Metastases to the ovary occur in 0.8-9.7 % of colorectal cancer (CRC) cases (Hanna and Cohen in C... more Metastases to the ovary occur in 0.8-9.7 % of colorectal cancer (CRC) cases (Hanna and Cohen in Clin Colorectal Cancer 3(4):215-222, 2004). The need to combine surgical resection of the primary tumor and bilateral oophorectomy is a matter of debate (Erroi et al. in J Surg Oncol 96(2):113-117, 2007). In a consecutive multi-hospital cohort of 30 CRC metastases to the ovary we came across four female patients (13 %; 95 % CI 3.6-34.1) with familial adenomatous polyposis (FAP). This number is high since the estimated incidence of FAP CRC is far below 1 % of all CRC and the expected incidence of FAP CRC that metastasized to the ovaries would thus be almost zero. In a second screen in nationwide databases we found that ovarian metastases occurred in at least 15 % of female FAP CRC cases. We provide now first evidence that especially in female FAP CRC patients bilateral oophorectomy during surgery should be discussed.
BACKGROUND: Cancer-specific hypermethylation of (promoter) CpG islands is common during the tumor... more BACKGROUND: Cancer-specific hypermethylation of (promoter) CpG islands is common during the tumorigenesis of colon cancer. Although associations between certain genetic aberrations, such as BRAF mutation and microsatellite instability, and the CpG island methylator phenotype (CIMP), have been found, the mechanisms by which these associations are established are still unclear. We studied genome-wide DNA methylation differences between colorectal tumors carrying a BRAF mutation and BRAF wildtype tumors. RESULTS: Using differential methylation hybridization on oligonucleotide microarrays representing 32,171 CpG-rich regions, we identified 1,770 regions with differential methylation between colorectal tumor and paired normal colon. Next, we compared the tumor/normal methylation ratios between different groups of patients. Related to CIMP, we identified 749 differentially methylated regions, of which 86% had a higher tumor/normal methylation ratio in the CIMP-positive group. We identifie...
Most colorectal cancer (CRC) cells with high levels of microsatellite instability (MSI-H) accumul... more Most colorectal cancer (CRC) cells with high levels of microsatellite instability (MSI-H) accumulate mutations at a microsatellite sequence in the gene encoding transforming growth factor β receptor II (TGFBR2). TGFβ signaling is therefore believed to be defective in these tumors, although CRC cells with TGFBR2 mutations have been reported to remain sensitive to TGFβ. We investigated how TGFβ signaling might continue in MSI-H CRC cells. We sequenced the A10 microsatellite sequence in the TGFBR2 gene of 32 MSI-H colon cancer tissues and 6 cell lines (HCT116, LS180, LS411N, RKO, SW48, and SW837). Activation of TGFβ signaling was detected by SMAD2 phosphorylation and through use of a TGFβ-responsive reporter construct in all CRC cell lines. Transcripts of TGFBR2 were knocked-down in CRC cells using short hairpin (sh)RNA. Full-length and mutant forms of TGFBR2 were expressed in LS411N cells which do not respond to TGFβ and their activities were measured. SMAD2 was phosphorylated in most...
Differentiating primary endometrioid or mucinous ovarian tumors from secondary ovarian tumors can... more Differentiating primary endometrioid or mucinous ovarian tumors from secondary ovarian tumors can be challenging. We compared somatic mutation profiles of primary and secondary ovarian cancers to investigate if these profiles can help diagnose ovarian tumors. Cancer-related genes (n = 115) were screened by target-enriched next-generation sequencing in formalin-fixed, paraffin-embedded tumor tissue from 43 primary endometrioid and mucinous ovarian carcinomas and 28 proven colorectal cancer metastases to the ovary. Results were validated by high-resolution melting curve analysis and Sanger sequencing. TP53, NOTCH1, PIK3CA, and FAT4 versus APC, TP53, KRAS, and FAT4 mutations were the most common in the primary ovarian tumors and ovarian colorectal cancer metastases, respectively. An inactivating APC mutation was found in 4.7% of primary ovarian tumors (2 of 43; 95% CI, 1.6%-10.9%). In contrast, inactivating APC mutations were identified in 71% of colorectal cancer metastases (20 of 28; 95% CI, 55%-88%) (P < 0.001; sensitivity: 71.4%, 95% CI, 51.1%-86.0%; specificity: 95.4%, 95% CI, 82.9%-99.1%). Loss of heterozygosity and APC promoter hypermethylation did not differ significantly between the primary and secondary ovarian tumors. NOTCH1 mutations were observed specifically in primary ovarian tumors, although at a low frequency, but not in metastases (6 of 41; 14.6%; 95% CI, 3.8%-25.4%). APC mutation analysis can be used to differentiate primary endometrioid and mucinous ovarian tumors from colorectal cancer metastases to the ovary.
