BACKGROUND: The serrated pathway represents a distinct molecular pathway of colorectal carcinogenesis and is associated with the p.V600E BRAF mutation. The objective of this study is to characterize the cancer family history and clinicopathologic features of colorectal cancer (CRC) patients according to the microsatellite instability (MSI) and BRAF mutation status of their tumors. METHODS: The tumors from 558 population-based CRC patients underwent pathologic examination and molecular analysis for MSI, BRAF, and germline mutations in mismatch repair genes MUTYH and APC. The cancer history in first-degree relatives (FDR) of index patients was ascertained. RESULTS: The risk of CRC in FDRs of index patients with MSI-H BRAF mutation [hazard ratio (HR) = 2.49; 95% confidence interval (95% CI), 1.57- 3.93] and microsatellite-stable BRAF mutation tumors (HR = 1.64; 95% CI, 1.01-2.66) was significantly elevated compared with FDRs of index patients with microsatellite-stable BRAF wild-type tumors. The incidence of nonmelanoma skin cancer was also significantly elevated in FDRs of patients with BRAF mutation CRC (HR = 2.52; 95% CI, 1.31-4.86). Furthermore, BRAF mutation CRC was associated with a distinct clinical, molecular, and pathologic phenotype. CONCLUSIONS: The increased incidence of cancer in FDRs of index CRC patients with the p.V600E BRAF mutation may be explained by a genetic predisposition to develop cancer through the serrated pathway of colorectal carcinogenesis. IMPACT: Family members of BRAF CRC patients have an increased predisposition to develop cancer. Future work should aim to identify the causative genetic factors.
BACKGROUND: The serrated pathway represents a distinct molecular pathway of colorectal carcinogenesis and is associated with the p.V600EBRAF mutation. The objective of this study is to characterize the cancer family history and clinicopathologic features of colorectal cancer (CRC) patients according to the microsatellite instability (MSI) and BRAF mutation status of their tumors. METHODS: The tumors from 558 population-based CRCpatients underwent pathologic examination and molecular analysis for MSI, BRAF, and germline mutations in mismatch repair genes MUTYH and APC. The cancer history in first-degree relatives (FDR) of index patients was ascertained. RESULTS: The risk of CRC in FDRs of index patients with MSI-H BRAF mutation [hazard ratio (HR) = 2.49; 95% confidence interval (95% CI), 1.57- 3.93] and microsatellite-stable BRAF mutation tumors (HR = 1.64; 95% CI, 1.01-2.66) was significantly elevated compared with FDRs of index patients with microsatellite-stable BRAF wild-type tumors. The incidence of nonmelanoma skin cancer was also significantly elevated in FDRs of patients with BRAF mutation CRC (HR = 2.52; 95% CI, 1.31-4.86). Furthermore, BRAF mutation CRC was associated with a distinct clinical, molecular, and pathologic phenotype. CONCLUSIONS: The increased incidence of cancer in FDRs of index CRCpatients with the p.V600EBRAF mutation may be explained by a genetic predisposition to develop cancer through the serrated pathway of colorectal carcinogenesis. IMPACT: Family members of BRAFCRCpatients have an increased predisposition to develop cancer. Future work should aim to identify the causative genetic factors.
Authors: A Joan Levine; Aung Ko Win; Daniel D Buchanan; Mark A Jenkins; John A Baron; Joanne P Young; Tiffany I Long; Daniel J Weisenberger; Peter W Laird; Rebecca L McCall; David J Duggan; Robert W Haile Journal: Cancer Prev Res (Phila) Date: 2011-12-05
Authors: Aung Ko Win; Daniel D Buchanan; Christophe Rosty; Robert J MacInnis; James G Dowty; Gillian S Dite; Graham G Giles; Melissa C Southey; Joanne P Young; Mark Clendenning; Michael D Walsh; Rhiannon J Walters; Alex Boussioutas; Thomas C Smyrk; Stephen N Thibodeau; John A Baron; John D Potter; Polly A Newcomb; Loïc Le Marchand; Robert W Haile; Steven Gallinger; Noralane M Lindor; John L Hopper; Dennis J Ahnen; Mark A Jenkins Journal: Gut Date: 2014-03-10 Impact factor: 23.059
Authors: Karla J González-Colunga; Leonardo S Lino-Silva; Rosa A Salcedo-Hernández; Erika B Ruiz-García; César Zepeda-Najar Journal: J Gastrointest Cancer Date: 2020-03
Authors: Aung Ko Win; Rhiannon J Walters; Daniel D Buchanan; Mark A Jenkins; Kevin Sweet; Wendy L Frankel; Albert de la Chapelle; Diane M McKeone; Michael D Walsh; Mark Clendenning; Sally-Ann Pearson; Erika Pavluk; Belinda Nagler; John L Hopper; Michael R Gattas; Jack Goldblatt; Jill George; Graeme K Suthers; Kerry D Phillips; Sonja Woodall; Julie Arnold; Kathy Tucker; Michael Field; Sian Greening; Steve Gallinger; Melyssa Aronson; Renee Perrier; Michael O Woods; Jane S Green; Neal Walker; Christophe Rosty; Susan Parry; Joanne P Young Journal: Am J Gastroenterol Date: 2012-04-24 Impact factor: 10.864
Authors: Daniel D Buchanan; Aung K Win; Michael D Walsh; Rhiannon J Walters; Mark Clendenning; Belinda Nagler; Sally-Ann Pearson; Finlay A Macrae; Susan Parry; Julie Arnold; Ingrid Winship; Graham G Giles; Noralane M Lindor; John D Potter; John L Hopper; Christophe Rosty; Joanne P Young; Mark A Jenkins Journal: Cancer Epidemiol Biomarkers Prev Date: 2013-03-05 Impact factor: 4.254
Authors: Amit A Negandhi; Angela Hyde; Elizabeth Dicks; William Pollett; Banfield H Younghusband; Patrick Parfrey; Roger C Green; Sevtap Savas Journal: PLoS One Date: 2013-04-23 Impact factor: 3.240
Authors: Christophe Rosty; David G Hewett; Ian S Brown; Barbara A Leggett; Vicki L J Whitehall Journal: J Gastroenterol Date: 2012-12-04 Impact factor: 7.527