Familial Cancer

, Volume 7, Issue 2, pp 163–172 | Cite as

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

  • Johanne Geary
  • Peter Sasieni
  • Richard Houlston
  • Louise Izatt
  • Ros Eeles
  • Stewart J. Payne
  • Samantha Fisher
  • Shirley V. Hodgson


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 syndrome HNPCC Gene analysis Familial relative risk Clustering 



absolute excess risk


central nervous system


colorectal cancer


hereditary non-polyposis colorectal cancer




relative risk



Our thanks go to Mr Huw JW Thomas, Mr James Mackay, Dr Huw Dorkins, Dr Susan Shanley and Professor Naz Rahman; also to all staff at the CR-UK Family Cancer Clinic, the Cancer Genetics Clinic, Royal Marsden NHS Foundation Trust, the North East Thames Regional Genetics Centre, the North West Thames Regional Genetics Service, the South East Thames Regional Genetics Centre and the South West Thames Regional Genetics Service for providing access to data to make this work possible. We are also grateful to the NHS: Audit, Information & Analysis Unit for funding the work on which this paper is based.

NCBI Reference Sequences: MLH1 RefSeq accession number NM_000249, MSH2 RefSeq accession number NM_000251.1, Mutation nomenclature based on A of ATG start methionine codon designated nucleotide number 1


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Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  • Johanne Geary
    • 1
    • 6
  • Peter Sasieni
    • 2
  • Richard Houlston
    • 3
  • Louise Izatt
    • 4
  • Ros Eeles
    • 3
  • Stewart J. Payne
    • 5
  • Samantha Fisher
    • 5
  • Shirley V. Hodgson
    • 1
  1. 1.Department of Medical GeneticsSt George’s University of LondonLondonUK
  2. 2.Cancer Research UK Centre for Epidemiology, Mathematics & StatisticsWolfson Institute of Preventive Medicine, Queen Mary’s School of MedicineLondonUK
  3. 3.Institute of Cancer ResearchBelmont, Sutton, SurreyUK
  4. 4.Department of Clinical GeneticsGuy’s and St. Thomas’ NHS Foundation TrustLondonUK
  5. 5.North West Thames Regional Genetics ServiceNorthwick Park & St Mark’s HospitalHarrow, LondonUK
  6. 6.Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life Newcastle upon TyneUK

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