title: Loss of heterozygosity: what is it good for?
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. georgina.ryland@petermac.org.|Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia. georgina.ryland@petermac.org.
authors.forename: Georgina L
authors.initials: GL
authors.lastname: Ryland
authors.affiliation: Bioinformatics Core Facility, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. maria.doyle@petermac.org.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Doyle
authors.affiliation: Bioinformatics and Cancer Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. david.goode@petermac.org.
authors.forename: David
authors.initials: D
authors.lastname: Goode
authors.affiliation: Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. samantha.boyle@petermac.org.
authors.forename: Samantha E
authors.initials: SE
authors.lastname: Boyle
authors.affiliation: Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. david.choong@petermac.org.
authors.forename: David Y H
authors.initials: DY
authors.lastname: Choong
authors.affiliation: Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. simone.rowley@petermac.org.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Rowley
authors.affiliation: Bioinformatics Core Facility, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. jason.li@petermac.org.
authors.forename: Jason
authors.initials: J
authors.lastname: Li
authors.affiliation: Cancer Genomics and Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. david.bowtell@petermac.org.
authors.forename: David D L
authors.initials: DD
authors.lastname: Bowtell
authors.affiliation: Molecular Genomics Core Facility, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. richard.tothill@petermac.org.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tothill
authors.affiliation: Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. ian.campbell@petermac.org.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. ian.campbell@petermac.org.|Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. ian.campbell@petermac.org.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Campbell
authors.affiliation: Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. kylie.gorringe@petermac.org.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. kylie.gorringe@petermac.org.|Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. kylie.gorringe@petermac.org.
authors.forename: Kylie L
authors.initials: KL
authors.lastname: Gorringe
mesh_terms: D005260:Female; D018628:Gene Dosage / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics; D016147:Genes, Tumor Suppressor; D023281:Genomics; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity; D010051:Ovarian Neoplasms / Q000235:genetics*