Abstract
The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P = 5.7 × 10-7). The association was stronger in those with ≥ 10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.
| Original language | English |
|---|---|
| Pages (from-to) | 260-263 |
| Number of pages | 4 |
| Journal | European Journal of Human Genetics |
| Volume | 23 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 20 2015 |
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ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
Cite this
Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP. / Cheng, Timothy H T; Gorman, Maggie; Martin, Lynn; Barclay, Ella; Casey, Graham; Newcomb, Polly A.; Conti, David V.; Schumacher, Fred; Gallinger, Steve; Lindor, Noralane M.; Hopper, John; Jenkins, Mark; Hunter, David J.; Kraft, Peter; Jacobs, Kevin B.; Cox, David G.; Yeager, Meredith; Hankinson, Susan E.; Wacholder, Sholom; Wang, Zhaoming; Welch, Robert; Hutchinson, Amy; Wang, Junwen; Yu, Kai; Chatterjee, Nilanjan; Orr, Nick; Willett, Walter C.; Colditz, Graham A.; Ziegler, Regina G.; Berg, Christine D.; Buys, Saundra S.; McCarty, Catherine A.; Feigelson, Heather Spencer; Calle, Eugenia E.; Thun, Michael J.; Hayes, Richard B.; Tucker, Margaret; Gerhard, Daniela S.; Fraumeni, Joseph F.; Hoover, Robert N.; Thomas, Gilles; Chanock, Stephen J.; Ciampa, Julia; Gonzalez-Bosquet, Jesus; Berndt, Sonja; Amundadottir, Laufey; Diver, W. Ryan; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Schumacher, Fredrick R.; Cancel-Tassin, Geraldine; Cussenot, Olivier; Valeri, Antoine; Andriole, Gerald L.; Crawford, E. David; Haiman, Christopher A.; Henderson, Brian; Kolonel, Laurence; Marchand, Loic Le; Siddiq, Afshan; Riboli, Elio; Key, Timothy J.; Kaaks, Rudolf; Isaacs, William; Isaacs, Sarah; Wiley, Kathleen E.; Gronberg, Henrik; Wiklund, Fredrik; Stattin, Pär; Xu, Jianfeng; Zheng, S. Lilly; Sun, Jielin; Vatten, Lars J.; Hveem, Kristian; Kumle, Merethe; Purdue, Mark P.; Johansson, Mattias; Zelenika, Diana; Toro, Jorge R.; Scelo, Ghislaine; Moore, Lee E.; Prokhortchouk, Egor; Wu, Xifeng; Kiemeney, Lambertus A.; Gaborieau, Valerie; Chow, Wong Ho; Zaridze, David; Matveev, Vsevolod; Lubinski, Jan; Trubicka, Joanna; Szeszenia-Dabrowska, Neonila; Lissowska, Jolanta; Rudnai, Péter; Fabianova, Eleonora; Bucur, Alexandru; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Boffetta, Paolo; Colt, Joanne S.; Davis, Faith G.; Schwartz, Kendra L.; Banks, Rosamonde E.; Selby, Peter J.; Harnden, Patricia; Hsing, Ann W.; Grubb, Robert L.; Boeing, Heiner; Vineis, Paolo; Clavel-Chapelon, Franc¸oise; Palli, Domenico; Tumino, Rosario; Krogh, Vittorio; Panico, Salvatore; Duell, Eric J.; Quirós, José Ramón; Sanchez, Maria José; Navarro, Carmen; Ardanaz, Eva; Dorronsoro, Miren; Khaw, Kay Tee; Allen, Naomi E.; Bueno-de-Mesquita, H. Bas; Peeters, Petra H M; Trichopoulos, Dimitrios; Linseisen, Jakob; Ljungberg, Börje; Overvad, Kim; Tjønneland, Anne; Romieu, Isabelle; Mukeria, Anush; Shangina, Oxana; Stevens, Victoria L.; Gapstur, Susan M.; Pharoah, Paul D.; Easton, Douglas F.; Weinstein, Stephanie J.; Njølstad, Inger; Tell, Grethe S.; Stoltenberg, Camilla; Kumar, Rajiv; Koppova, Kvetoslava; Benhamou, Simone; Oosterwijk, Egbert; Vermeulen, Sita H.; Aben, Katja K H; Van Der Marel, Saskia L.; Ye, Yuanqing; Wood, Christopher G.; Pu, Xia; Mazur, Alexander M.; Boulygina, Eugenia S.; Chekanov, Nikolai N.; Foglio, Mario; Lechner, Doris; Gut, Ivo; Heath, Simon; Blanche, Hélène; Skryabin, Konstantin G.; McKay, James D.; Rothman, Nathaniel; Lathrop, Mark; Brennan, Paul; Saunders, Brian; Thomas, Huw; Clark, Sue; Tomlinson, Ian.
In: European Journal of Human Genetics, Vol. 23, No. 2, 20.02.2015, p. 260-263.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP
AU - Cheng, Timothy H T
AU - Gorman, Maggie
AU - Martin, Lynn
AU - Barclay, Ella
AU - Casey, Graham
AU - Newcomb, Polly A.
AU - Conti, David V.
AU - Schumacher, Fred
AU - Gallinger, Steve
AU - Lindor, Noralane M.
AU - Hopper, John
AU - Jenkins, Mark
AU - Hunter, David J.
AU - Kraft, Peter
AU - Jacobs, Kevin B.
AU - Cox, David G.
AU - Yeager, Meredith
AU - Hankinson, Susan E.
AU - Wacholder, Sholom
AU - Wang, Zhaoming
AU - Welch, Robert
AU - Hutchinson, Amy
AU - Wang, Junwen
AU - Yu, Kai
AU - Chatterjee, Nilanjan
AU - Orr, Nick
AU - Willett, Walter C.
