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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

Models of LOH. Boxes = genes; “X” = inactivating mutation; A, B = alternative alleles of a single nucleotide polymorphism. In the top panels, the black line on the graph represents the overall frequency of LOH observed in tumour samples across the chromosome, while the red bars are the frequency of mutation in a particular gene. Thus, for the classic two-hit model, the frequency of mutation is similar to the frequency of LOH, while in the low frequency model, the frequency of LOH is higher than the mutation rate, because each sample is mutated in a different gene. In the bar graphs below, at left, the red bars represent the frequency of the A allele that is retained in samples with LOH at the locus; thus, the risk locus (*) has a higher proportion of the risk allele (A) retained after LOH compared to a non-risk locus, where the A and B alleles are equally retained. At right, the graphs represents the average reduction in expression of a gene in samples with LOH, compared to samples without LOH; genes in LOH regions show a reduction in expression
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Fig1: Models of LOH. Boxes = genes; “X” = inactivating mutation; A, B = alternative alleles of a single nucleotide polymorphism. In the top panels, the black line on the graph represents the overall frequency of LOH observed in tumour samples across the chromosome, while the red bars are the frequency of mutation in a particular gene. Thus, for the classic two-hit model, the frequency of mutation is similar to the frequency of LOH, while in the low frequency model, the frequency of LOH is higher than the mutation rate, because each sample is mutated in a different gene. In the bar graphs below, at left, the red bars represent the frequency of the A allele that is retained in samples with LOH at the locus; thus, the risk locus (*) has a higher proportion of the risk allele (A) retained after LOH compared to a non-risk locus, where the A and B alleles are equally retained. At right, the graphs represents the average reduction in expression of a gene in samples with LOH, compared to samples without LOH; genes in LOH regions show a reduction in expression

Mentions: From the data above it appears that we did not identify dominant, very frequently mutated novel genes where selection for a classic two-hit tumour suppressor gene was apparent. So what, if anything, is the LOH for? We considered five possibilities (Fig. 1) and assessed each in turn.Fig. 1


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)

Models of LOH. Boxes = genes; “X” = inactivating mutation; A, B = alternative alleles of a single nucleotide polymorphism. In the top panels, the black line on the graph represents the overall frequency of LOH observed in tumour samples across the chromosome, while the red bars are the frequency of mutation in a particular gene. Thus, for the classic two-hit model, the frequency of mutation is similar to the frequency of LOH, while in the low frequency model, the frequency of LOH is higher than the mutation rate, because each sample is mutated in a different gene. In the bar graphs below, at left, the red bars represent the frequency of the A allele that is retained in samples with LOH at the locus; thus, the risk locus (*) has a higher proportion of the risk allele (A) retained after LOH compared to a non-risk locus, where the A and B alleles are equally retained. At right, the graphs represents the average reduction in expression of a gene in samples with LOH, compared to samples without LOH; genes in LOH regions show a reduction in expression
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Models of LOH. Boxes = genes; “X” = inactivating mutation; A, B = alternative alleles of a single nucleotide polymorphism. In the top panels, the black line on the graph represents the overall frequency of LOH observed in tumour samples across the chromosome, while the red bars are the frequency of mutation in a particular gene. Thus, for the classic two-hit model, the frequency of mutation is similar to the frequency of LOH, while in the low frequency model, the frequency of LOH is higher than the mutation rate, because each sample is mutated in a different gene. In the bar graphs below, at left, the red bars represent the frequency of the A allele that is retained in samples with LOH at the locus; thus, the risk locus (*) has a higher proportion of the risk allele (A) retained after LOH compared to a non-risk locus, where the A and B alleles are equally retained. At right, the graphs represents the average reduction in expression of a gene in samples with LOH, compared to samples without LOH; genes in LOH regions show a reduction in expression
Mentions: From the data above it appears that we did not identify dominant, very frequently mutated novel genes where selection for a classic two-hit tumour suppressor gene was apparent. So what, if anything, is the LOH for? We considered five possibilities (Fig. 1) and assessed each in turn.Fig. 1

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