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Phenocopy Hypothesis

by Drea Thew

Women from BRCA families (families found to have a BRCA1 or BRCA2 mutation) who test negative for the mutation are usually considered “true negatives,” and advised that their risk for breast and ovarian cancer is comparable to that of women in the general population. A British study published in the November 2006 issue of the Journal of Medical Genetics questions whether this is always true. Additional studies will be critical to deciding which assessment is correct.

The study involved 277 English families with a known BRCA mutation and high rates of breast and ovarian cancer. Information regarding 1,444 women in these families was collected and analyzed: 531 were living relatives of the first family member to test positively for a mutation. Of these, 258 tested negative for the family mutation, including 28 with breast cancer at ages ranging from 23 to 87 (median age 49), and four with ovarian cancer at ages ranging from 60 to 66. Researchers identified study participants who were diagnosed with breast or ovarian cancer but negative for their family mutation as “phenocopies”—they expressed a genetic condition (in this case cancer), even though they didn’t actually have a known gene mutation. Compared to the expected number of cancers in the general population, the incidence of breast cancer in the study phenocopy group was about 5.3 times higher.

The authors concluded that among the families in this study, the female first-degree relatives of known BRCA1/2 carriers, who themselves test negative, have a breast cancer risk approximately 3.2 times that of the general population. They estimated the absolute risk for breast cancer in these women as approximately 6.4% by age 50 and recommended true negatives begin breast screening at age 35. This recommendation is significant, because it advises screenings begin 5 to 15 years earlier than current standards dictate. It is important to note, however, that this study did not suggest that a true negative’s risk is nearly as high as women with a BRCA mutation. Similarly, the authors do not conclude that women who tested negative are candidates for chemoprevention or risk-reducing surgery.

Limitations of the study involved the inclusion of “untested affected” women in the analysis (those who had breast or ovarian cancer, but whose mutation status was unknown because they had not received BRCA testing) as well as the inclusion of individuals who were diagnosed with cancer prior to genetic testing. Researchers estimated how many would likely test negative for the family mutation. This was done in part to include enough participants to assure that the differences in risk were not due to chance.

Due to these limitations and additional concerns, other researchers urge caution in reaching conclusions based on the results from a single study. “This is a fascinating and potentially disturbing study, but it is the first and requires confirmation before it changes our thinking and action,” said Dr. Judy Garber director of the Cancer Genetics Program at Dana-Farber Cancer Institute. “Other groups need to look at their data to see whether the same finding is observed. If it is, then we need to change the way BRCA-negative women are counseled and cared for. If not, then we should not alarm all of those women unnecessarily.”

Dr. Timothy Rebbeck of the University of Pennsylvania notes that early studies of BRCA families found higher lifetime risks for cancer than later studies. Risks have been revised downward as research has evolved with different populations and different study designs. “It’s entirely possible that looking at the same question using larger or different samples, we will get different answers,” said Rebbeck. “The message to BRCA-negative women reading this study should be ‘don’t panic over these numbers.’”

Geneticist Dr. Rebecca Sutphen at Moffitt Cancer Center points out another limitation of such studies: only a select group of families have been tested thus far. “Studying only tested families with large numbers of individuals with breast or ovarian cancer, including due to other reasons, would artificially elevate estimates of cancer risk. The published findings should be considered only in the research context and not be used to guide clinical decisions.”

Dr. Kenneth Offit at Memorial Sloan-Kettering says that the most definitive way to settle the question is to look at the occurrence of breast cancer prospectively in women after a negative BRCA test. His group and others are looking at that question (see pg. 2 sidebar). He points out that when the analysis of Smith et al. was restricted only to breast cancer cases diagnosed after a negative BRCA test, the observed risk was not increased, although there was a weak, statistically insignificant trend.

It is important to note that all women are at risk for breast cancer. None should be complacent about screening and following up on symptoms. If the phenocopy hypothesis proved to be true, what might be causing an increased breast cancer risk in women who are true negatives? One possibility is the presence of unidentified “modifier genes” in families that may intensify the effect of BRCA mutations in carriers and somewhat elevate risk in non-carriers. Environmental exposures that are shared within families, diet and lifestyle choices, and reproductive factors may also play a role.

Although tremendous strides have been made since the early ‘90s, our understanding of hereditary breast and ovarian cancer is still relatively young. Many questions remain unanswered. Scientific inquiry by its very nature is slow. It takes time to design and complete quality studies, and requires a sufficient period for results to be challenged, reassessed and confirmed or refuted by therest of the research community. For those of us whose lives and families are affected by hereditary cancer, it’s not easy to remain patient as the process continues. FORCE will continue to advocate for research funding and attention for our community, so that we can have conclusive answers to these
complex questions.

Testing the BRCA Phenocopy Hypothesis

The British study established the BRCA phenocopy hypothesis: that true negative women in BRCA families have a higher breast cancer risk than the general population. This hypothesis is already being tested by other prominent BRCA researchers. Steven Narod of the University of Toronto and colleagues Jacek Gronwald, Cezary Cybulski and Jan Lubinski will publish their findings in the Journal of Medical Genetics. They note that the selection method could influence the findings of the British study: “The more cases of breast cancer [in a family], the more likely testing is to occur. That is, the presence of phenocopies in the family increases the likelihood that testing would be conducted. Hence, the greater than expected number of phenocopies observed in the families.”

Dr. Narod, renowned BRCA researcher, intends to continue to counsel true negative women as if they are not at increased risk for breast or ovarian cancer. Researchers at Memorial Sloan Kettering and the University of Pennsylvania also plan to analyze their own databases of BRCA families to determine the rate of phenocopies among them.

References

Smith A, Moran A, Boyd MC, Bulman M, et al. Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening. Journal of Medical Genetics, 2007; 44:10-15.

Antoniou AC, Pharoah PD, McMullan G, Day NE, et al. Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study. Genetic Epidemiology, 2001; 21:1-18.

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