Inherited predisposition plays a role in 10-30% of colorectal cancer (CRC) cases. Of the large families with a clearly positive family history of CRC, ∼40% is not affected by known CRC syndromes.... Show moreInherited predisposition plays a role in 10-30% of colorectal cancer (CRC) cases. Of the large families with a clearly positive family history of CRC, ∼40% is not affected by known CRC syndromes. The existence of families with unexplained forms of inherited CRC--familial CRC--suggests the presence of still unknown high- or moderate-risk CRC predisposing factors. While the genomic profiles of sporadic CRCs have been studied extensively, few studies have analysed the tumour profiles of hereditary or familial CRC. Here, we review recent advances in genomic tumour profiling in familial CRC in comparison with sporadic CRC. In addition, we discuss the role of known CRC risk factors in familial CRC. Show less
Corver, W.E.; Ruano, D.; Weijers, K.; Nieuwenhuizen, M.P. van; Miranda, N. de; Eijk, R. van; ... ; Morreau, H. 2012
Many hereditary nonpolyposis colorectal cancers (CRCs) cannot be explained by Lynch syndrome. Other high penetrance genetic risk factors are likely to play a role in these mismatch repair (MMR)... Show moreMany hereditary nonpolyposis colorectal cancers (CRCs) cannot be explained by Lynch syndrome. Other high penetrance genetic risk factors are likely to play a role in these mismatch repair (MMR)-proficient CRC families. Because genomic profiles of CRC tend to vary with CRC susceptibility syndromes, our aim is to analyze the genomic profile of MMR-proficient familial CRC to obtain insight into the biological basis of MMR-proficient familial CRC. We studied 30 MMR-proficient familial colorectal carcinomas, from 15 families, for genomic aberrations, including gains, physical losses, and copy-neutral loss of heterozygosity LOH (cnLOH) using SNP array comparative genomic hybridization. In addition, we performed somatic mutation analysis for KRAS, BRAF, PIK3CA and GNAS. The frequency of 20q gain (77%) is remarkably increased when compared with sporadic CRC, suggesting that 20q gain is involved in tumor progression of familial CRC. There is also a significant increase in the frequency of cnLOH and, as a consequence, a reduced frequency of physical loss compared with sporadic CRC. The most frequent aberrations observed included gains of 7p, 7q, 8q, 13q, 20p and 20q as well as physical losses of 17p, 18p and 18q. Most of these changes are also observed in sporadic CRC. Mutations in KRAS were identified in 37% of the MMR-proficient CRCs, and mutations in BRAF were identified in 16%. No mutations were identified in PIK3CA or chromosome 20 candidate gene GNAS. We show that the patterns of chromosomal instability of MMR-proficient familial CRC are clearly distinct from those from sporadic CRC. Both the increased gain on chromosome 20 and the increased levels of cnLOH suggest the presence of yet undiscovered germline defects that can, in part, underlie the cancer risk in these families. Show less
Approximately 40% of colorectal cancer (CRC) families with a diagnosis of hereditary nonpolyposis CRC on the basis of clinical criteria are not a consequence of mismatch repair (MMR) deficiency.... Show moreApproximately 40% of colorectal cancer (CRC) families with a diagnosis of hereditary nonpolyposis CRC on the basis of clinical criteria are not a consequence of mismatch repair (MMR) deficiency. Such families provide supporting evidence for the existence of a hitherto unidentified highly penetrant gene mutation. To gain further understanding of MMR-competent familial colorectal cancer (FCC), we studied seven large families with an unexplained predisposition for CRC to identify genetic regions that could harbor CRC risk factors. First, we conducted a genome-wide linkage scan using 10K single-nucleotide polymorphism (SNP) arrays to search for disease loci. Second, we studied the genomic profiles of the tumors of affected family members to identify commonly altered genomic regions likely to harbor tumor suppressor genes. Finally, we studied the possible role of recently identified low-risk variants in the familial aggregation of CRC in these families. Linkage analysis did not reveal clear regions of linkage to CRC. However, our results provide support linkage to 3q, a region that has previously been linked to CRC susceptibility. Tumor profiling did not reveal any genomic regions commonly targeted in the tumors studied here. Overall, the genomic profiles of the tumors show some resemblance to sporadic CRC, but additional aberrations were also present. Furthermore, the FCC families did not appear to have an enrichment of low-risk CRC susceptibility loci. These data suggest that factors other than a highly penetrant risk factor, such as low or moderate-penetrance risk factors, may explain the increased cancer risk in a subset of familial CRCs. (C) 2010 Wiley-Liss, Inc. Show less
