Familial Cancer

, Volume 7, Issue 2, pp 163–172

Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC)


  • Johanne Geary
    • Department of Medical GeneticsSt George’s University of London
    • Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life
  • Peter Sasieni
    • Cancer Research UK Centre for Epidemiology, Mathematics & StatisticsWolfson Institute of Preventive Medicine, Queen Mary’s School of Medicine
  • Richard Houlston
    • Institute of Cancer Research
  • Louise Izatt
    • Department of Clinical GeneticsGuy’s and St. Thomas’ NHS Foundation Trust
  • Ros Eeles
    • Institute of Cancer Research
  • Stewart J. Payne
    • North West Thames Regional Genetics ServiceNorthwick Park & St Mark’s Hospital
  • Samantha Fisher
    • North West Thames Regional Genetics ServiceNorthwick Park & St Mark’s Hospital
    • Department of Medical GeneticsSt George’s University of London

DOI: 10.1007/s10689-007-9164-6

Cite this article as:
Geary, J., Sasieni, P., Houlston, R. et al. Familial Cancer (2008) 7: 163. doi:10.1007/s10689-007-9164-6


The family histories of 130 individuals with documented hereditary non-polyposis colorectal cancer (HNPCC) (caused by mutations in mismatch-repair (MMR) genes MSH2 (n = 64), MLH1 (n = 62) or MSH6 (n = 4)) were obtained, and incidence of cancers in those families was compared to that in the general population. There were a total of 982 cancers in 723 individuals. Colorectal cancer (CRC) was the commonest type (64% and 55% in individuals from families with germline MLH1 and MSH2 mutations respectively). Median age at diagnosis of first CRC in MSH6 mutation families was 59 years compared to 45 years in both MLH1 and MSH2 mutation families. The relative risk (RR) of endometrial cancer was 55 in MSH2 mutation families, compared with 27 in MLH1 mutation families, and 37 in MSH6 mutation families; median age at diagnosis 49 years. Even within MSH2 families, endometrial cancer tended to cluster, with 28 of the 58 cases coming from families with three or more cases (P < 0.001). Absolute risk of endometrial cancer in MLH1 families was still greater than any other cancer (other than CRC). 5% of cancers in both MLH1 and MSH2 mutation families were gastric (RR = 12); 53% of these were diagnosed before 50 years. Seven cases of small intestinal cancer occurred in MSH2 and MLH1 mutation families (RR = 26). There were 13 cases of cancer of the ureter; all were in MSH2 families. These cancers tended to cluster within families (P < 0.001); three of seven families with urothelial cancer had such cases in two or more individuals; two others had kidney cancer. Nineteen of 27 ovarian cancers (70%) were in MSH2 mutation families and 70% of these were diagnosed before age 50 years. There were 9 cases of sebaceous skin cancer, 3 in two MLH1 and 6 in four MSH2 mutation families. Of 22 pancreatic cancers, 14 were known to be diagnosed before 60 years. Breast cancer RR was 1.7 overall. The type of mutation (truncating or other type, and site of mutation) showed no obvious correlation with the presence or absence of extra-colonic cancers in families.


Lynch syndromeHNPCCGene analysisFamilial relative riskClustering



absolute excess risk


central nervous system


colorectal cancer


hereditary non-polyposis colorectal cancer




relative risk

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© Springer Science+Business Media B.V. 2007