Genomic approaches for hereditary colorectal cancer: Lynch syndrome, new polyposis syndromes and beyond

DD Buchanan1,2, M Clendenning1, C Rosty1,3,4, MC Southey5, B Pope6, FA Macrae7,8,9, IM Winship7,8, AK Win2, JL Hopper2,10 and MA Jenkins2

  1. Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
  2. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
  3. Envoi Specialist Pathologists, Herston, Queensland, Australia
  4. University of Queensland, School of Medicine, Herston, Queensland, Australia
  5. Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
  6. Victorian Life Sciences Computation Initiative, The University of Melbourne, Carlton, Victoria, Australia
  7. Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia
  8. Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia
  9. Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Parkville, Victoria, Australia
  10. Department of Epidemiology and Institute of Health and Environment, School of Public Health, Seoul National University, Seoul, Korea

Up to 5% of all colorectal cancers (CRC) are due to the well characterised inherited syndromes, including Lynch syndrome, caused by germline mutations in the DNA mismatch repair (MMR) genes. Tumour mismatch repair (MMR) deficiency, determined by immunohistochemical loss of MMR protein expression, is used diagnostically to identify individuals with CRC likely to be caused by Lynch syndrome. However, for a high proportion of CRC tumours with MMR-deficiency the individual does not have an identifiable germline mutation in a MMR gene; this is categorised as ‘suspected Lynch syndrome’. We have used whole genome sequencing and tumour profiling to identify additional causes of MMR-deficient CRC tumours through the identification of new susceptibility genes and bi-allelic somatic mutations in the MMR genes, respectively. This has enabled the stratification of suspected Lynch syndrome CRCs into groups for clinical management. Recently, germline mutations in the polymerase proofreading genes POLE and POLD1 have been identified in CRC and polyposis affected families, however, the age- and sex-specific CRC risks for carriers have not yet been quantified. We will present the prevalence and spectrum of POLE and POLD1 variants/mutations among familial CRCs and the first estimates of both relative and absolute risks of CRC for POLE and POLD1 mutation carriers. Furthermore, tumour profiling has enabled the identification of a hypermutated tumour phenotype in POLE or POLD1 mutation carriers that can be used to aid the diagnosis of carriers and genetic variant classification. Finally, we provide an update of our work describing new CRC susceptibility genes identified from whole genome and whole exome sequencing of 203 CRC-affected individuals from 90 families from the Australasian Colorectal Cancer Family Registry.