Roon, E.H.J. van; Puijenbroek, M. van; Middeldorp, A.; Eijk, R. van; Meijer, E.J. de; Erasmus, D.; ... ; Morreau, H. 2010
Background: To investigate the etiology of MLH1 promoter methylation in mismatch repair (MMR) mutation-negative early onset MSI-H colon cancer. As this type of colon cancer is associated with high... Show moreBackground: To investigate the etiology of MLH1 promoter methylation in mismatch repair (MMR) mutation-negative early onset MSI-H colon cancer. As this type of colon cancer is associated with high ages, young patients bearing this type of malignancy are rare and could provide additional insight into the etiology of sporadic MSI-H colon cancer. Methods: We studied a set of 46 MSI-H colon tumors cases with MLH1 promoter methylation which was enriched for patients with an age of onset below 50 years (n = 13). Tumors were tested for CIMP marker methylation and mutations linked to methylation: BRAF, KRAS, GADD45A and the MLH1 -93G>A polymorphism. When available, normal colon and leukocyte DNA was tested for GADD45A mutations and germline MLH1 methylation. SNP array analysis was performed on a subset of tumors. Results: We identified two cases (33 and 60 years) with MLH1 germline promoter methylation. BRAF mutations were less frequent in colon cancer patients below 50 years relative to patients above 50 years (p-value: 0.044). CIMP-high was infrequent and related to BRAF mutations in patients below 50 years. In comparison with published controls the G>A polymorphism was associated with our cohort. Although similar distribution of the pathogenic A allele was observed in the patients with an age of onset above and below 50 years, the significance for the association was lost for the group under 50 years. GADD45A sequencing yielded an unclassified variant. Tumors from both age groups showed infrequent copy number changes and loss-of-heterozygosity. Conclusion: Somatic or germline GADD45A mutations did not explain sporadic MSI-H colon cancer. Although germline MLH1 methylation was found in two individuals, locus-specific somatic MLH1 hypermethylation explained the majority of sporadic early onset MSI-H colon cancer cases. Our data do not suggest an intrinsic tendency for CpG island hypermethylation in these early onset MSI-H tumors other than through somatic mutation of BRAF. Show less
Dillen, J. van; Spaans, M.; Keijsteren, W. van; Dillen, M. van; Vredevoogd, C.; Huizen, M. van; Middeldorp, A. 2010
Objective: To assess the length and angle of mediolateral episiotomies performed by midwives and resident gynecologists at 3 teaching hospitals in the Netherlands, and determine the incidence of... Show moreObjective: To assess the length and angle of mediolateral episiotomies performed by midwives and resident gynecologists at 3 teaching hospitals in the Netherlands, and determine the incidence of obstetric anal sphincter injury. Methods: In this prospective audit conducted between February and September 2008, all women delivered at the 3 hospitals were examined in the labor room for perineal injury. When an injury was assessed as being grade 2 or higher, it was re-evaluated. The incidence of anal sphincter injury was then compared with that reported in the preceding year. Results: Of 1979 women delivered, 420 (21.2%) were given an episiotomy and 58 (2.9%) sustained anal sphincter injury. The episiotomies formed a mean angle of 40 degrees with the perineal midline. There was no difference in length or angle between the episiotomies performed by resident gynecologists and those performed by midwives, and the angle of most episiotomies was sufficiently wide. Compared with the preceding year, the rate of anal sphincter injury was significantly higher. Conclusion: The quality of episiotomies did not differ when performed by midwives or resident gynecologists. To improve the recognition and classification of obstetric anal sphincter injuries, audits based on an internationally accredited classification could easily become a part of routine hospital practice. (C) 2009 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. Show less
