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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

Mutation load. Frequency of mutations of various types in copy number neutral and copy number loss regions, compared to the overall frequency of LOH across the exome (“LOH overall”). Deleterious mutations are enriched in CNN-LOH; all other mutations types are less frequent in copy number loss regions
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Fig3: Mutation load. Frequency of mutations of various types in copy number neutral and copy number loss regions, compared to the overall frequency of LOH across the exome (“LOH overall”). Deleterious mutations are enriched in CNN-LOH; all other mutations types are less frequent in copy number loss regions

Mentions: We then evaluated whether there was a difference in mutation frequency in CNN versus CNL regions of LOH on a case by case basis as above (Fig. 3). Excluding TP53, there were fewer mutations in regions of CNL-LOH than would have been expected based on the overall percentage of the exome affected (19.8 % of mutations were in CNL-LOH regions, whereas 26.8 % of the exome was affected by CNL-LOH, p < 0.0001, Binomial test). The difference was less striking when considering overtly deleterious mutations only (24.6 % vs 26.8 %, p = 0.09, Binomial test). For CNN-LOH, the overall difference was small (8.8 % of mutations vs 8.7 % of the exome affected by CNN-LOH, p = 0.7, Binomial test), however there were more deleterious mutations than expected (10.3 % vs 8.7 %, p = 0.05, Binomial test). When TP53 was included, both total mutations (9.2 %) and deleterious mutations (11.4 %) in CNN-LOH regions were increased. Silent mutations were the most likely to be underrepresented in CNL-LOH regions (17.2 % vs 26.8 %). It is possible, therefore, that mutations are seen less often in CNL-LOH regions simply as a consequence of decreased DNA dosage. The enrichment of deleterious mutations in CNN-LOH regions, however, suggests the presence of positive selection for mutations in TSGs.Fig. 3


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)

Mutation load. Frequency of mutations of various types in copy number neutral and copy number loss regions, compared to the overall frequency of LOH across the exome (“LOH overall”). Deleterious mutations are enriched in CNN-LOH; all other mutations types are less frequent in copy number loss regions
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: Mutation load. Frequency of mutations of various types in copy number neutral and copy number loss regions, compared to the overall frequency of LOH across the exome (“LOH overall”). Deleterious mutations are enriched in CNN-LOH; all other mutations types are less frequent in copy number loss regions
Mentions: We then evaluated whether there was a difference in mutation frequency in CNN versus CNL regions of LOH on a case by case basis as above (Fig. 3). Excluding TP53, there were fewer mutations in regions of CNL-LOH than would have been expected based on the overall percentage of the exome affected (19.8 % of mutations were in CNL-LOH regions, whereas 26.8 % of the exome was affected by CNL-LOH, p < 0.0001, Binomial test). The difference was less striking when considering overtly deleterious mutations only (24.6 % vs 26.8 %, p = 0.09, Binomial test). For CNN-LOH, the overall difference was small (8.8 % of mutations vs 8.7 % of the exome affected by CNN-LOH, p = 0.7, Binomial test), however there were more deleterious mutations than expected (10.3 % vs 8.7 %, p = 0.05, Binomial test). When TP53 was included, both total mutations (9.2 %) and deleterious mutations (11.4 %) in CNN-LOH regions were increased. Silent mutations were the most likely to be underrepresented in CNL-LOH regions (17.2 % vs 26.8 %). It is possible, therefore, that mutations are seen less often in CNL-LOH regions simply as a consequence of decreased DNA dosage. The enrichment of deleterious mutations in CNN-LOH regions, however, suggests the presence of positive selection for mutations in TSGs.Fig. 3

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