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Loss of heterozygosity: what is it good for?

Ryland GL, Doyle MA, Goode D, Boyle SE, Choong DY, Rowley SM, Li J, Australian Ovarian Cancer Study GroupBowtell DD, Tothill RW, Campbell IG, Gorringe KL - BMC Med Genomics (2015)

Bottom Line: Modified two-hit hypothesis: reduction to homozygosity of low penetrance germline predisposition alleles.It is likely that selection for regions of LOH depends on its effect on multiple genes.Selection for copy number neutral LOH may better fit the classic two-hit model whereas selection for copy number loss may be attributed to its effect on multi-gene haploinsufficiency.

View Article: PubMed Central - PubMed

Affiliation: Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. georgina.ryland@petermac.org.

ABSTRACT

Background: Loss of heterozygosity (LOH) is a common genetic event in cancer development, and is known to be involved in the somatic loss of wild-type alleles in many inherited cancer syndromes. The wider involvement of LOH in cancer is assumed to relate to unmasking a somatically mutated tumour suppressor gene through loss of the wild type allele.

Methods: We analysed 86 ovarian carcinomas for mutations in 980 genes selected on the basis of their location in common regions of LOH.

Results: We identified 36 significantly mutated genes, but these could only partly account for the quanta of LOH in the samples. Using our own and TCGA data we then evaluated five possible models to explain the selection for non-random accumulation of LOH in ovarian cancer genomes: 1. Classic two-hit hypothesis: high frequency biallelic genetic inactivation of tumour suppressor genes. 2. Epigenetic two-hit hypothesis: biallelic inactivation through methylation and LOH. 3. Multiple alternate-gene biallelic inactivation: low frequency gene disruption. 4. Haplo-insufficiency: Single copy gene disruption. 5. Modified two-hit hypothesis: reduction to homozygosity of low penetrance germline predisposition alleles. We determined that while high-frequency biallelic gene inactivation under model 1 is rare, regions of LOH (particularly copy-number neutral LOH) are enriched for deleterious mutations and increased promoter methylation, while copy-number loss LOH regions are likely to contain under-expressed genes suggestive of haploinsufficiency. Reduction to homozygosity of cancer predisposition SNPs may also play a minor role.

Conclusion: It is likely that selection for regions of LOH depends on its effect on multiple genes. Selection for copy number neutral LOH may better fit the classic two-hit model whereas selection for copy number loss may be attributed to its effect on multi-gene haploinsufficiency. LOH mapping alone is unlikely to be successful in identifying novel tumour suppressor genes; a combined approach may be more effective.

No MeSH data available.


Related in: MedlinePlus

Expression. The percentage of significantly differentially expressed genes in regions where the majority (>2/3) of LOH is either copy number loss, neutral or neither. Only regions with at least 20 % LOH were included
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Fig4: Expression. The percentage of significantly differentially expressed genes in regions where the majority (>2/3) of LOH is either copy number loss, neutral or neither. Only regions with at least 20 % LOH were included

Mentions: We previously observed a correlation between the percentage of genes under-expressed and the percentage of cases with CNL-LOH, as opposed to CNN-LOH, in a region-wise comparison of LOH vs. no LOH [6]. In an analysis of TCGA data, we compared the expression of 10,925 genes between cases with and without LOH. 3,780 genes (34.6 %) were significantly differentially expressed (at a multiple testing p-value threshold of 4.56x10−6), and all significant genes were under-expressed in samples with LOH compared to samples without LOH. When comparing CNN-LOH to CNL-LOH in genes with at least 20 % frequency of LOH, only 1/163 genes (0.6 %) at CNN-LOH enriched loci were significantly differentially expressed, compared to 2701/5740 (47 %) CNL-LOH enriched genes (p < 0.0001, Chi-squared test, Fig. 4). This result supports the idea that chromosomal regions with CNL-LOH may contain genes where loss of a single copy results in reduced gene expression and a selective advantage to the cell. In contrast, chromosomal regions with little copy number loss may contain essential genes for which haplo-insufficiency is cell lethal.Fig. 4


Loss of heterozygosity: what is it good for?

