Genetic Testing for BRCA1 and BRCA2

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Most breast cancer is not hereditary.  Available estimates say that genetic susceptibility (among white women) is involved in 5 to 10% of breast malignancies and 10 to 15% of ovarian cancers (BRCA mutations can cause either).

We all possess wonderful genes called tumor suppressors. Two of the genes known to suppress breast and ovarian cancer tumors are called BRCA1 and BRCA2.  BRCA (pronounced brack’ uh) stands for BReast CAncer.  Normally, we have two healthy copies of each tumor suppressor gene.  When a mutation, or change, occurs causing one gene to work incorrectly, the cell can still continue to suppress abnormal growth UNTIL something breaks the second gene as well. When both genes of a pair are damaged, the gene can no longer work its tumor suppressing magic and cancer can result. So when one inherits a BRCA gene with a harmful mutation, it means there is just one gene, instead of a pair, standing guard, resisting tumor-generating forces.  One’s risk of breast cancer is then higher than that of the general population.  It could be as much as five times higher, 60% instead of 12%, although this might be an overestimate. (Source: http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA#a2)

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It is important to appreciate that not all children of an adult with a BRCA1 or BRCA2 mutation will inherit the damaged gene instead of the healthy one. Genetic counselors can help various family members estimate the risk they face.  Naturally, those who have experienced the disease, or survivors who knew relatives who were killed by it, feel great concern for relatives that may face increased risk.  However, knowledge of risk is something not everyone desires. Perception of the burden of having breast or ovarian cancer varies also.

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But what about minor children?  For many years, most genetics professionals have counseled against genetic testing of children to determine either carrier status or genetic susceptibility.  Personally, I am convinced that it is not the test or test results themselves that can be harmful to children. Rather, it is the meaning given those results by the adults with influence over the children.  Even mature teenagers are vulnerable to being overwhelmed by their parents’ interpretation of test results.  Parents and others must have the fortitude to override their worry and concern in order to respect family member’s autonomy and right to make their own decisions in the wake of genetic knowledge, regardless of their age or attitude.

© 2011, 2012 Jane Belland Karwoski                                        http://twitter.com/mybluegenome

Don’t Blame Mother

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It shouldn’t be about blame, of course, in the first place. But, what is incomplete about the diagram below?

When a child is diagnosed with an X-linked recessive disorder, the inheritance pattern is often illustrated with a diagram like this one. Notice where the buck stops.

What parents might be shown

What could going back one more previous generation reveal? There are (at least) five possibilities.

First, let’s be clear, the mother might not be a carrier to begin with.

There might not have been a genetic alteration previous to the diagnosed child; the mutation (to use the “m-word”) just sprang up suddenly in the early embryotic divisions of the affected fetus, causing the disorder. In that case, the mother is not a carrier. However, this diagram might be used to explain how things usually work, even when the mother has not been  identified as a carrier through genetic testing.

A second possibility: the mother does have the mutation, but only in some of her ova, or egg cells. She, also, would not be identified as a carrier because the mutation does not affect the DNA in her entire body. A blood test would not reveal the mosaicism (that means some egg cells are affected, others are not) because the DNA in the rest of her body, and many of her ova, does not code for the disorder.

Further possibilities occur when the mother is identified by genetic testing as a carrier in the usual sense (each pregnancy having 25% chance of an affected son, 25% chance of a carrier daughter, 50% chance of an unaffected child, as illustrated in the diagram). But how does she happen to be a carrier?

That brings us to the third possibility: A “spontaneous mutation” occurred making the mother a carrier without previous genetic history in the family. It is often estimated that in some X-linked recessive disorders, around 30% of affected pregnancies result from such “out of the blue” genetic changes.

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Fourth possibility: She was a carrier daughter of a carrier mother. The damaged gene “runs in the family,” although there may never have been an affected son born to anyone before this. Of course, everything said above about the mother, can also be applied in the grandmother’s case.

Fifth possibility: Because a daughter gets an X chromosome from each parent, the mother could have inherited the mutation from her father! Gosh, that’s something you seldom hear!

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But yes, in spermatogenesis, mutations occur. If the sperm carrying an X chromosome with an altered gene fertilizes the egg, well, there you have it, a new carrier daughter. No one will suspect, there will be no reason to test, until an affected grandchild of the new carrier’s father is born and begins to manifest symptoms of a disorder that no one knew ran in the family…because it didn’t.

I’m not sure why knowledge of these different scenarios should affect the burden of guilt felt by many mothers who are implicated in genetic inheritance patterns, but I strongly suspect that it does. After all, guilt is an emotion and therefore irrational to begin with. It is easy to say, “It’s nobody’s fault.” But in the case of X-linked recessive disorders, given the way the inheritance has been diagrammed for generations, is it any wonder so many moms feel it all came from them?