Screening of BMPR1a for pathogenic mutations in familial colorectal cancer type X families from Newfoundland
- 110 Downloads
The Canadian province of Newfoundland and Labrador (NL) reports one of the highest incidence rates of familial colorectal cancer (CRC) worldwide. The NL population is an invaluable resource for studying genetic disorders because of a unique ancestry, and a willingness to participate in research studies. Familial colorectal cancer type X (FCCTX) describes a cluster of families with strong predisposition for CRC, of unknown etiology. A putative link between FCCTX and BMPR1a mutations has been identified in the Finnish population; however these findings have not been independently replicated. To investigate a potential connection between BMPR1a and FCCTX, we screened a cohort of 22 probands from unrelated NL FCCTX families using Sanger sequencing. This analysis did not independently replicate findings seen in Finland; as no candidate pathogenic BMPR1a mutations were uncovered. Our findings highlight that BMPR1a mutations are not a major contributor of FCCTX incidence in NL. Further investigation of additional FCCTX populations may assist in delineating a role for BMPR1a, if any, in FCCTX globally.
KeywordsBMPR1a Familial colorectal cancer type X Candidate gene Newfoundland and Labrador
The authors declare they hold no conflict of interest with respect to this work. We would foremost like to thank the study participants who donated their time, personal information and family histories. Their support is integral to our ongoing research. DRE generated and analyzed DNA sequence data using laboratory protocols and analysis software. He assisted in reviewing patient phenotypic information, performed a literature review, and prepared the manuscript. JSG collected the phenotypic information for each patient over a period of several decades and reviewed the manuscript. MOW conceived of the study, participated in study design and supervised the collection of molecular and genetic data. All authors read and approved the final manuscript. This work was funded by the Research and Development Corporation of Newfoundland and Labrador (RDCNL), and the Canadian Cancer Society Research Institute (CCSRI).
- 1.Canadian Cancer Society’s Advisory Committee on Cancer Statistics (2015) Canadian Cancer Statistics. Canadian Cancer Society, Toronto, ONGoogle Scholar
- 3.Woods MO, Younghusband HB, Parfrey PS, Gallinger S, McLaughlin J, Dicks E, Stuckless S, Pollett A, Bapat B, Mrkonjic M, de la Chapelle A, Clendenning M, Thibodeau SN, Simms M, Dohey A, Williams P, Robb D, Searle C, Green JS, Green RC (2010) The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease. Gut 59(10):1369–1377CrossRefPubMedPubMedCentralGoogle Scholar
- 4.Lindor NM, Rabe K, Petersen G, Haile R, Casey G, Baron J, Gallinger S, Bapat B, Aronson M, Hopper J, Jass J, LeMarchand L, Grove J, Potter J, Newcomb P, Terdiman J, Conrad P, Moslein G, Goldberg R, Ziogas A, Anton-Culver H, de Andrade M, Siegmund K, Thibodeau SN, Boardman LA, Seminara D. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 293(16):1979–1985Google Scholar
- 6.Leach FS, Nicolaides NC, Papadopoulos N, Liu B, Jen J, Parsons R, Peltomäki P, Sistonen P, Aaltonen LA, Nyström-Lahti M, Guan X-Y, Zhang J, Meltzer PS, Yu J-W, Kao F-T, Chen DJ, Cerosaletti KM, Fournier REK, Todd S, Lewis T, Leach RJ, Naylor SL, Weissenbach J, Mecklin J-P, Järvinen H, Petersen GM, Hamilton SR, Green J, Jass J, Watson P, Lynch HT, Trent JM, de la Chapelle A, Kinzler KW, Vogelstein B (1993) Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75(6):1215–1225CrossRefPubMedGoogle Scholar
- 8.Chubb D, Broderick P, Dobbins SE, Frampton M, Kinnersley B, Penegar S, Price A, Ma YP, Sherborne AL, Palles C, Timofeeva MN, Bishop DT, Dunlop MG, Tomlinson I, Houlston RS (2016) Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer. Nat Commun 7:11883CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Fernandez-Rozadilla C, Brea-Fernández A, Bessa X, Alvarez-Urturi C, Abulí A, Clofent J, Payá A, EPICOLON Consortium, Jover R, Xicola R, Llor X, Andreu M, Castells A, Carracedo A, Castellví-Bel S, Ruiz-Ponte C (2013) BMPR1A mutations in early-onset colorectal cancer with mismatch repair proficiency. Clin Genet 84(1):94–96CrossRefPubMedGoogle Scholar
- 10.Esteban-Jurado C, Vila-Casadesús M, Garre P, Lozano JJ, Pristoupilova A, Beltran S, Muñoz J, Ocaña T, Balaguer F, López-Cerón M, Cuatrecasas M, Franch-Expósito S, Piqué JM, Castells A, Carracedo A, Ruiz-Ponte C, Abulí A, Bessa X, Andreu M, Bujanda L, Caldés T, Castellví-Bel S, EPICOLON Consortium (2015) Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer. Genet Med 17:131–142CrossRefPubMedGoogle Scholar