Population-based study of changing breast cancer risk in Icelandic BRCA2 mutation carriers, 1920-2000.
Level 3 - non-randomized controlled study
Retrospective population-based kin-cohort study with statistical modeling
PubMed 16418514 · doi:10.1093/jnci/djj012
What was done
Researchers evaluated changing breast cancer incidence and mortality before age 70 from 1920 to 2002 among Icelandic carriers of the BRCA2 founder mutation 999del5. Using the Icelandic Cancer Registry, they determined the mutation status of 847 breast cancer probands diagnosed between 1921 and 1985 (selected without knowledge of family history). They then calculated cumulative breast cancer risk and mortality by age 70 using Poisson modeling based on observed risks in first-degree relatives followed through 2002.
What was found
Of 847 probands, 88 carried the BRCA2 999del5 mutation and 759 did not. Modeled cumulative breast cancer incidence before age 70 in mutation carriers rose from 18.6% (95% CI = 11.0% to 29.5%) in 1920 to 71.9% (95% CI = 45.9% to 100%) in 2002 (P < .001). This approximately fourfold increase mirrored parallel increases in non-carrier relatives (2.6% to 10.7%) and the general Icelandic population (1.8% to 7.5%). Over the same period, cumulative breast cancer mortality before age 70 among carriers increased from 12.1% (95% CI = 5.3% to 23.9%) to 26.9% (95% CI = 10.9% to 55.5%) (P = .08).
Why it matters
This study shows that penetrance of a high-risk cancer gene is not static over time and may be substantially modified by secular changes in environmental or lifestyle risk factors. Genetic counseling risk estimates must account for birth cohort and calendar period.
Limits
The analysis is restricted to a single founder mutation in the Icelandic population, limiting generalizability to other mutations and ethnic groups. Risk was modeled from first-degree relatives rather than direct genotyping of all cohort members. Probands were ascertained through breast cancer diagnosis rather than population screening, introducing potential selection bias, and specific lifestyle or reproductive modifiers were not measured.
Cited by
- context Data from Iceland showed that carrying a BRCA2 mutation was associated with a difference of up to seven years in healthy aging/lifespan, predominantly due to cancer.