC. A remarkably high level of nonclonal structural rearrangements, mostly in the form of seemingly balanced translocations, was found in 23 tumors; namely, in 6 of 8 BCC with clonal karyotypic abnormalities and in 17 of 25 without. It is possible that some of these aberrations represent additional neoplastic clones, thus indicating an even higher level of cytogenetic heterogeneity in BCC. We think that the most likely interpretation of the results is that BCC may have a multicellular origin, reflecting field cancerization of the skin. During subsequent tumor development, the selection pressure narrows down the number of clones that infiltrate t...
DNA ploidy analysis is useful for prognostication in cancer patients, but the genomic details und... more DNA ploidy analysis is useful for prognostication in cancer patients, but the genomic details underlying ploidy changes are not fully understood. To improve this understanding, we compared DNA ploidy status with karyotypic and comparative genomic hybridization data on 51 endometrial adenocarcinomas. Out of 34 DNA diploid tumors evaluated by CGH, 16 (47%) showed imbalances, though only two had more than four copy number changes. Ten (29%) had aberrations involving chromosome 1, seven (21%) involving chromosome 10, while one tumor had a chromosome 8 aberration. Four of the seven DNA tetraploid tumors (57%) had imbalances detected by CGH with two (29%) having more than four. Six out of eight DNA aneuploid tumors showed imbalances by CGH, with five (63%) having more than four. The aberrations were observed on chromosomes 1 and 8 in five/eight (63%) cases while four imbalances (50%) involved chromosomes 5, 7 and X. Not surprisingly, we observed a significant correlation between increasin...
Purpose To investigate the prognostic value of the overall karyotypic features and specific chrom... more Purpose To investigate the prognostic value of the overall karyotypic features and specific chromosome aberrations in colorectal cancer (CRC). Patients and Methods Cytogenetic features of 150 primary CRCs investigated at the time of surgery were correlated with patient survival by univariate and multivariate analyses, using classical clinicopathologic parameters as covariates. Results In univariate analysis, in addition to tumor grade and clinical stage, structural aberrations as well as rearrangements of chromosomes 8 and 16 were significantly correlated with shorter overall survival. Karyotypic complexity, rearrangements of chromosomes 8 and 16, and loss of chromosome 4 were significantly correlated with shorter disease-free survival. In multivariate analysis, in addition to tumor grade, the type of chromosome aberrations (structural or numerical), ploidy, and loss of chromosome 18 came across as independent prognostic factors in the group of all patients. In the subset of patient...
Chromosome banding analysis of solid tumors often yields incomplete karyotypes because of the com... more Chromosome banding analysis of solid tumors often yields incomplete karyotypes because of the complex rearrangements encountered. The addition of fluorescence in situ hybridization (FISH) methods has helped improve the accuracy of solid tumor cytogenetics, but the absence of screening qualities from standard FISH approaches has proved a severe limitation. We describe the cytogenetic analysis of ten solid tumors using G-banding followed by cross-species color banding (RxFISH), a FISHbased screening technique giving a chromosome-specific banding pattern based on the genomic homologies between humans and gibbons. The addition of RxFISH analysis in all cases led to the identification of previously unidentified intra-as well as interchromosomal rearrangements, thus giving a much more certain and detailed karyotype. In two gastric stromal sarcomas, a tumor type for which no cytogenetic data were hitherto available, numerical chromosomal aberrations dominated, but one of the tumors also carried an unbalanced 7;17-translocation with the same breakpoint in chromosome 17 as that seen in endometrial stromal sarcomas.
