PURPOSE: The first two studies aiming for the high-throughput identification of the somatic mutation spectrum of colorectal cancer (CRC) tumors were published in 2006 and 2007. Using exome sequencing, they described 69 and 140 candidate cancer genes (CAN genes), respectively. We hypothesized that germline variants in these genes may influence CRC risk, similar to APC, which is causing CRC through germline and somatic mutations. METHODS: After excluding the well-established CRC genes APC, KRAS, TP53, and ABCA1, we analyzed 35 potentially functional single-nucleotide polymorphisms (SNPs) in 10 CAN genes (OBSCN, MLL3, PKHD1, SYNE1, ERCC6, FBXW7, EPHB6/TRPV6, ELAC1/SMAD4, EPHA3, and ADAMTSL3) using KBiosciences Competitive Allele-Specific PCR™ genotyping assays. In addition to CRC risk (1,399 CRC cases, 838 controls), we also considered the influence of the SNPs on patients' survival (406 cases). RESULTS: In spite of the fact that our in silico analyses suggested functional relevance for the studied genes and SNPs, our data did not support a strong influence of the studied germline variants on CRC risk and survival. The strongest association with CRC risk and survival was found for MLL3 (rs6464211, OR 1.50, p = 0.002, dominant model; HR 2.12, p = 0.020, recessive model). Two SNPs in EPHB6/TRPV6 (dominant model) showed marginal associations with survival (rs4987622 HR 0.58 p = 0.028 and rs6947538 HR 0.64, p = 0.036, respectively). CONCLUSION: Although somatic mutations in the CAN genes have been related to the development and progression of various types of cancers in several next-generation sequencing or expression analyses, our study suggests that the studied potentially functional germline variants are not likely to affect CRC risk or survival.
PURPOSE: The first two studies aiming for the high-throughput identification of the somatic mutation spectrum of colorectal cancer (CRC) tumors were published in 2006 and 2007. Using exome sequencing, they described 69 and 140 candidate cancer genes (CAN genes), respectively. We hypothesized that germline variants in these genes may influence CRC risk, similar to APC, which is causing CRC through germline and somatic mutations. METHODS: After excluding the well-established CRC genes APC, KRAS, TP53, and ABCA1, we analyzed 35 potentially functional single-nucleotide polymorphisms (SNPs) in 10 CAN genes (OBSCN, MLL3, PKHD1, SYNE1, ERCC6, FBXW7, EPHB6/TRPV6, ELAC1/SMAD4, EPHA3, and ADAMTSL3) using KBiosciences Competitive Allele-Specific PCR™ genotyping assays. In addition to CRC risk (1,399 CRC cases, 838 controls), we also considered the influence of the SNPs on patients' survival (406 cases). RESULTS: In spite of the fact that our in silico analyses suggested functional relevance for the studied genes and SNPs, our data did not support a strong influence of the studied germline variants on CRC risk and survival. The strongest association with CRC risk and survival was found for MLL3 (rs6464211, OR 1.50, p = 0.002, dominant model; HR 2.12, p = 0.020, recessive model). Two SNPs in EPHB6/TRPV6 (dominant model) showed marginal associations with survival (rs4987622 HR 0.58 p = 0.028 and rs6947538 HR 0.64, p = 0.036, respectively). CONCLUSION: Although somatic mutations in the CAN genes have been related to the development and progression of various types of cancers in several next-generation sequencing or expression analyses, our study suggests that the studied potentially functional germline variants are not likely to affect CRC risk or survival.
Authors: Arun K Nalla; Theodore F Williams; Casey P Collins; Dustin T Rae; Grant D Trobridge Journal: Mol Carcinog Date: 2015-10-29 Impact factor: 4.784
Authors: Abdul K Siraj; Tariq Masoodi; Rong Bu; Shaham Beg; Saif S Al-Sobhi; Fouad Al-Dayel; Mohammed Al-Dawish; Fowzan S Alkuraya; Khawla S Al-Kuraya Journal: Am J Hum Genet Date: 2016-05-26 Impact factor: 11.025
Authors: Stephanie A Schubert; Dina Ruano; Fadwa A Elsayed; Arnoud Boot; Stijn Crobach; Arantza Farina Sarasqueta; Bruce Wolffenbuttel; Melanie M van der Klauw; Jan Oosting; Carli M Tops; Ronald van Eijk; Hans Fa Vasen; Rolf Ham Vossen; Maartje Nielsen; Sergi Castellví-Bel; Clara Ruiz-Ponte; Ian Tomlinson; Malcolm G Dunlop; Pavel Vodicka; Juul T Wijnen; Frederik J Hes; Hans Morreau; Noel Fcc de Miranda; Rolf H Sijmons; Tom van Wezel Journal: Br J Cancer Date: 2017-07-25 Impact factor: 7.640
Authors: Shun Lu; Calogerina Catalano; Stefanie Huhn; Barbara Pardini; Linda Partu; Veronika Vymetalkova; Ludmila Vodickova; Miroslav Levy; Thomas Buchler; Kari Hemminki; Pavel Vodicka; Asta Försti Journal: PLoS One Date: 2019-05-15 Impact factor: 3.240
Authors: Suleiman H Suleiman; Mahmoud E Koko; Wafaa H Nasir; Ommnyiah Elfateh; Ubai K Elgizouli; Mohammed O E Abdallah; Khalid O Alfarouk; Ayman Hussain; Shima Faisal; Fathelrahamn M A Ibrahim; Maurizio Romano; Ali Sultan; Lawrence Banks; Melanie Newport; Francesco Baralle; Ahmed M Elhassan; Hiba S Mohamed; Muntaser E Ibrahim Journal: Front Genet Date: 2015-09-15 Impact factor: 4.599