The aim of our study was to examine the role of genetic factors on early-onset colorectal cancer after excluding the impact of germline mutations in the two major mismatch repair genes. A total of 131 incident probands, under 45 years at diagnosis of a first primary colorectal cancer selected from the Victorian Cancer Registry, and their first- and second-degree relatives, were interviewed. Germline DNA from all 12 probands with a family history meeting the modified Amsterdam Criteria for Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and a random sample of 31 of the remaining probands was screened for mutations in hMSH2 and hMLH1 via manual sequencing. Germline mutations were identified in 6 of the 131 probands (5%), all from the "HNPCC" families. Of the remaining 125 probands, 51 (41%) reported at least one first- or second-degree relative with colorectal cancer with an excess of colorectal cancer in first-degree relatives (SMR = 2.7, 95% CI = 1.7-4.1, p < 0.001). The lifetime risk to age 70 for first-degree relatives was 8.0% (5.0-12.8%), compared to the Victorian population risk of 3.2% (p = 0.01). The best fitting major gene model was a recessively-inherited risk of 98% to age 70 (95% CI = 24-100%) carried by 0.17% of the population and would explain 15% of all colorectal cancer in cases with a diagnosis before age 45. Early-onset colorectal cancer is strongly familial even after excluding families found to be segregating a mutation in either of the 2 major mismatch repair genes. There is evidence for a role of yet to be identified genes associated with a high recessively-inherited risk of colorectal cancer. © 2002 Wiley-Liss, Inc.

After hMSH2 and hMLH1 - What next? Analysis of three-generational, population-based, early-onset colorectal cancer families

BAGLIETTO, LAURA;
2002-01-01

Abstract

The aim of our study was to examine the role of genetic factors on early-onset colorectal cancer after excluding the impact of germline mutations in the two major mismatch repair genes. A total of 131 incident probands, under 45 years at diagnosis of a first primary colorectal cancer selected from the Victorian Cancer Registry, and their first- and second-degree relatives, were interviewed. Germline DNA from all 12 probands with a family history meeting the modified Amsterdam Criteria for Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and a random sample of 31 of the remaining probands was screened for mutations in hMSH2 and hMLH1 via manual sequencing. Germline mutations were identified in 6 of the 131 probands (5%), all from the "HNPCC" families. Of the remaining 125 probands, 51 (41%) reported at least one first- or second-degree relative with colorectal cancer with an excess of colorectal cancer in first-degree relatives (SMR = 2.7, 95% CI = 1.7-4.1, p < 0.001). The lifetime risk to age 70 for first-degree relatives was 8.0% (5.0-12.8%), compared to the Victorian population risk of 3.2% (p = 0.01). The best fitting major gene model was a recessively-inherited risk of 98% to age 70 (95% CI = 24-100%) carried by 0.17% of the population and would explain 15% of all colorectal cancer in cases with a diagnosis before age 45. Early-onset colorectal cancer is strongly familial even after excluding families found to be segregating a mutation in either of the 2 major mismatch repair genes. There is evidence for a role of yet to be identified genes associated with a high recessively-inherited risk of colorectal cancer. © 2002 Wiley-Liss, Inc.
2002
Jenkins, Mark A.; Baglietto, Laura; Dite, Gillian S.; Jolley, Damien J.; Southey, Melissa C.; Whitty, Jonathan; Mead, Leeanne J.; John, D. James B. S....espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/817275
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