Ryland GL, Doyle MA, Goode D, Boyle SE, Choong DY, Rowley SM, Li J, Australian Ovarian Cancer Study GroupBowtell DD, Tothill RW, Campbell IG, Gorringe KL - BMC Med Genomics (2015)

Expression. The percentage of significantly differentially expressed genes in regions where the majority (>2/3) of LOH is either copy number loss, neutral or neither. Only regions with at least 20 % LOH were included
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4522148&req=5

Fig4: Expression. The percentage of significantly differentially expressed genes in regions where the majority (>2/3) of LOH is either copy number loss, neutral or neither. Only regions with at least 20 % LOH were included
Mentions: We previously observed a correlation between the percentage of genes under-expressed and the percentage of cases with CNL-LOH, as opposed to CNN-LOH, in a region-wise comparison of LOH vs. no LOH [6]. In an analysis of TCGA data, we compared the expression of 10,925 genes between cases with and without LOH. 3,780 genes (34.6 %) were significantly differentially expressed (at a multiple testing p-value threshold of 4.56x10−6), and all significant genes were under-expressed in samples with LOH compared to samples without LOH. When comparing CNN-LOH to CNL-LOH in genes with at least 20 % frequency of LOH, only 1/163 genes (0.6 %) at CNN-LOH enriched loci were significantly differentially expressed, compared to 2701/5740 (47 %) CNL-LOH enriched genes (p < 0.0001, Chi-squared test, Fig. 4). This result supports the idea that chromosomal regions with CNL-LOH may contain genes where loss of a single copy results in reduced gene expression and a selective advantage to the cell. In contrast, chromosomal regions with little copy number loss may contain essential genes for which haplo-insufficiency is cell lethal.Fig. 4

Bottom Line: Modified two-hit hypothesis: reduction to homozygosity of low penetrance germline predisposition alleles.It is likely that selection for regions of LOH depends on its effect on multiple genes.Selection for copy number neutral LOH may better fit the classic two-hit model whereas selection for copy number loss may be attributed to its effect on multi-gene haploinsufficiency.

View Article: PubMed Central - PubMed

Affiliation: Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. georgina.ryland@petermac.org.

ABSTRACT

Background: Loss of heterozygosity (LOH) is a common genetic event in cancer development, and is known to be involved in the somatic loss of wild-type alleles in many inherited cancer syndromes. The wider involvement of LOH in cancer is assumed to relate to unmasking a somatically mutated tumour suppressor gene through loss of the wild type allele.

Methods: We analysed 86 ovarian carcinomas for mutations in 980 genes selected on the basis of their location in common regions of LOH.

Results: We identified 36 significantly mutated genes, but these could only partly account for the quanta of LOH in the samples. Using our own and TCGA data we then evaluated five possible models to explain the selection for non-random accumulation of LOH in ovarian cancer genomes: 1. Classic two-hit hypothesis: high frequency biallelic genetic inactivation of tumour suppressor genes. 2. Epigenetic two-hit hypothesis: biallelic inactivation through methylation and LOH. 3. Multiple alternate-gene biallelic inactivation: low frequency gene disruption. 4. Haplo-insufficiency: Single copy gene disruption. 5. Modified two-hit hypothesis: reduction to homozygosity of low penetrance germline predisposition alleles. We determined that while high-frequency biallelic gene inactivation under model 1 is rare, regions of LOH (particularly copy-number neutral LOH) are enriched for deleterious mutations and increased promoter methylation, while copy-number loss LOH regions are likely to contain under-expressed genes suggestive of haploinsufficiency. Reduction to homozygosity of cancer predisposition SNPs may also play a minor role.

Conclusion: It is likely that selection for regions of LOH depends on its effect on multiple genes. Selection for copy number neutral LOH may better fit the classic two-hit model whereas selection for copy number loss may be attributed to its effect on multi-gene haploinsufficiency. LOH mapping alone is unlikely to be successful in identifying novel tumour suppressor genes; a combined approach may be more effective.

No MeSH data available.


Related in: MedlinePlus