Minerva
BMJ 2002; 325 doi: https://doi.org/10.1136/bmj.325.7362.502 (Published 31 August 2002) Cite this as: BMJ 2002;325:502All rapid responses
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Minerva's intepretation of a recent article in JNCI [1] is highly
misleading (August 31st). [Given that it is arguably the most read
section of the BMJ I felt a response was called for and should be
published.]
People who think that the lifetime risk of breast cancer
(penetrance) associated with a mutation in BRCA1 or BRCA2 is high are not
mistaken. Penetrance estimates are usually derived using pedigree data
from families in which a mutation has been found to be segregating. These
families have been ascertained by carrying out a mutation search in a
series of probands--other individuals in the families of mutation
positive probands may also then be tested. The ascertainement criteria
for the probands can be divided into three broad categories:
(i) an
individual (usually with cancer) from a multi-case family;
(ii) a woman
with breast cancer from a case series unselected for family history;
(iii)
an individual from the general population, unselected either for case
status or for family history.
It is also possible to use data from a
standard case-control study design estimate penetrance without the need
for pedigree data. Let the average penetrance for all mutation carriers
at birth be x. Pedigree data from the third category of study and
population based case-control data will provide an unbiased estimate of x.
Pedigree data from the first two categories will over estimate x if, as
seems highly likely, there are other genes that modify risk, there are
other risk factors that run in families that modify risk, or some
mutations confer higher risks than others. Under these circumstances, the
penetrance estimates from the first category of families will also be
higher than those from the second, as observed in published data. There
are no published studies that have used pedigree data from the third
category of proband, but one case-control study [2] did report the
penetrance for BRCA1 (46% by age 70 compared to US population risk of 8%)
and BRCA2 (26% by age 70) to be somewhat lower than most (but not all)
estimates from unselected case series. However, the confidence limits on
the estimates were wide, and there are data to suggest that the controls
from this study may have been selected from a high-risk pool. This would
have resulted in an underestimate of risk. Thus, although the magnitude
of the overestimation of category 1 and 2 studies is not known with any
precision, it is unlikely to be large, and so breast cancer risk averaged
across all mutation carriers should probably be considered to be high.
A further consideration is the clinical utility of any given
penetrance estimate. The average risk, x, over all mutation carriers,
whether or not it is considered high, will not be appropriate for
counselling the majority of individuals who are found to carry mutations.
Most cancer genetics clinics restrict BRCA mutation testing to families
with multiple cases of breast and/or ovarian cancer (category 1). For
counselling purposes, penetrance estimates derived from similar multi-case
families will provide the most appropriate average risks. Families of
mutation positive probands, ascertained through a case series unselected
for family history, that have been tested in a research setting may also
present to a cancer genetics clinic (category 2).
Penetrance estimates
derived from these type of data are then appropriate for counselling
mutation positive women in these families. It is highly unlikely that
mutation testing in the general population, unselected for family history
or case status, will be carried out in the foreseeable future, with the
possible exception of populations, such as the Ashkenazim, where there are
common founder mutations.
Of course, any penetrance estimate, represents an average across a
given population sub-group. The challenge to genetic epidemiology is to
develop algorithms that take into account other risk factor data that will
provide more precise individual risk estimates to aid the counselling
process. In the meantime, the penetrance estimates we have now provide a
useful and valid working tool.
1. Begg CB. On the use of familial aggregation in population-based
case probands for calculating penetrance. J Natl Cancer Inst
2002;94(16):1221-6.
2. Satagopan JM, Offit K, Foulkes W, Robson ME, Wacholder S, Eng CM, et
al. The lifetime risks of breast cancer in Ashkenazi Jewish carriers of
BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev 2001;10(5):467
-73.
Competing interests: No competing interests
BOLD BUT HAIRY OLDER MEN
I was intrigued but faintly concerned by Minerva's reference to the
item concerning lions preferences for hair colour.
I am sure that there is a hidden message in this. Is she perpetuating the
male fantasy that blondes have more fun? (Most often with someone else)
Has a recent hair rinse gone slightly off colour?
Where does this leave us damn nearly bald, but otherwise hirsuite, middle
aged men who periodically count the number of new white hairs fortunately
hidden from the public?
Competing interests: No competing interests