© 2004 by Oxford University Press
© 2004 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: BRCA1 and BRCA2 Founder Mutations and the Risk of Colorectal Cancer
Affiliations of authors: Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan Medical School, Ann Arbor (BLN, JDB, SBG); Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor (BLN, SBG); Department of Human Genetics, University of Michigan Medical School, Ann Arbor (SBG); Department of Community Medicine and Epidemiology, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel (GR); CHS National Cancer Control Center, Haifa, Israel (GR)
Correspondence to: Stephen B. Gruber, MD, PhD, MPH, Division of Molecular Medicine and Genetics, 4301 MSRB III, Box 0638, 1150 W. Medical Center Dr., University of Michigan, Ann Arbor, MI 48109-0638 (e-mail: sgruber{at}umich.edu)
BRCA1 and/or BRCA2 (BRCA1/2) mutations induce alterations in DNA repair pathways, thereby forcing cells to use more error-prone repair pathways such as nonhomologous end-joining and/or single-strand annealing rather than recombination between homologous DNA sequences (1). In conjunction with these recognized effects on DNA integrity, Friedenson notes that the point estimates of the odds ratios (ORs) for BRCA1/2 carriers from our case–control study of colorectal cancer were slightly higher for those younger than 65 years than for those 65 years old or older and suggests that colorectal cancer within BRCA1/2 mutation carriers might progress more rapidly. Although this is a reasonable theoretical possibility, we would like to highlight that the statistical evidence Friedenson cites from our study in support of this argument is weak (2). We did not observe a statistically significantly increased risk of colorectal cancer among either younger or older subjects who carry BRCA1/2 mutations (for those <65 years old, OR = 3.14, 95% confidence interval [CI] = 0.64 to 15.43; for those 
65 years old, OR = 0.96, 95% CI = 0.48 to 1.91), and the interaction term testing the hypothesis that these results differed from one another was not statistically significant (P = .22) (2).
To further address this hypothesis with our interim dataset, we analyzed age at diagnosis of colorectal cancer, Dukes’ stage, and histologic grade among BRCA1/2 founder mutation carriers and compared it with those among noncarriers. If the hypothesis that colorectal cancer progresses more rapidly in BRCA1/2 mutation carriers is clinically meaningful, then one might expect that BRCA1/2 mutation carriers, compared with noncarriers, would present with colorectal cancer at an earlier age and have more advanced or aggressive disease.
The mean age at diagnosis of colorectal cancer for BRCA1/2 carriers was slightly lower than that of noncarriers (69.1 versus 72.3 years, respectively), and this difference was not statistically significant (P = .13). We suggest that this very modest age difference is unlikely to influence recommendations regarding screening. Confirmed Dukes’ stage is currently available for 20 (83.3%) of the 24 BRCA1/2 mutation carriers with colorectal cancer and for 806 (82.7%) of the 975 noncarrier patients with colorectal cancer. Given the small number of BRCA1/2 mutation carriers, we compared patients with Dukes’ stage A or B colorectal cancer to patients with Dukes’ stage C or D colorectal cancer. Twelve (60%) of the 20 BRCA1/2 mutation carriers with colorectal cancer and 518 (64.3%) of the 806 noncarrier patients with colorectal cancer had stage A or B disease, indicating that BRCA1/2 mutation carriers did not present with more advanced disease (P = .69).
Histologic grade was available for 16 (66.7%) of the 24 BRCA1/2 mutation carriers with colorectal cancer and 747 (76.6%) of the 975 noncarrier patients with colorectal cancer. Of the colorectal tumors in the 16 BRCA1/2 mutation carriers, one (6.25%) was poorly differentiated, 12 (75%) were moderately differentiated, and three (18.75%) were well differentiated. Of the colorectal tumors in the 747 noncarrier patients with colorectal cancer, 57 (7.6%) tumors were poorly differentiated, 558 (74.7%) were moderately differentiated, and 132 (17.7%) were well differentiated. Compared with noncarriers, BRCA1/2 mutation carriers had no detectable difference in colorectal tumor grade (P = .98).
Kaplan–Meier survival analyses were conducted with the survival data available on 996 (99.4%) of the 1002 Ashkenazi Jewish patients with colorectal cancer (Fig. 1). BRCA1/2 mutation carrier status did not statistically significantly affect median survival after a diagnosis of colorectal cancer (P = .87).
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Our data and those from Kirchhof et al. (3) provide evidence that Ashkenazi BRCA1/2 founder mutations are not strongly associated with an increased risk of colorectal cancer. Furthermore, BRCA1/2 mutations do not statistically significantly affect the age at diagnosis, Dukes’ stage, tumor grade, or survival after a diagnosis of colorectal cancer, indicating that colorectal cancer within BRCA1/2 mutation carriers is unlikely to progress more rapidly or present at a substantially younger age. Therefore, although we acknowledge the possibility that colorectal cancer arising in BRCA1/2 carriers may be pathogenetically distinct, we disagree with Friedenson’s suggestion that BRCA1/2 mutation carriers should consider earlier and augmented screening. We advocate that BRCA1/2 mutation carriers follow the colorectal cancer screening guidelines outlined for the general population (4).
NOTES
Supported in part by National Institutes of Health grants RO1-CA81488 (SBG), NIGMS T32 GM07863 (BLN), and T32 HG00040 (BLN).
REFERENCES
1 Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 2002;108:171–82.[CrossRef][Web of Science][Medline]
2 Niell BL, Rennert G, Bonner JD, Almog R, Gruber SB. BRCA1 and BRCA2 founder mutations and the risk of colorectal cancer. J Natl Cancer Inst 2004;96:15–21.
3 Kirchhoff T, Satagopan JM, Kauff ND, Huang H, Kolachana P, Palmer C, et al. Frequency of BRCA1 and BRCA2 mutations in unselected Ashkenazi Jewish patients with colorectal cancer. J Natl Cancer Inst 2004;96:68–70.
4 Winawer S, Fletcher R, Rex D, Bond J, Burt R, Ferrucci J, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale—update based on new evidence. Gastroenterology 2003;124:544–60.[CrossRef][Web of Science][Medline]
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J Natl Cancer Inst 2004 96: 1184-1185.
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