About 20% of ovarian carcinomas show alterations of 19p13 and/or 19q13 in the form of added extra... more About 20% of ovarian carcinomas show alterations of 19p13 and/or 19q13 in the form of added extra material whose origin often is from chromosome 11. Based on earlier spectral karyotype analysis of the ovarian cancer cell line SKOV-3, which shows an unbalanced translocation der(19)t(11;19), the aim of this study was to determine the precise breakpoints of that derivative chromosome. After rough delimitation of the breakpoints of microdissected derivative chromosomes by array analysis, we designed a matrix of primers spanning 11q13.2 and 19p13.2 detecting multiple amplicons on genomic and cDNA. Sequencing the amplicons, accurate localization of both breakpoints on both chromosomes was possible and we found that exon 14 of HOOK2 from chromosome 19 and exon 2 of ACTN3 from chromosome 11 were fused in the derivative chromosome. The breakpoint in the HOOK2 gene was in an intrinsic triplet of nucleic acids leading to a shift in the ACTN3 reading frame in the derivative chromosome. This frameshift alteration should give rise to an early stop codon causing a loss of function of ACTN3. Signals in two-dimensional Western blotting exactly match to calculated molecular mass and the isoelectric point of the fusion protein. V
Cytogenetic analysis of short-term cultures from seven pulmonary hamartomas revealed an abnormal ... more Cytogenetic analysis of short-term cultures from seven pulmonary hamartomas revealed an abnormal karyotype in six of them. The most characteristic aberration was an exchange of material between 6p21 and 14q24, found in three tumours. Abnormalities of either 6p or 14q were seen in another two hamartomas. Other regions that were rearranged more than once were 12q (three times) and 17p (twice), sometimes in exchange with 6p or 14q and giving rise to complex derivative chromosomes. Only one tumour had aberrations that did not involve 6p, 12q, 14q, or 17p. These resultstogether with the data on three previously reported pulmonary hamartomas, two of which also had t(6;14)-show that recombinations between 6p2l and 14q24 are common, and hence probably pathogenetically important. The data support the view that these tumours are genuine neoplasms rather than developmental anomalies. The coexistence of a common 14q24 breakpoint in uterine leiomyomas and pulmonary hamartomas indicates that a gene important in the genesis of both tumours exists in this band. ml-' selenious acid, 5.35 jig ml-' linoleic acid, 1.25 mg ml-' bovine serum albumin, and 6.25 jig ml-' transferrin. After 3 days, the cultures were exposed to Colcemid (0.01 jig ml-') for 6 h and harvested by hypotonic treatment in 0.05 M KCI and repeated fixations in methanol: acetic acid (3:1). The slides from all cases were incubated overnight at 6O°C, treated for 4 h in 2 x SSC at 60°C and then G-banded with Wright's stain. The subsequent chromosome analysis followed the recommendations of the ISCN (1991).
The issue of whether multiple, ipsilateral or bilateral, breast carcinomas represent multiple pri... more The issue of whether multiple, ipsilateral or bilateral, breast carcinomas represent multiple primary tumours or dissemination of a single carcinomatous process has been difficult to resolve, especially for individual patients. We have addressed the problem by comparative genomic hybridisation analysis of 26 tumours from 12 breast cancer patients with multiple ipsilateral and/or bilateral carcinoma lesions. Genomic imbalances were detected in 25 of the 26 (96%) tumours. Using the genomic imbalances detected in these 26 lesions as well as those previously found by us in an independent series of 35 unifocal breast carcinomas, we compared a probabilistic model for likelihood of independence with unsupervised hierarchical clustering methodologies to determine the clonal relatedness of multiple tumours in breast cancer patients. We conclude that CGH analysis of multiple breast carcinomas followed by unsupervised hierarchical clustering of the genomic imbalances is more reliable than previous criteria to determine the tumours' clonal relationship in individual patients, that most ipsilateral breast carcinomas arise through intramammary spreading of a single breast cancer, and that most patients with bilateral breast carcinomas have two different diseases.
S_ry Cytogenetic analysis was performed on short-term cell cultures of two foci (A and B) from ea... more S_ry Cytogenetic analysis was performed on short-term cell cultures of two foci (A and B) from each of three multifocal breast carcinomas. In case I, four clones (three related and one unrelated) were detected in sample A. In sample B, two of the three related clones and the unrelated cone seen in A were found, as was also a third subclone showing a pattern of clonal evolution slightly different from that detected in A. In ca Case H A multifocal tumour was detected in the right breast of a 68-year-old woman. The A focus measured 23 mm in diameter, the B focus 15 mm. The histopathological examination revealed a tubuloductal carcinoma in A and a ductal carcinoma in situ with areas of severe epithelial hyperplasia in B. The two foci were separated by 0.5 cm of grossly normal breast tissue. There were no lymph node or distant metastases.
