abstract
BACKGROUND:
Genetic
anticipation, the earlier onset of disease in successive generations,
has been reported in hereditary breast and ovarian cancer syndrome
(HBOC), but little is known about its underlying mechanisms.
Ascertainment bias has been suggested as a reason in previous studies.
Likewise, cohort effect, which may be caused by environmental factors,
can be misinterpreted as genetic anticipation.
METHODS:
The
authors reviewed the pedigrees of 176 kindreds, segregating those with
deleterious mutations in breast cancer genes 1 and 2 (BRCA1/BRCA2) who
had at least 2 consecutive generations of the same cancer (breast or
ovarian). By using mutation probabilities as analytical weights in
weighted random-effect models, generational differences in the age at
onset of breast/ovarian cancer were calculated. The analyses were
further controlled for ascertainment bias by excluding probands and
adjusting for birth-cohort effect in the anticipation models.
RESULTS:
The
mean age at the onset of breast cancer for the probands' generation was
41.9 years, which was 6.8 years and 9.8 years earlier than the parents'
and grandparents' generations, respectively. The anticipation effect
for breast cancer remained significant after excluding the probands.
There was a birth-cohort effect: patients who were born in 1930s and
1940s had breast cancer 5.0 years and 7.6 years earlier than patients
who were born before 1920. The difference in breast cancer age of onset
across generations was no longer significant after adjusting for
birth-cohort effect.
CONCLUSIONS:
The observed anticipation effect was driven mainly by a decrease in age
of onset across birth cohorts, underscoring the need for risk-reducing
interventions that target changing environmental/lifestyle factors in
BRCA1/BRCA2 carriers.
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