Penetrance analysis of the PALB2 c.1592delT founder mutation.
OBJECTIVE
PALB2 is a recently identified breast cancer susceptibility gene. We have previously identified in the Finnish population a PALB2 c.1592delT founder truncation mutation that is associated with an increased risk of breast cancer. In the present study, we wanted to assess in more detail the increased risk (hazard ratio, HR) and the age-specific cumulative risk (penetrance) of c.1592delT with regard to susceptibility to breast and other forms of cancer.


METHODS
Modified segregation analyses fitted under maximum likelihood theory were used to estimate age-specific cumulative risks and HRs using the families of mutation carriers identified from a consecutive series of breast cancer cases unselected for age at onset or family history.


RESULTS
We found a substantially increased risk of breast cancer [HR, 6.1; 95% confidence interval (95% CI), 2.2-17.2; P = 0.01] equivalent to a 40% (95% CI, 17-77) breast cancer risk by age 70 years, comparable to that for carriers of mutations in BRCA2. We found marginal evidence (P = 0.06) that the HR for breast cancer decreased with age by 4.2% per year (95% CI, 0.2-8.1), from 7.5-fold at age 30 years to 2.0-fold at age 60 years.


CONCLUSIONS
Our results suggest that it may be appropriate to offer PALB2 c.1592delT mutation testing to Finnish women with breast cancer, especially those with an early age at onset or a family history of breast or related cancers, and to offer carriers the option of participation in extended disease surveillance programs.
Erkko
Hannele
H
Laboratory of Cancer Genetics, Oulu University Hospital, Finland.
Dowty
James G
JG
Nikkilä
Jenni
J
Syrjäkoski
Kirsi
K
Mannermaa
Arto
A
Pylkäs
Katri
K
Southey
Melissa C
MC
Holli
Kaija
K
Kallioniemi
Anne
A
Jukkola-Vuorinen
Arja
A
Kataja
Vesa
V
Kosma
Veli-Matti
VM
Xia
Bing
B
Livingston
David M
DM
Winqvist
Robert
R
Hopper
John L
JL
D000328:Adult; D017677:Age Distribution; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D005387:Finland / Q000453:epidemiology; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins