Mechanisms underlying losses of heterozygosity in human colorectal cancers

Thiagalingam, Sam; Laken, Steven J.; Willson, James K.V.; Markowitz, Sanford D.; Kinzler, Kenneth W.; Vogelstein, Bert; Lengauer, Christoph

doi:10.1073/pnas.051625398

Cited by 193 publications

(141 citation statements)

References 47 publications

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“…The gain or loss of an entire chromosome arm rather than of a small segment is thus a favored mechanism, and possibly represents one of the earliest events in CIN. A study that combined karyotyping and marker analysis showed that individual chromosome arms could be gained in near-diploid cells, 47 which suggests that no polyploid intermediate would be necessary to start the BFB cycle in cancer. Instead, and in agreement with the initial experiments in maize, 25 gaining a single "reactive" chromosome arm is enough Figure 1.…”

Section: Back To Bfbmentioning

confidence: 99%

“…Although it is unlikely that spindle-induced rupture is selective for a specific centromere, not all chromosome arms undergo changes at the same rate; in many cases, one chromosome arm is lost while the other is preserved or amplified. 47 Arms that contain oncogenes such as c-Myc (8q), ErbB2 (17q) or Pik3CA (3q) are amplified much more often than average. 33 Even though mitotic centromere rupture and gain of chromosome arms are random events, oncogenes located on amplified arms thus seem to offer a selective growth advantage.…”

Section: Evidence From Tumorsmentioning

confidence: 99%

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Are aneuploidy and chromosome breakage caused by a CINgle mechanism?

Martı́nez-A

Wely

2010

Cell Cycle

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G enetic instability is a hallmark of cancer. Most tumors show complex patterns of translocations, amplifications and deletions, which have occupied scientists for decades. A specific problem arises in carcinomas with a genetic defect termed chromosomal instability; these solid tumors undergo gains and losses of entire chromosomes, as well as segmental defects caused by chromosome breaks. To date, the apparent inconsistency between intact and broken chromosomes has precluded identification of an underlying mechanism. The recent identification of centromeric breaks alongside aneuploidy in cells with spindle defects indicates that a single mechanism could account for all genetic alterations characteristic of chromosomal instability. Since a poorly controlled spindle can cause merotelic attachments, kinetochore distortion and subsequent chromosome breakage, spindle defects can generate the sticky ends necessary to start a breakagefusion-bridge cycle. The characteristic breakpoint of spindle-generated damage, adjacent to the centromere, also explains the losses and gains of whole chromosome arms, which are especially prominent in low-grade tumors. The recent data indicate that spindle defects are an early event in tumor formation, and an important initiator of carcinogenesis.

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Section: Back To Bfbmentioning

confidence: 99%

Section: Evidence From Tumorsmentioning

confidence: 99%

Are aneuploidy and chromosome breakage caused by a CINgle mechanism?

Martı́nez-A

Wely

2010

Cell Cycle

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“…In some cases, the deviation from 50%:50% is dependent on the parent of origin, such as genomic imprinting (Reik and Walter, 2001;Barlow, 2011;Bartolomei and Ferguson-Smith, 2011) and imprinted X chromosome inactivation (Wake et al, 1976;Huynh and Lee, 2001;Xue et al, 2002;Dindot et al, 2004;Wang et al, 2013a). In other cases, the AI is random or sequence dependent, such as random X chromosome inactivation (Heard et al, 1997), autosomal random monoallelic expression (RMAE; Gimelbrant et al, 2007), allelic exclusion of immunoglobulin genes (Vettermann and Schlissel, 2010), cis-regulating expression quantitative trait loci (cis-eQTL), loss of heterozygosity in cancer (Thiagalingam et al, 2001) and monoallelic expression of olfactory receptors (Chess et al, 1994). Technical details of the methods for quantifying differential allelic expression (DAE) accurately are critical to study AI.…”

Section: Introductionmentioning

confidence: 99%

Using next-generation RNA sequencing to identify imprinted genes

2014

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Genomic imprinting is manifested as differential allelic expression (DAE) depending on the parent-of-origin. The most direct way to identify imprinted genes is to directly score the DAE in a context where one can identify which parent transmitted each allele. Because many genes display DAE, simply scoring DAE in an individual is not sufficient to identify imprinted genes. In this paper, we outline many technical aspects of a scheme for identification of imprinted genes that makes use of RNA sequencing (RNA-seq) from tissues isolated from F1 offspring derived from the pair of reciprocal crosses. Ideally, the parental lines are from two inbred strains that are not closely related to each other. Aspects of tissue purity, RNA extraction, library preparation and bioinformatic inference of imprinting are all covered. These methods have already been applied in a number of organisms, and one of the most striking results is the evolutionary fluidity with which novel imprinted genes are gained and lost within genomes. The general methodology is also applicable to a wide range of other biological problems that require quantification of allele-specific expression using RNA-seq, such as cis-regulation of gene expression, X chromosome inactivation and random monoallelic expression.

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“…For example, LOH of chromosome 5q is correlated with biallelic inactivation of the tumor suppressor gene, adenomatous polyposis coli (APC), a process that occurs early in the multistep colorectal carcinogenesis (Fearon and Vogelstein, 1990). Other frequently observed LOH in CRC involves chromosomes 1p, 8p, 17p and 18q (Thiagalingam et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer

et al. 2004

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Krüppel-like factor 4 (KLF4 or GKLF) is an inhibitor of the cell cycle. The gene encoding KLF4 is localized on chromosome 9q, previously shown to exhibit allelic loss in colorectal cancer (CRC). In this study, we show that the mean level of KLF4 mRNA in a panel of 30 CRC was 52% that of paired normal colonic tissues. Similarly, the levels of KLF4 mRNA and protein in a panel of six established CRC cell lines were significantly lower than those of an untransformed colonic epithelial cell line. Using highly polymorphic DNA markers that .ank the KLF4 locus, we found evidence for loss of heterozygosity (LOH) in two of eight surgically resected CRC specimens. In addition, LOH was observed in .ve of six CRC cell lines with one additional cell line exhibiting hemizygous deletion in the KLF4 gene. We also found that the 5′-untranslated region of KLF4 was hypermethylated in a subset of resected CRC specimens and cell lines. Lastly, the open-reading frame of KLF4 in two of three CRC cell lines examined contained several point mutations that resulted in a diminished ability to activate the p21 WAF1/Cip1 promoter. These findings indicate that KLF4 is a potential tumor suppressor gene in CRC.

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Mechanisms underlying losses of heterozygosity in human colorectal cancers

Cited by 193 publications

References 47 publications

Are aneuploidy and chromosome breakage caused by a CINgle mechanism?

Are aneuploidy and chromosome breakage caused by a CINgle mechanism?

Using next-generation RNA sequencing to identify imprinted genes

Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer

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