British Journal of Cancer (2008) 98, 997 – 1000 & 2008 Cancer Research UK All rights reserved 0007 – 0920/08 $30.00 www.bjcancer.com Association of colorectal adenoma with other malignancies in Swedish families E Hiripi*,1, J Lorenzo Bermejo1, J Sundquist2 and K Hemminki1,2 1Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Germany; 2Karolinska Institute, Center for Family and Community Medicine, Huddinge 141 83, Sweden Using the Swedish Family-Cancer Database covering over 11.5 million individuals, estimated relative risks (RRs) for colorectal adenoma were using Poisson’s regression. The RR of colorectal adenoma was found to be increased among first-degree relatives of patients with colorectal cancer (2.72; 95% confidence interval ¼ 2.46 – 3.00) and among the offspring and siblings of patients with endometrial and prostate cancers. We also found an increased risk of colorectal adenoma for the offspring of individuals with stomach cancer and leukaemia, and for siblings of those with pancreatic cancer and multiple myeloma. Our results suggest that colorectal adenoma may share a genetic aetiology with cancer even at extracolorectal sites. Increases of colorectal adenoma in families affected by prostate cancer and acute leukaemia cannot be attributed to known cancer syndromes, although the play of chance cannot be excluded. British Journal of Cancer (2008) 98, 997 – 1000. doi:10.1038/sj.bjc.6604276 www.bjcancer.com Published online 19 February 2008 & 2008 Cancer Research UK Keywords: familial risk; colorectal adenoma; extracolorectal cancer Most colorectal cancers (CRCs) develop through sequential malignant transformations of adenomatous polyps (Bond, 2000). Mutations in the adenomatous polyposis coli gene are responsible for the early stage of adenoma formation in familial adenomatous polyposis (Houlston, 2001; Lynch and de la Chapelle, 2003; Molatore and Ranzani, 2004) and mutations in the mismatch- repair genes are associated with hereditary nonpolyposis CRC (HNPCC) (Lynch and de la Chapelle, 2003; Molatore and Ranzani, 2004). The later stages of adenoma development into CRCs include K-ras, p53 and mismatch-repair genes (Lynch and de la Chapelle, 2003; Molatore and Ranzani, 2004). The adenoma – carcinoma sequence implies that colorectal adenomas and carcinomas have common risk factors. A family history of CRC increases the risk of CRC (Slattery and Kerber, 1994; Hemminki and Li, 2001; Andrieu et al, 2004; Stefansson et al, 2006) and is a strong risk factor for adenoma growth (Lindgren et al, 2002; Almendingen et al, 2003). Although an association between CRC risk and a family history of extra-colorectal malignancies has been reported previously (Slattery and Kerber, 1994; Hemminki and Li, 2001; Andrieu et al, 2004), little is known on the corresponding risk of colorectal adenoma. We have therefore quantified the risk of colorectal adenoma among individuals with a family history of any cancer using the nationwide Swedish Family-Cancer Database with its unique capacity for accurate and unbiased assessment (Hemminki and Li, 2001; Hemminki et al, 2001b). *Correspondence: Dr E Hiripi; E-mail: e.hiripi@dkfz-heidelberg.de Received 2 November 2007; revised 18 January 2008; accepted 25 January 2008; published online 19 February 2008 MATERIALS AND METHODS The population-based Swedish Family-Cancer Database was created by linking the Multigeneration Register at Statistics Sweden to the Swedish Cancer Registry (Hemminki et al, 2001b). This is based on compulsory reports from pathologists and cytologists, on every cancer diagnosis on surgically removed tissues, biopsies, cytological specimens, bone marrow aspirates and autopsies (Center for Epidemiology, 2004). The Multigenera- tion Register includes individuals born in Sweden after 1931 and their biological parents and its latest update covers over 11.5 million individuals. Cancer/adenoma data were retrieved from the Swedish Cancer Registry from 1961 to 2004. Database coverage is practically complete but some familial links are missing from offspring born before 1941 and dying in 1960 – 1997 reducing the number of fatal cancers among offspring. This is unlikely to bias familial studies because familial and sporadic cases would be reduced proportionately (Hemminki et al, 1998; Hemminki and Vaittinen, 1999). The present study relies on individuals with information about both parents. Family history was restricted to first-degree relatives, parents, and siblings. From International Classification of Diseases (ICD-7) the following codes were used: for colorectal adenomas 094; CRCs by anatomic site: 1530 (ascending), 1531 (transverse), 1532 (descending), 1533 (sigmoid), 1538 (multiple sites), 1534 and 1539 (other sites), 154 – excluding 1541 (rectum). Follow-up started from the date of birth, immigration or 1 January 1961, whichever occurred last. Follow-up ended on the date of diagnosis of CRC or colorectal adenoma, death, emigration, or the closing date of the study (31 December 2004), whichever came first. Relative risks (RRs) with 95% confidence intervals (CIs) were used to compare adenoma incidence among those whose family was y g o l o i e d i p E