Progression and Tumor Heterogeneity Analysis in Early Rectal Cancer

Lips, Esther H.; Eijk, Ronald van; Graaf, Eelco J. R. de; Doornebosch, Pascal G.; Miranda, Noel F C C de; Oosting, Jan; Karsten, Tom; Eilers, Paul H.C.; Tollenaar, Rob A.E.M.; Wezel, Tom van; Morreau, Hans

doi:10.1158/1078-0432.ccr-07-2052

Cited by 40 publications

(40 citation statements)

References 46 publications

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“…On the basis of the literature and our work, a frequency of 30-50% has been reported for 20q gain in sporadic CRC. 27,36 Although Abdel-Rahman et al reported only 54% of 20q gain in MMR-proficient familial CRC, this was found in almost all tumors that showed abnormalities. 35 When compared with the 20q gain frequency in a series of sporadic rectal carcinomas (36%), which was previously analyzed using the same methodology, we found that the frequency of 20q gain is significantly higher in MMR-proficient familial CRC (p ¼ 3.4 Â 10 À3 ) as compared with the rectal cancers, which rarely show MMR-deficiency.…”

Section: Gain Of Chromosome 20qmentioning

confidence: 99%

“…The observed aberrations that were most frequent in the MMR-proficient familial CRCs are well-known CRC aberrations, which are typically observed in sporadic CRCs. 27,36 We compared the profile of aberrations in our MMR-proficient familial CRCs series to that of sporadic CRC, MAP carcinomas and Lynch carcinomas series that we analyzed previously, using the same methodology. 17,19,26,27 The frequencies of gains at 8q and 13q, physical losses at 17p and chromosome 18 and cnLOH at 5q are similar in MMR-proficient familial CRC and sporadic CRC (Table S2).…”

Section: Snp Array Profilingmentioning

confidence: 99%

“…35 When compared with the 20q gain frequency in a series of sporadic rectal carcinomas (36%), which was previously analyzed using the same methodology, we found that the frequency of 20q gain is significantly higher in MMR-proficient familial CRC (p ¼ 3.4 Â 10 À3 ) as compared with the rectal cancers, which rarely show MMR-deficiency. 27 The choice of the CRC series to compare 20q gain is critical. We therefore supported the increased 20q gain with an additional comparison to 29 left-sided MSS cases from a series used for prognostic profiling of CRC.…”

Section: Gain Of Chromosome 20qmentioning

confidence: 99%

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Increased frequency of 20q gain and copy‐neutral loss of heterozygosity in mismatch repair proficient familial colorectal carcinomas

Middeldorp

Eijk

Oosting

et al. 2011

Intl Journal of Cancer

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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)-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 MMRproficient 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.

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Section: Gain Of Chromosome 20qmentioning

confidence: 99%

Section: Snp Array Profilingmentioning

confidence: 99%

Section: Gain Of Chromosome 20qmentioning

confidence: 99%

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Increased frequency of 20q gain and copy‐neutral loss of heterozygosity in mismatch repair proficient familial colorectal carcinomas

Middeldorp

Eijk

Oosting

et al. 2011

Intl Journal of Cancer

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“…For analysis, we used a novel algorithm, lesser allele intensity ratio (LAIR), which is incorporated in beadarraySNP (5 (28), and can be useful in preoperative molecular staging of rectal cancer (29).…”

Section: Introductionmentioning

confidence: 99%

Genome-wide Allelic State Analysis on Flow-Sorted Tumor Fractions Provides an Accurate Measure of Chromosomal Aberrations

Corver

Middeldorp²,

Haar³

et al. 2008

Cancer Research

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Chromosomal aberrations are a common characteristic of cancer and are associated with copy number abnormalities and loss of heterozygosity (LOH). Tumor heterogeneity, low tumor cell percentage, and lack of knowledge of the DNA content impair the identification of these alterations especially in aneuploid tumors. To accurately detect allelic changes in carcinomas, we combined flow-sorting and single nucleotide polymorphism arrays. Cells derived from archival cervical and colon cancers were flow-sorted based on differential vimentin and keratin expression and DNA content and analyzed on single nucleotide polymorphism arrays. A new algorithm, the lesser allele intensity ratio, was used to generate a molecular measure of chromosomal aberrations for each case. Flow-sorting significantly improved the detection of copy number abnormalities; 31.8% showed an increase in amplitude and 23.2% were missed in the unsorted fraction, whereas 15.9% were detected but interpreted differently. Fluorescence in situ hybridization copy numbers, as well as the high similarity between the DNA index and the allelic state index, which is the average of the allelic states across the genome, validated the method. This new approach provides an individual molecular measure of chromosomal aberrations and will likely have repercussions for preoperative molecular staging, classification, and prognostic profiling of tumors, particularly for heterogeneous aneuploid tumors, and allows the study of the underlying molecular genetic mechanisms and clonal evolution of tumor subpopulations. [Cancer Res 2008;68(24):10333-40]

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“…35 A subset of 60 tumors (14 FF and 46 FFPE) was used to determine the sensitivity and specificity of the assay on FF and FFPE tissue. The tumor cell percentage in the series was 50 to 80%.…”

Section: Samplesmentioning

confidence: 99%

Sensitive and Specific KRAS Somatic Mutation Analysis on Whole-Genome Amplified DNA from Archival Tissues

Eijk

Puijenbroek

Chhatta

et al. 2010

The Journal of Molecular Diagnostics

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Kirsten RAS (KRAS) is a small GTPase that plays a key role in Ras/mitogen-activated protein kinase signaling; somatic mutations in KRAS are frequently found in many cancers. The most common KRAS mutations result in a constitutively active protein. Accurate detection of KRAS mutations is pivotal to the molecular diagnosis of cancer and may guide proper treatment selection. Here , we describe a two-step KRAS mutation screening protocol that combines whole-genome amplification (WGA) , high-resolution melting analysis (HRM) as a prescreen method for mutation carrying samples , and direct Sanger sequencing of DNA from formalin-fixed , paraffin-embedded (FFPE) tissue , from which limited amounts of DNA are available. We developed target-specific primers , thereby avoiding amplification of homologous KRAS sequences. The addition of herring sperm DNA facilitated WGA in DNA samples isolated from as few as 100 cells. KRAS mutation screening using high-resolution melting analysis on wgaDNA from formalin-fixed, paraffin-embedded tissue is highly sensitive and specific; additionally, this method is feasible for screening of clinical specimens, as illustrated by our analysis of pancreatic cancers. Furthermore , PCR on wgaDNA does not introduce genotypic changes , as opposed to unamplified genomic DNA. This method can , after validation , be applied to virtually any potentially mutated region in the genome.

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Progression and Tumor Heterogeneity Analysis in Early Rectal Cancer

Cited by 40 publications

References 46 publications

Increased frequency of 20q gain and copy‐neutral loss of heterozygosity in mismatch repair proficient familial colorectal carcinomas

Increased frequency of 20q gain and copy‐neutral loss of heterozygosity in mismatch repair proficient familial colorectal carcinomas

Genome-wide Allelic State Analysis on Flow-Sorted Tumor Fractions Provides an Accurate Measure of Chromosomal Aberrations

Sensitive and Specific KRAS Somatic Mutation Analysis on Whole-Genome Amplified DNA from Archival Tissues

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