Increased cancer predisposition in family members of colorectal cancer patients harboring the p.V600E BRAF mutation: a population-based study.
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.


CONCLUSIONS
Family members of BRAF CRC patients have an increased predisposition to develop cancer. Future work should aim to identify the causative genetic factors.
Wish
Tyler A
TA
Health Sciences Centre, 300 Prince Philip Drive, St. John's, NL A1B3V6, Canada.
Hyde
Angela J
AJ
Parfrey
Patrick S
PS
Green
Jane S
JS
Younghusband
H Banfield
HB
Simms
Michelle I
MI
Fontaine
Dan G
DG
Dicks
Elizabeth L
EL
Stuckless
Susan N
SN
Gallinger
Steven
S
McLaughlin
John R
JR
Woods
Michael O
MO
Green
Roger C
RC
D000328:Adult; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045647:DNA Glycosylases / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase