EDITORIAL

One Less Thing to Worry About: The Shrinking Spectrum of Tumors in BRCA Founder Mutation Carriers

Judy E. Garber, Sapna Syngal

Affiliations of authors: Division of Population Sciences, Dana-Farber Cancer Institute (JEG, SS), and Division of Gastroenterology, Brigham and Women’s Hospital (SS), Harvard Medical School, Boston, MA.

Correspondence to: Judy E. Garber, MD, MPH, Dana-Farber Cancer Institute, 44 Binney St., SM 209, Boston, MA 02115 (e-mail: judy_garber{at}dfci.harvard.edu)

Defining the spectrum of disease associated with germline mutations in cancer susceptibility genes can be a difficult business. Many of the multiple cancer syndromes were defined clinically long ago, generally when astute clinicians and epidemiologists recognized that rare tumors, sometimes associated with congenital anomalies, clustered in families, and that survivors of certain neoplasms often developed other rare malignancies. The development of the Knudson–Strong hypothesis (1) provided a framework on which to place these observations, particularly when the cancers developed at earlier ages than are typical of the general population. Evidence that these rare tumors occurred more often than chance would dictate was relatively easy to gather, because the infrequency of the tumor made it possible to demonstrate statistically significant differences from population-based figures with relatively small numbers of study subjects. Examples of these syndromes include multiple endocrine neoplasias type 2A (2), Li–Fraumeni syndrome (3), and osteo- and soft tissue sarcomas associated with retinoblastoma (4).

As part of the explosion in cancer genetics of the last decade, many new cancer susceptibility genes have been identified, more often for their association with a single cancer that dominates a syndrome. Both high- and low-penetrance genes have been recognized, and the search for the several susceptibility genes that underlie the wide array of malignancies to date has yielded important genes for many of the common cancers, including breast and colorectal cancer and melanoma but not the more intractable lung or prostate cancers. We now anticipate that geneticists and epidemiologists will assemble panels of specific genes with a range of penetrances underlying common as well as rare cancers, and that understanding the mechanisms of the tissue specificity of these genes will provide important clues to their function and perhaps to the etiology of the apparently sporadic forms of the various malignancies (5).

Defining the spectrum of tumors associated with germline mutations in each specific syndrome has remained challenging, especially for the more common cancers. In this issue of the Journal, two teams have wrestled with the issue of the extent to which colorectal cancer is part of the hereditary breast/ovarian cancer syndrome. In the more common hereditary cancer syndromes, recognition of even comparatively small increases in the risks of associated cancers may affect the human and economic costs of caring for the increasingly recognized mutation carriers. The first reports of a fourfold increased risk of colorectal cancer in patients with the hereditary breast cancer syndromes came from early studies of linked families from the Breast Cancer Linkage Consortium (6), when BRCA1 had been mapped but not yet cloned. Earlier epidemiologic studies had demonstrated an increased rate of colon cancers among the family members of individuals with multiple primary breast and colon cancers (7) and an increased incidence of colon cancer among women with a family history of breast cancer (9). Studies have evolved, and some investigations of associated cancers in series of individuals carrying germline mutations in the gene or genes underlying a specific syndrome have been criticized for selection biases that might influence the cohorts (10). In recent efforts to assess the spectrum of tumors in BRCA1 and BRCA2 mutation carriers in families from a cancer risk clinic (11) and the Breast Cancer Linkage Consortium (12) published in the Journal, experienced investigators have acknowledged the limitations of these approaches. In the accompanying editorial, Gruber and Petersen called for population-based studies to address these questions (13).

Assembling population-based cohorts of mutation carriers of even common cancer susceptibility genes of sufficient size to assess the risk of less frequent cancers is not yet feasible for most syndromes. The genes are generally large, making the costs of analyses excessive for studies of sufficient power to address the question. In this issue of the Journal, Niell et al. (14) used perhaps the best available, least biased approach. In their population-based case–control study of incident colorectal cancer cases from five major hospitals in Israel with matched control subjects, they examined the prevalence of the three common founder mutations in BRCA1 and BRCA2 in the Ashkenazi Jewish population. They identified similar rates of mutations in the case patients and control subjects (odds ratio [OR] = 1.24, 95% confidence interval [CI] = 0.68 to 2.26). They were able to assess colorectal cancer risk in mutation carriers and, again, observed no increased risk compared with control subjects (OR = 1.21, 95% CI = 0.67 to 2.19). They also did not find an increased risk of colorectal cancer associated with a family history of breast cancer in a female relative (OR = 1.03, 95% CI = 0.75 to 1.41), in contrast to earlier studies.

In the related brief communication, Kirchhoff et al. (15) assembled 586 unselected case patients with colorectal cancer who identified themselves as Ashkenazi Jews from the Memorial Sloan-Kettering Cancer Center and compared the rate of BRCA1/2 founder mutations to that in 5012 Ashkenazi Jewish control subjects from the Washington, DC, Jewish volunteer cohort assembled by National Cancer Institute investigators. This group’s regular use of DNA from paraffin sections permits unbiased and nearly complete specimen collection from identified cases and the application of inexpensive analytic methodologies that, though different for case patients and control subjects, have been sensitive in their hands. Again, there was no difference in the mutation prevalence between the groups (relative risk [RR] for colorectal cancer = 0.50, 95% CI = 0.22 to 1.14), showing no association with the BRCA founder mutations.

These studies were certainly well done, but are they the final words on the subject? It depends on the exact question one is trying to answer. An increased risk of colorectal cancer in BRCA carriers may yet be demonstrated, but it seems more and more likely that it will be a small increase, if that, or limited to a particular subset of carriers. The recommendations of Kirchhoff et al. (15), therefore, seem appropriate. Intensified targeted colorectal cancer screening and prevention should be directed only to the subset of BRCA mutation carriers who have remarkable personal or family colorectal cancer history or other risk factors. However, these studies cannot address some particular issues that are germane to the genetic links between hereditary colorectal and breast cancer. Neither study had sufficient power to evaluate a possible increased risk of colorectal cancer associated with either gene independently, and it is clear that the tumor spectra of BRCA1 and BRCA2 are not identical. These studies also cannot address the possibilities of mutation-specific risk or the effects of modifying influences, particularly the various dietary and hormonal exposures that have been shown to modify the risks of sporadic colorectal cancer (16). Niell et al. (14) did examine a possible modifying effect of another Ashkenazi founder mutation, the I1307K mutation in the APC gene, on the BRCA-associated risk as a covariate but, as they acknowledge, with limited power. No effect was observed.

Links between breast and colorectal cancer are certainly present in other inherited cancer syndromes and should be considered when there appears to be an excess of both breast and colorectal cancer in certain families. Muir–Torre, Peutz–Jeghers, and Cowden syndromes come to mind, as well as the recent demonstration of the CHEK2 1100delC mutation in European hereditary breast and colon cancer families (17). Therefore, there will continue to be interest in the possible connections between these two tumors. However, from currently available literature, including the important addition of the two studies in this issue of the Journal, it appears that for most individuals at increased risk of breast cancer, including those with the common breast/ovarian cancer founder mutations, colorectal cancer is at least one issue that they don’t have to worry so much about. Considering recent similar studies excluding excess prostate cancer risk among BRCA1 carriers, one might conclude that BRCA1 really does discriminate, conferring remarkable risk of breast, ovarian, and related cancers on women only. The tissue specificity of cancer risk for this DNA repair gene remains a subject of important basic scientific inquiry. Rigorous epidemiologic studies continue to inform those inquiries and to clarify the genetics of hereditary cancer syndromes.

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