Short-term cultures from 20 pancreatic tumours, three endocrine and 17 exocrine, were cytogenetic... more Short-term cultures from 20 pancreatic tumours, three endocrine and 17 exocrine, were cytogenetically analysed. All three endocrine tumours had a normal chromosome complement. Clonal chromosome aberrations were detected in 13 of the 17 exocrine tumours: simple karyotypic changes were found in five carcinomas and numerous numerical and/or structural changes in eight. When the present findings and those previously reported by our group were viewed in conjunction, the most common numerical imbalances among the 22 karyotypically abnormal pancreatic carcinomas thus available for evaluation turned out to be, in order of falling frequency,-18,-Y, + 20, + 7, + 11 and-12. Imbalances brought about by structural changes most frequently affected chromosomes I (losses in lp but especially gains of lq), 8 (in particular 8q gains but also 8p losses), and 17 (mostly 17q gain but also loss of 17p). Chromosomal bands lp32, 1q1O, 6q21, 7p22, 8p2l, 8ql 1, 14pl 1, l5q10-1 1, and 17qll were the most common breakpoint sites affected by the structural rearrangements. Abnormal karyotypes were detected more frequently in poorly differentiated and anaplastic carcinomas than in moderately and well differentiated tumours.
Thirty tumorous lesions from seven patients with colorectal cancer were short-term cultured and c... more Thirty tumorous lesions from seven patients with colorectal cancer were short-term cultured and cytogenetically analysed: 16 nonadenomatous polyps, six adenomas, seven carcinomas, including one in polyp, and one lymph node metastasis. Clonal chromosome aberrations were found in 20 samples in 100% of the carcinomas, in 100% of the adenomas and in 37.5% of the non-adenomatous polyps, i.e. all ten lesions with a normal karyotype were histologically diagnosed as hyperplastic polyps. Although adenomas and carcinomas shared several karyotypic features, two chromosome aberrations, der(8;17)(q10;q10) and-14, were found in carcinomas but not in adenomas, indicating that they might be specifically associated with carcinoma development in the large bowel mucosa. The karyotypic similarity seen between the malignant and benign tumours in the same patient, and also sometimes among non-malignant polyps in the same case, indicates that these microscopically distinct lesions may be part of a single neoplastic clonal expansion.
Malignant ovarian germ cell tumors (OGCTs) include immature teratomas (ITs), dysgerminomas (DGs),... more Malignant ovarian germ cell tumors (OGCTs) include immature teratomas (ITs), dysgerminomas (DGs), endodermal sinus tumors (ESTs), choriocarcinomas, and embryonal carcinomas. Knowledge about the genetic changes associated with malignant OGCT development is sparse. We therefore analyzed 25 OGCTs (12 DGs, 4 ESTs, and 9 ITs) for gains and losses by comparative genomic hybridization. In total, more gains than losses were observed, and the number of alterations ranged from 0-20 per tumor. The average number of changes among DGs, ESTs, and ITs was 10, 6, and 1.4, respectively. The most common changes in DGs were gains from chromosome arms 1p (33%), 6p (33%), 12p (67%), 12q (75%), 15q (42%), 20q (50%), 21q (67%), and 22q (58%); gains of the whole of chromosomes 7 (42%), 8 (42%), 17 (42%), and 19 (50%); and losses from 13q (58%). Two of three DGs with a gonadoblastoma component showed gains of 3p21 and loss of 5p, whereas none of the nine pure DGs had these changes, suggesting that they migh...
The reciprocal translocation t(9;16)(q22;p13) was identified in three short-term cultured basal c... more The reciprocal translocation t(9;16)(q22;p13) was identified in three short-term cultured basal cell carcinomas (BCCs). The t(9;16) was the sole anomaly in one clone in two tumors and was accompanied by a second change that also affected the long arm of chromosome 9 in the third. In addition, other cytogenetically unrelated abnormal clones were also found in all three BCCs. The identification of t(9;16)(q22;p13) as a primary chromosomal abnormality in a subset of BCCs (we found it in 3 of 22 tumors) is especially intriguing against the background that the PTCH gene, which when mutated in the germ line presumably gives rise to the autosomal dominant basal cell nevus or Gorlin's syndrome, maps to chromosome band 9q22. None of the genes rearranged in the BCC-specific t(9;16)(q22;p13) translocation have been identified, but we hypothesize that the translocation represents the cytogenetic corollary of a tumorigenic recombination of PTCH with an as yet unknown gene in 16p13. If so, th...
