Correspondence to: Bernard Friedenson, PhD, Department of Biochemistry and Molecular Genetics, College of Medicine, University of IllinoisChicago, 900 S. Ashland Ave., Chicago, IL 60607 (e-mail: molmeddoc{at}yahoo.com)
Recently, excellent studies (1,2) concluded that Ashkenazi founder mutations in BRCA1 and/or BRCA2 (BRCA1/2) are not associated with a clinically meaningful increased risk of colorectal cancer. However, the possibility remains that once transformation begins in mutation carriers, colorectal cancer will progress more rapidly so that it can be detected at a younger age. Point estimates (1) suggest that BRCA1/2 founder mutation carriers might be at increased risk for earlier colorectal cancer (for those <65 years old, odds ratio [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; P for interaction = .22). However, Kirchoff et al. (2) cite a lack of evidence for earlier onset colorectal cancer. In the absence of definitive investigation, largely hypothetical functional interrelationships and limited evidence suggest that BRCA mutation carriers should still consider risk factor reduction methods for colorectal cancer (available at http://www.cancer.gov/cancerinfo/pdq/prevention/colorectal/healthprofessional [last accessed: June 25, 2004]), and mutation carriers should still be vigilant for the disease, perhaps with earlier and augmented screening.
BRCA proteins work in multiple pathways, signaling cell cycle delays for a variety of DNA lesions or leading to apoptosis for severe damage. BRCA proteins function in transcriptional regulation and chromatin remodeling, and they are required to repair double-strand breaks by homology-directed recombinationthe most accurate method. Double-strand breaks in mammalian chromosomes stimulate the activity of recombination repair enzymes by more than 100-fold, accounting for 30%50% of repairs (3).
In transformed colon cells of BRCA mutation carriers, BRCA functions are probably lost. In almost all colorectal cancers, the APC gene mutates, presumably leading to MYC overexpression (Fig. 1), which causes unrestrained cell proliferation and blocks cell differentiation (4). Excess MYC expression in normal human cells even within one cell division cycle increases the frequency of chromosomal breaks by several orders of magnitude (4). BRCA1 and NBS1 are identified targets of MYC, directly linking MYC to double-strand break repair and processes preserving genome integrity (5). MYC has no effect on nucleotide excision repair but inhibits homology-directed recombination repair of double-strand breaks (4). This consequence of MYC overexpression implies that it is BRCA-dependent pathways that are inhibited or already lost because homology-directed recombination repairs require BRCA proteins. In a BRCA mutation carrier with only one normal allele, MYC-associated loss of homology-directed recombination repair should occur earlier than in individuals with two normal BRCA alleles. BRCA expression is reduced in at least some sporadic colon adenocarcinomas (6). Somatic loss of one normal BRCA allele is common not only in hereditary but also in sporadic breast tumors.
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Abnormal cells survive to proliferate. Double-strand breaks may continue unrepaired, or repairs are rerouted into inappropriate, error-prone pathways (nonhomologous end-joining and single-strand annealing) that may also be suppressed by MYC. Resulting base deletions, insertions, translocations, fusions, and other activities render the genome more unstable.
The exact sequence of events and the relative contributions of MYC- and BRCA-mediated gene abnormalities (Fig. 1), some from limited evidence and others largely from hypotheses, need experimental clarification. If p53 loss occurs instead before the normal BRCA allele is lost, it might argue against a statistically significant earlier onset of colorectal cancer in BRCA mutation carriers because p53 loss is ordinarily a late event in transformation. Nevertheless, Fig. 1 shows that Niell et al. (1) may have detected colorectal cancers that had an earlier onset associated with loss of BRCA gene function.
The total lifetime risk for colorectal cancer is not strongly elevated in BRCA founder mutation carriers (1,2), unlike that for breast cancer. One factor in explaining this difference might be that breast and colorectal tumors arise from separate stem cell populations. Colon cancer may arise from mutations in colon stem cell crypts, but most breast cancers may develop from mutated stem cells within the breast luminal epithelial compartment.
REFERENCES
1 Niell BL, Rennert G, Bonner JD, Almog R, Tomsho LP, Gruber SB. BRCA1 and BRCA2 founder mutations and the risk of colorectal cancer. J Natl Cancer Inst 2004;96:1521.
2 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;96:6870.
3 Liang F, Han M, Romanienko P, Jasin M. Homology-directed repair is a major double-strand break repair pathway in mammalian cells. Proc Natl Acad Sci U S A 1998;95:51727.
4 Karlsson A, Deb-Basu D, Cherry A, Turner S, Ford J, Felsher DW. Defective double-strand DNA break repair and chromosomal translocations by MYC overexpression. Proc Natl Acad Sci U S A 2003;100:99749.
5 Menssen A, Hermeking H. Characterization of the c-MYC-regulated transcriptome by SAGE: identification and analysis of c-MYC target genes. Proc Natl Acad Sci U S A 2002;99:62749.
6 Romagnolo DF, Chirnomas RB, Ku J, Jeffy BD, Payne CM, Holubec H, et al. Deoxycholate, an endogenous tumor promoter and DNA damaging agent, modulates BRCA-1 expression in apoptosis-sensitive epithelial cells: loss of BRCA-1 expression in colonic adenocarcinomas. Nutr Cancer 2003;46:8292.[CrossRef][ISI][Medline]
7 Smith PD, Crossland S, Parker G, Osin P, Brooks L, Waller J, et al. Novel p53 mutants selected in BRCA-associated tumours which dissociate transformation suppression from other wild-type p53 functions. Oncogene 1999;18:24519.[CrossRef][ISI][Medline]
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