The potential of indolizine derivatives as anticancer agents has been shown through recent studie... more The potential of indolizine derivatives as anticancer agents has been shown through recent studies. Herein, we present our experimental results, showing that pyrido[2,3-b]indolizine derivatives are effective against colorectal cancer (CRC) cell lines. Several pyrido[2,3-b]indolizine derivatives were synthesized and their anticancer potential was evaluated against three CRC cell lines and two normal fibroblast cultures. Our experiments identified 4-(3,4)-dihydroxyphenyl)-2-phenylpyrido[2,3-b]indolizine-10-carbonitrile (4f) as being active against all CRC cell lines at concentrations non-cytotoxic against fibroblast cultures. Additionally, cell-cycle analysis indicated that pyrido[2,3-b]indolizines can affect cell-cycle progression, with treated cells accumulating in the S- and G2/M-phase. The hydroxyl groups in both the 3- and 4- positions of the aromatic substituent on C4 of the indolizine nucleus are crucial for activity against CRC cell lines. Further manipulation of the number an...
Mitochondrial-rich oncocytic thyroid tumors frequently show near-haploidization and endoreduplica... more Mitochondrial-rich oncocytic thyroid tumors frequently show near-haploidization and endoreduplication (masked haploidization), which manifests as a near-homozygous genome (NHG). We now extend this investigation to include adrenocortical cancer and parathyroid carcinoma (PaTC), which we studied for a NHG in association with mitochondrial DNA mutations. Sixty endocrine tumors from 59 patients were studied, including 46 thyroid tumor samples of varying histology, 11 adrenocortical cancers, and 3 PaTCs. Genome-wide SNP array analysis and DNA content analysis were combined to determine the chromosomal dosage (allelic state). The entire mitochondrial genome was also studied for mutations. In addition, tumors were characterized for somatic mutations in a subset of genes that are directly or indirectly implicated in cellular metabolism. In addition to a subset of thyroid cancers (n = 5), a NHG was also observed in 1 of 3 PaTCs and 6 of 11 adrenocortical cancers. All but one of the tumors with a NHG (n = 12) showed oncocytic metaplasia (P = 0.0001, two-tailed Fisher's exact). One or more damaging or disrupting mtDNA mutations were found in 68% (41/60) of tumor samples. No correlation was found between mtDNA mutations and the oncocytic phenotype or a NHG, and none of the mutations in nuclear encoded genes correlated with the oncocytic phenotype or a NHG. A subset of oncocytic tumors of the thyroid, parathyroid, and adrenocortical carcinomas carries a NHG. Although damaging/disrupting mtDNA mutations are frequently found in oncocytic and nononcocytic endocrine tumors, neither correlates with a NHG phenotype nor with an oncocytic phenotype.
Metastases to the ovary occur in 0.8-9.7 % of colorectal cancer (CRC) cases (Hanna and Cohen in C... more Metastases to the ovary occur in 0.8-9.7 % of colorectal cancer (CRC) cases (Hanna and Cohen in Clin Colorectal Cancer 3(4):215-222, 2004). The need to combine surgical resection of the primary tumor and bilateral oophorectomy is a matter of debate (Erroi et al. in J Surg Oncol 96(2):113-117, 2007). In a consecutive multi-hospital cohort of 30 CRC metastases to the ovary we came across four female patients (13 %; 95 % CI 3.6-34.1) with familial adenomatous polyposis (FAP). This number is high since the estimated incidence of FAP CRC is far below 1 % of all CRC and the expected incidence of FAP CRC that metastasized to the ovaries would thus be almost zero. In a second screen in nationwide databases we found that ovarian metastases occurred in at least 15 % of female FAP CRC cases. We provide now first evidence that especially in female FAP CRC patients bilateral oophorectomy during surgery should be discussed.
BACKGROUND: Cancer-specific hypermethylation of (promoter) CpG islands is common during the tumor... more BACKGROUND: Cancer-specific hypermethylation of (promoter) CpG islands is common during the tumorigenesis of colon cancer. Although associations between certain genetic aberrations, such as BRAF mutation and microsatellite instability, and the CpG island methylator phenotype (CIMP), have been found, the mechanisms by which these associations are established are still unclear. We studied genome-wide DNA methylation differences between colorectal tumors carrying a BRAF mutation and BRAF wildtype tumors. RESULTS: Using differential methylation hybridization on oligonucleotide microarrays representing 32,171 CpG-rich regions, we identified 1,770 regions with differential methylation between colorectal tumor and paired normal colon. Next, we compared the tumor/normal methylation ratios between different groups of patients. Related to CIMP, we identified 749 differentially methylated regions, of which 86% had a higher tumor/normal methylation ratio in the CIMP-positive group. We identifie...