Short-term cultures from 115 squamous cell carcinomas (SCC) of the head and neck were cytogenetic... more Short-term cultures from 115 squamous cell carcinomas (SCC) of the head and neck were cytogenetically investigated. Thirty-six of the tumors have been reported previously, whereas 79 are new cases. The material was divided into two series based on the medium used. The 80 tumors of series I were cultured in RPMI 1640 supplemented with fetal calf serum, glutamine, antibiotics, insulin, cholera toxin, and epidermal growth factor. The 35 tumors of series II were cultured in a chemically defined, serum-free medium with a low calcium concentration, MCDB 153, which stimulates epithelial growth while inhibiting fibroblasts. A total of 83 tumors with clonal karyotypic abnormalities were detected in the two series. Series II had a higher proportion of tumors with complex karyotypic changes than series I (43% versus 15%), a lower proportion of tumors with pseudo- or neardiploid clones characterized by simple rearrangements (3% versus 34%), and a lower frequency of unrelated clones (3% versus 2...
Cytogenetic analysis of short-term cultures from benign intestinal tumors revealed clonal chromos... more Cytogenetic analysis of short-term cultures from benign intestinal tumors revealed clonal chromosome aberrations in five colorectal adenomas, one adenoma of the papilla Vateri, and one hyperplastic polyp of the rectum. One adenoma had numerical aberrations only, but in all other tumors structural rearrangements were found that led to loss of genetic material from 1p. In three of the cases, the deletion was restricted to the 1p36 band; the rest had lost larger 1p segments. The rearrangement of chromosome 1 was the sole karyotypic anomaly in three adenomas, all with mild or moderate dysplasia, and in the hyperplastic polyp. Both adenomas that had additional aberrations beyond the 1p loss showed severe dysplasia. We conclude that cytogenetically detectable loss of genetic information from 1p36 is an early, seemingly primary, premalignant event in intestinal tumorigenesis. The fact that the adenomas with 1p- as the sole change showed only mild or moderate dysplasia and that the del(1p) ...
We report the finding of clonal chromosome abnormalities in short-term cultures from 44 squamous ... more We report the finding of clonal chromosome abnormalities in short-term cultures from 44 squamous cell carcinomas of the head and neck region. Eleven tumors had gain or loss of the Y chromosome, sometimes one clone with +Y and another with -Y, as the sole anomaly, whereas the remaining 33 all carried structural rearrangements and usually were cytogenetically complex with multiple aberrations. The chromosomal bands most frequently involved were, in decreasing order of frequency, 8p11-q11, 1p11-q11, 3p11-q11, 11q13, 13p11-q11, 1p13, 5p11-q11, 7p11-q11, 15p11-q11, and 14p11-q11. Almost one-half of the breakpoints were located in centromeric or juxtacentromeric bands. Recurrent aberrations included i(8q), i(5p), i(1q), del(3)(p11-12), del(5)(p11), t(1;1)(p13;q25), and der(14;15)(q10;q10). To see whether the karyotypic features of head and neck squamous cell carcinoma differ depending on exact tumor site, we added to the present series our previously published 23 karyotypically abnormal h...
In an attempt to quantify the nonrandomness of primary neoplasia-associated acquired chromosomal ... more In an attempt to quantify the nonrandomness of primary neoplasia-associated acquired chromosomal aberrations in humans, we have retrieved information from a computerized data base on the chromosomal abnormalities of 9069 human neoplasms. By restricting the survey to the 1985 cases with a solitary structural rearrangement, we attempted to limit the analysis to only those aberrations that were most likely to represent pathogenetically important, primary changes. The breakpoints of the primary abnormalities thus identified clustered to 71 bands. It furthermore turned out that 27 of the 41 oncogene sites known with reasonable precision (i.e., localized within one or two bands) coincide with bands consistently involved in neoplasia-associated rearrangements. These comparisons add to the evidence that acquired, cancer-associated chromosomal aberrations are nonrandom in distribution, that only a limited number of genomic sites are consistently involved in primary neoplasia-associated aberr...
Cytogenetic analysis of short-term cultures from 33 basal cell carcinomas (BCC), a type of neopla... more Cytogenetic analysis of short-term cultures from 33 basal cell carcinomas (BCC), a type of neoplasm for which no previous karyological data exist, revealed clonal chromosome aberrations, all of them different, in 8 tumors. In 2 cases, 2 cytogenetically unrelated clones were detected, suggesting a multicellular origin in at least a subset of BCC. A remarkably high level of nonclonal structural rearrangements, mostly in the form of seemingly balanced translocations, was found in 23 tumors; namely, in 6 of 8 BCC with clonal karyotypic abnormalities and in 17 of 25 without. It is possible that some of these aberrations represent additional neoplastic clones, thus indicating an even higher level of cytogenetic heterogeneity in BCC. We think that the most likely interpretation of the results is that BCC may have a multicellular origin, reflecting field cancerization of the skin. During subsequent tumor development, the selection pressure narrows down the number of clones that infiltrate t...
