Deciphering the genetics of hereditary non-syndromic colorectal cancer.
Previously we have localized to chromosome 3q21-q24, a predisposition locus for colorectal cancer (CRC), through a genome-wide linkage screen (GWLS) of 69 families without familial adenomatous polyposis or hereditary non-polyposis CRC. To further investigate Mendelian susceptibility to CRC, we exten...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2008
|
| _version_ | 1826258242907406336 |
|---|---|
| author | Papaemmanuil, E Carvajal-Carmona, L Sellick, G Kemp, Z Webb, E Spain, S Sullivan, K Barclay, E Lubbe, S Jaeger, E Vijayakrishnan, J Broderick, P Gorman, M Martin, L Lucassen, A Bishop, D Evans, D Maher, E Steinke, V Rahner, N Schackert, H Goecke, T Holinski-Feder, E Propping, P Van Wezel, T |
| author_facet | Papaemmanuil, E Carvajal-Carmona, L Sellick, G Kemp, Z Webb, E Spain, S Sullivan, K Barclay, E Lubbe, S Jaeger, E Vijayakrishnan, J Broderick, P Gorman, M Martin, L Lucassen, A Bishop, D Evans, D Maher, E Steinke, V Rahner, N Schackert, H Goecke, T Holinski-Feder, E Propping, P Van Wezel, T |
| author_sort | Papaemmanuil, E |
| collection | OXFORD |
| description | Previously we have localized to chromosome 3q21-q24, a predisposition locus for colorectal cancer (CRC), through a genome-wide linkage screen (GWLS) of 69 families without familial adenomatous polyposis or hereditary non-polyposis CRC. To further investigate Mendelian susceptibility to CRC, we extended our screen to include a further GWLS of an additional 34 CRC families. We also searched for a disease gene at 3q21-q24 by linkage disequilibrium mapping in 620 familial CRC cases and 960 controls by genotyping 1676 tagging SNPs and sequencing 30 candidate genes from the region. Linkage analysis was conducted using the Affymetrix 10K SNP array. Data from both GWLSs were pooled and multipoint linkage statistics computed. The maximum NPL score (3.01; P=0.0013) across all families was at 3q22, maximal evidence for linkage coming from families segregating rectal CRC. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD=2.79; P=0.00034), with an estimated 43% of families linked. In the case-control analysis, the strongest association was obtained at rs698675 (P=0.0029), but this was not significant after adjusting for multiple testing. Analysis of candidate gene mapping to the region of maximal linkage on 3q22 failed to identify a causal mutation. There was no evidence for linkage to the previously reported 9q CRC locus (NPL=0.95, P=0.23; HLOD(dominant)=0.40, HLOD(recessive)=0.20). Our findings are consistent with the hypothesis that variation at 3q22 contributes to the risk of CRC, but this is unlikely to be mediated through a restricted set of alleles. |
| first_indexed | 2024-03-06T18:30:54Z |
| format | Journal article |
| id | oxford-uuid:09a07608-f370-4e39-a64e-5173a57f2ce4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:30:54Z |
| publishDate | 2008 |
| record_format | dspace |
| spelling | oxford-uuid:09a07608-f370-4e39-a64e-5173a57f2ce42022-03-26T09:19:21ZDeciphering the genetics of hereditary non-syndromic colorectal cancer.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:09a07608-f370-4e39-a64e-5173a57f2ce4EnglishSymplectic Elements at Oxford2008Papaemmanuil, ECarvajal-Carmona, LSellick, GKemp, ZWebb, ESpain, SSullivan, KBarclay, ELubbe, SJaeger, EVijayakrishnan, JBroderick, PGorman, MMartin, LLucassen, ABishop, DEvans, DMaher, ESteinke, VRahner, NSchackert, HGoecke, THolinski-Feder, EPropping, PVan Wezel, TPreviously we have localized to chromosome 3q21-q24, a predisposition locus for colorectal cancer (CRC), through a genome-wide linkage screen (GWLS) of 69 families without familial adenomatous polyposis or hereditary non-polyposis CRC. To further investigate Mendelian susceptibility to CRC, we extended our screen to include a further GWLS of an additional 34 CRC families. We also searched for a disease gene at 3q21-q24 by linkage disequilibrium mapping in 620 familial CRC cases and 960 controls by genotyping 1676 tagging SNPs and sequencing 30 candidate genes from the region. Linkage analysis was conducted using the Affymetrix 10K SNP array. Data from both GWLSs were pooled and multipoint linkage statistics computed. The maximum NPL score (3.01; P=0.0013) across all families was at 3q22, maximal evidence for linkage coming from families segregating rectal CRC. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD=2.79; P=0.00034), with an estimated 43% of families linked. In the case-control analysis, the strongest association was obtained at rs698675 (P=0.0029), but this was not significant after adjusting for multiple testing. Analysis of candidate gene mapping to the region of maximal linkage on 3q22 failed to identify a causal mutation. There was no evidence for linkage to the previously reported 9q CRC locus (NPL=0.95, P=0.23; HLOD(dominant)=0.40, HLOD(recessive)=0.20). Our findings are consistent with the hypothesis that variation at 3q22 contributes to the risk of CRC, but this is unlikely to be mediated through a restricted set of alleles. |
| spellingShingle | Papaemmanuil, E Carvajal-Carmona, L Sellick, G Kemp, Z Webb, E Spain, S Sullivan, K Barclay, E Lubbe, S Jaeger, E Vijayakrishnan, J Broderick, P Gorman, M Martin, L Lucassen, A Bishop, D Evans, D Maher, E Steinke, V Rahner, N Schackert, H Goecke, T Holinski-Feder, E Propping, P Van Wezel, T Deciphering the genetics of hereditary non-syndromic colorectal cancer. |
| title | Deciphering the genetics of hereditary non-syndromic colorectal cancer. |
| title_full | Deciphering the genetics of hereditary non-syndromic colorectal cancer. |
| title_fullStr | Deciphering the genetics of hereditary non-syndromic colorectal cancer. |
| title_full_unstemmed | Deciphering the genetics of hereditary non-syndromic colorectal cancer. |
| title_short | Deciphering the genetics of hereditary non-syndromic colorectal cancer. |
| title_sort | deciphering the genetics of hereditary non syndromic colorectal cancer |
| work_keys_str_mv | AT papaemmanuile decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT carvajalcarmonal decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT sellickg decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT kempz decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT webbe decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT spains decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT sullivank decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT barclaye decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT lubbes decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT jaegere decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT vijayakrishnanj decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT broderickp decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT gormanm decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT martinl decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT lucassena decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT bishopd decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT evansd decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT mahere decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT steinkev decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT rahnern decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT schackerth decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT goecket decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT holinskifedere decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT proppingp decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer AT vanwezelt decipheringthegeneticsofhereditarynonsyndromiccolorectalcancer |