Most colorectal cancer (CRC) cells with high levels of microsatellite instability (MSI-H) accumul... more Most colorectal cancer (CRC) cells with high levels of microsatellite instability (MSI-H) accumulate mutations at a microsatellite sequence in the gene encoding transforming growth factor β receptor II (TGFBR2). TGFβ signaling is therefore believed to be defective in these tumors, although CRC cells with TGFBR2 mutations have been reported to remain sensitive to TGFβ. We investigated how TGFβ signaling might continue in MSI-H CRC cells. We sequenced the A10 microsatellite sequence in the TGFBR2 gene of 32 MSI-H colon cancer tissues and 6 cell lines (HCT116, LS180, LS411N, RKO, SW48, and SW837). Activation of TGFβ signaling was detected by SMAD2 phosphorylation and through use of a TGFβ-responsive reporter construct in all CRC cell lines. Transcripts of TGFBR2 were knocked-down in CRC cells using short hairpin (sh)RNA. Full-length and mutant forms of TGFBR2 were expressed in LS411N cells which do not respond to TGFβ and their activities were measured. SMAD2 was phosphorylated in most...
Differentiating primary endometrioid or mucinous ovarian tumors from secondary ovarian tumors can... more Differentiating primary endometrioid or mucinous ovarian tumors from secondary ovarian tumors can be challenging. We compared somatic mutation profiles of primary and secondary ovarian cancers to investigate if these profiles can help diagnose ovarian tumors. Cancer-related genes (n = 115) were screened by target-enriched next-generation sequencing in formalin-fixed, paraffin-embedded tumor tissue from 43 primary endometrioid and mucinous ovarian carcinomas and 28 proven colorectal cancer metastases to the ovary. Results were validated by high-resolution melting curve analysis and Sanger sequencing. TP53, NOTCH1, PIK3CA, and FAT4 versus APC, TP53, KRAS, and FAT4 mutations were the most common in the primary ovarian tumors and ovarian colorectal cancer metastases, respectively. An inactivating APC mutation was found in 4.7% of primary ovarian tumors (2 of 43; 95% CI, 1.6%-10.9%). In contrast, inactivating APC mutations were identified in 71% of colorectal cancer metastases (20 of 28; 95% CI, 55%-88%) (P < 0.001; sensitivity: 71.4%, 95% CI, 51.1%-86.0%; specificity: 95.4%, 95% CI, 82.9%-99.1%). Loss of heterozygosity and APC promoter hypermethylation did not differ significantly between the primary and secondary ovarian tumors. NOTCH1 mutations were observed specifically in primary ovarian tumors, although at a low frequency, but not in metastases (6 of 41; 14.6%; 95% CI, 3.8%-25.4%). APC mutation analysis can be used to differentiate primary endometrioid and mucinous ovarian tumors from colorectal cancer metastases to the ovary.
The potential of indolizine derivatives as anticancer agents has been shown through recent studie... more The potential of indolizine derivatives as anticancer agents has been shown through recent studies. Herein, we present our experimental results, showing that pyrido[2,3-b]indolizine derivatives are effective against colorectal cancer (CRC) cell lines. Several pyrido[2,3-b]indolizine derivatives were synthesized and their anticancer potential was evaluated against three CRC cell lines and two normal fibroblast cultures. Our experiments identified 4-(3,4)-dihydroxyphenyl)-2-phenylpyrido[2,3-b]indolizine-10-carbonitrile (4f) as being active against all CRC cell lines at concentrations non-cytotoxic against fibroblast cultures. Additionally, cell-cycle analysis indicated that pyrido[2,3-b]indolizines can affect cell-cycle progression, with treated cells accumulating in the S- and G2/M-phase. The hydroxyl groups in both the 3- and 4- positions of the aromatic substituent on C4 of the indolizine nucleus are crucial for activity against CRC cell lines. Further manipulation of the number an...
Mitochondrial-rich oncocytic thyroid tumors frequently show near-haploidization and endoreduplica... more Mitochondrial-rich oncocytic thyroid tumors frequently show near-haploidization and endoreduplication (masked haploidization), which manifests as a near-homozygous genome (NHG). We now extend this investigation to include adrenocortical cancer and parathyroid carcinoma (PaTC), which we studied for a NHG in association with mitochondrial DNA mutations. Sixty endocrine tumors from 59 patients were studied, including 46 thyroid tumor samples of varying histology, 11 adrenocortical cancers, and 3 PaTCs. Genome-wide SNP array analysis and DNA content analysis were combined to determine the chromosomal dosage (allelic state). The entire mitochondrial genome was also studied for mutations. In addition, tumors were characterized for somatic mutations in a subset of genes that are directly or indirectly implicated in cellular metabolism. In addition to a subset of thyroid cancers (n = 5), a NHG was also observed in 1 of 3 PaTCs and 6 of 11 adrenocortical cancers. All but one of the tumors with a NHG (n = 12) showed oncocytic metaplasia (P = 0.0001, two-tailed Fisher's exact). One or more damaging or disrupting mtDNA mutations were found in 68% (41/60) of tumor samples. No correlation was found between mtDNA mutations and the oncocytic phenotype or a NHG, and none of the mutations in nuclear encoded genes correlated with the oncocytic phenotype or a NHG. A subset of oncocytic tumors of the thyroid, parathyroid, and adrenocortical carcinomas carries a NHG. Although damaging/disrupting mtDNA mutations are frequently found in oncocytic and nononcocytic endocrine tumors, neither correlates with a NHG phenotype nor with an oncocytic phenotype.
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Papers by Tom Van Wezel