DNA ploidy analysis is useful for prognostication in cancer patients, but the genomic details und... more DNA ploidy analysis is useful for prognostication in cancer patients, but the genomic details underlying ploidy changes are not fully understood. To improve this understanding, we compared DNA ploidy status with karyotypic and comparative genomic hybridization data on 51 endometrial adenocarcinomas. Out of 34 DNA diploid tumors evaluated by CGH, 16 (47%) showed imbalances, though only two had more than four copy number changes. Ten (29%) had aberrations involving chromosome 1, seven (21%) involving chromosome 10, while one tumor had a chromosome 8 aberration. Four of the seven DNA tetraploid tumors (57%) had imbalances detected by CGH with two (29%) having more than four. Six out of eight DNA aneuploid tumors showed imbalances by CGH, with five (63%) having more than four. The aberrations were observed on chromosomes 1 and 8 in five/eight (63%) cases while four imbalances (50%) involved chromosomes 5, 7 and X. Not surprisingly, we observed a significant correlation between increasin...
Purpose To investigate the prognostic value of the overall karyotypic features and specific chrom... more Purpose To investigate the prognostic value of the overall karyotypic features and specific chromosome aberrations in colorectal cancer (CRC). Patients and Methods Cytogenetic features of 150 primary CRCs investigated at the time of surgery were correlated with patient survival by univariate and multivariate analyses, using classical clinicopathologic parameters as covariates. Results In univariate analysis, in addition to tumor grade and clinical stage, structural aberrations as well as rearrangements of chromosomes 8 and 16 were significantly correlated with shorter overall survival. Karyotypic complexity, rearrangements of chromosomes 8 and 16, and loss of chromosome 4 were significantly correlated with shorter disease-free survival. In multivariate analysis, in addition to tumor grade, the type of chromosome aberrations (structural or numerical), ploidy, and loss of chromosome 18 came across as independent prognostic factors in the group of all patients. In the subset of patient...
Chromosome banding analysis of solid tumors often yields incomplete karyotypes because of the com... more Chromosome banding analysis of solid tumors often yields incomplete karyotypes because of the complex rearrangements encountered. The addition of fluorescence in situ hybridization (FISH) methods has helped improve the accuracy of solid tumor cytogenetics, but the absence of screening qualities from standard FISH approaches has proved a severe limitation. We describe the cytogenetic analysis of ten solid tumors using G-banding followed by cross-species color banding (RxFISH), a FISHbased screening technique giving a chromosome-specific banding pattern based on the genomic homologies between humans and gibbons. The addition of RxFISH analysis in all cases led to the identification of previously unidentified intra-as well as interchromosomal rearrangements, thus giving a much more certain and detailed karyotype. In two gastric stromal sarcomas, a tumor type for which no cytogenetic data were hitherto available, numerical chromosomal aberrations dominated, but one of the tumors also carried an unbalanced 7;17-translocation with the same breakpoint in chromosome 17 as that seen in endometrial stromal sarcomas.
About 20% of ovarian carcinomas show alterations of 19p13 and/or 19q13 in the form of added extra... more About 20% of ovarian carcinomas show alterations of 19p13 and/or 19q13 in the form of added extra material whose origin often is from chromosome 11. Based on earlier spectral karyotype analysis of the ovarian cancer cell line SKOV-3, which shows an unbalanced translocation der(19)t(11;19), the aim of this study was to determine the precise breakpoints of that derivative chromosome. After rough delimitation of the breakpoints of microdissected derivative chromosomes by array analysis, we designed a matrix of primers spanning 11q13.2 and 19p13.2 detecting multiple amplicons on genomic and cDNA. Sequencing the amplicons, accurate localization of both breakpoints on both chromosomes was possible and we found that exon 14 of HOOK2 from chromosome 19 and exon 2 of ACTN3 from chromosome 11 were fused in the derivative chromosome. The breakpoint in the HOOK2 gene was in an intrinsic triplet of nucleic acids leading to a shift in the ACTN3 reading frame in the derivative chromosome. This frameshift alteration should give rise to an early stop codon causing a loss of function of ACTN3. Signals in two-dimensional Western blotting exactly match to calculated molecular mass and the isoelectric point of the fusion protein. V
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Papers by Sverre Heim