Bias Explains Most of the Parent-of-Origin Effect on Breast Cancer Risk in BRCA1/2 Mutation Carriers.
Paternal transmission of a BRCA mutation has been reported to increase the risk of breast cancer in offspring more than when the mutation is maternally inherited. As this effect might be caused by referral bias, the aim of this study was to assess the parent-of-origin effect of the BRCA1/2 mutation on the breast cancer lifetime risk, when adjusted for referral bias.



A Dutch national cohort including 1,314 proven BRCA1/2 mutation carriers and covering 54,752 person years. Data were collected by family cancer clinics, via questionnaires and from the national Dutch Cancer Registry. The parent-of-origin effect was assessed using Cox regression analyses, both unadjusted and adjusted for referral bias. Referral bias was operationalized by number of relatives with cancer and by personal cancer history.



The mutation was of paternal origin in 330 (42%, P < 0.001) BRCA1 and 222 (42%, P < 0.001) BRCA2 carriers. Paternal origin increased the risk of prevalent breast cancer for BRCA1 [HR, 1.54; 95% confidence interval (CI), 1.19-2.00] and BRCA2 carriers (HR, 1.40; 95% CI, 0.95-2.06). Adjusted for referral bias by several family history factors, these HRs ranged from 1.41 to 1.83 in BRCA1 carriers and 1.27 to 1.62 in BRCA2 carriers. Adjusted for referral bias by personal history, these HRs were 0.66 (95% CI, 0.25-1.71) and 1.14 (95% CI, 0.42-3.15), respectively.



A parent-of-origin effect is present after correction for referral bias by family history, but correction for the personal cancer history made the effect disappear.



There is no conclusive evidence regarding incorporating a BRCA1/2 parent-of-origin effect in breast cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 25(8); 1251-8. ©2016 AACR.
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. j.r.vos@umcg.nl.
Janet R
JR
Vos
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Jan C
JC
Oosterwijk
Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands.
Cora M
CM
Aalfs
Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
Matti A
MA
Rookus
Department of Clinical Genetics, VU University Medical Centre, Amsterdam, the Netherlands.
Muriel A
MA
Adank
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Annemarie H
AH
van der Hout
Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
Christi J
CJ
van Asperen
Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, the Netherlands.
Encarna B
EB
Gómez Garcia
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
Arjen R
AR
Mensenkamp
Department of Medical Oncology, Family Cancer Clinic, Erasmus University MC Cancer Institute, Rotterdam, the Netherlands.
Agnes
A
Jager
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Margreet G E M
MG
Ausems
Department of Gynecological Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Marian J
MJ
Mourits
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Geertruida H
GH
de Bock
D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D000072740:Paternal Inheritance / Q000235:genetics*; D016016:Proportional Hazards Models; D012017:Referral and Consultation; D012307:Risk Factors
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human