AU - Colditz, Graham A.
AU - Ziegler, Regina G.
AU - Berg, Christine D.
AU - Buys, Saundra S.
AU - McCarty, Catherine A.
AU - Feigelson, Heather Spencer
AU - Calle, Eugenia E.
AU - Thun, Michael J.
AU - Hayes, Richard B.
AU - Tucker, Margaret
AU - Gerhard, Daniela S.
AU - Fraumeni, Joseph F.
AU - Hoover, Robert N.
AU - Thomas, Gilles
AU - Chanock, Stephen J.
AU - Ciampa, Julia
AU - Gonzalez-Bosquet, Jesus
AU - Berndt, Sonja
AU - Amundadottir, Laufey
AU - Diver, W. Ryan
AU - Albanes, Demetrius
AU - Virtamo, Jarmo
AU - Weinstein, Stephanie
AU - Schumacher, Fredrick R.
AU - Cancel-Tassin, Geraldine
AU - Cussenot, Olivier
AU - Valeri, Antoine
AU - Andriole, Gerald L.
AU - Crawford, E. David
AU - Haiman, Christopher A.
AU - Henderson, Brian
AU - Kolonel, Laurence
AU - Marchand, Loic Le
AU - Siddiq, Afshan
AU - Riboli, Elio
AU - Key, Timothy J.
AU - Kaaks, Rudolf
AU - Isaacs, William
AU - Isaacs, Sarah
AU - Wiley, Kathleen E.
AU - Gronberg, Henrik
AU - Wiklund, Fredrik
AU - Stattin, Pär
AU - Xu, Jianfeng
AU - Zheng, S. Lilly
AU - Sun, Jielin
AU - Vatten, Lars J.
AU - Hveem, Kristian
AU - Kumle, Merethe
AU - Purdue, Mark P.
AU - Johansson, Mattias
AU - Zelenika, Diana
AU - Toro, Jorge R.
AU - Scelo, Ghislaine
AU - Moore, Lee E.
AU - Prokhortchouk, Egor
AU - Wu, Xifeng
AU - Kiemeney, Lambertus A.
AU - Gaborieau, Valerie
AU - Chow, Wong Ho
AU - Zaridze, David
AU - Matveev, Vsevolod
AU - Lubinski, Jan
AU - Trubicka, Joanna
AU - Szeszenia-Dabrowska, Neonila
AU - Lissowska, Jolanta
AU - Rudnai, Péter
AU - Fabianova, Eleonora
AU - Bucur, Alexandru
AU - Bencko, Vladimir
AU - Foretova, Lenka
AU - Janout, Vladimir
AU - Boffetta, Paolo
AU - Colt, Joanne S.
AU - Davis, Faith G.
AU - Schwartz, Kendra L.
AU - Banks, Rosamonde E.
AU - Selby, Peter J.
AU - Harnden, Patricia
AU - Hsing, Ann W.
AU - Grubb, Robert L.
AU - Boeing, Heiner
AU - Vineis, Paolo
AU - Clavel-Chapelon, Franc¸oise
AU - Palli, Domenico
AU - Tumino, Rosario
AU - Krogh, Vittorio
AU - Panico, Salvatore
AU - Duell, Eric J.
AU - Quirós, José Ramón
AU - Sanchez, Maria José
AU - Navarro, Carmen
AU - Ardanaz, Eva
AU - Dorronsoro, Miren
AU - Khaw, Kay Tee
AU - Allen, Naomi E.
AU - Bueno-de-Mesquita, H. Bas
AU - Peeters, Petra H M
AU - Trichopoulos, Dimitrios
AU - Linseisen, Jakob
AU - Ljungberg, Börje
AU - Overvad, Kim
AU - Tjønneland, Anne
AU - Romieu, Isabelle
AU - Mukeria, Anush
AU - Shangina, Oxana
AU - Stevens, Victoria L.
AU - Gapstur, Susan M.
AU - Pharoah, Paul D.
AU - Easton, Douglas F.
AU - Weinstein, Stephanie J.
AU - Njølstad, Inger
AU - Tell, Grethe S.
AU - Stoltenberg, Camilla
AU - Kumar, Rajiv
AU - Koppova, Kvetoslava
AU - Benhamou, Simone
AU - Oosterwijk, Egbert
AU - Vermeulen, Sita H.
AU - Aben, Katja K H
AU - Van Der Marel, Saskia L.
AU - Ye, Yuanqing
AU - Wood, Christopher G.
AU - Pu, Xia
AU - Mazur, Alexander M.
AU - Boulygina, Eugenia S.
AU - Chekanov, Nikolai N.
AU - Foglio, Mario
AU - Lechner, Doris
AU - Gut, Ivo
AU - Heath, Simon
AU - Blanche, Hélène
AU - Skryabin, Konstantin G.
AU - McKay, James D.
AU - Rothman, Nathaniel
AU - Lathrop, Mark
AU - Brennan, Paul
AU - Saunders, Brian
AU - Thomas, Huw
AU - Clark, Sue
AU - Tomlinson, Ian
PY - 2015/2/20
Y1 - 2015/2/20
N2 - The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P = 5.7 × 10-7). The association was stronger in those with ≥ 10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.
AB - The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P = 5.7 × 10-7). The association was stronger in those with ≥ 10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.
UR - http://www.scopus.com/inward/record.url?scp=84930571831&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84930571831&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2014.74
DO - 10.1038/ejhg.2014.74
M3 - Article
C2 - 24801760
AN - SCOPUS:84930571831
VL - 23
SP - 260
EP - 263
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
IS - 2
ER -