Anti-Müllerian hormone serum concentrations of women with germline BRCA1 or BRCA2 mutations.
OBJECTIVE
Do women with ITALIC! BRCA1 or ITALIC! BRCA2 mutations have reduced ovarian reserve, as measured by circulating anti-Müllerian hormone (AMH) concentration?


CONCLUSIONS
Women with a germline mutation in ITALIC! BRCA1 have reduced ovarian reserve as measured by AMH.


BACKGROUND
The DNA repair enzymes encoded by ITALIC! BRCA1 and ITALIC! BRCA2 are implicated in reproductive aging. Circulating AMH is a biomarker of ovarian reserve and hence reproductive lifespan.


METHODS
This was a cross-sectional study of AMH concentrations of 693 women at the time of enrolment into the Kathleen Cuningham Foundation Consortium for research in the Familial Breast Cancer (kConFab) cohort study (recruitment from 19 August 1997 until 18 September 2012). AMH was measured on stored plasma samples between November 2014 and January 2015 using an electrochemiluminescence immunoassay platform.


METHODS
Eligible women were from families segregating ITALIC! BRCA1 or ITALIC! BRCA2 mutations and had known mutation status. Participants were aged 25-45 years, had no personal history of cancer, retained both ovaries and were not pregnant or breastfeeding at the time of plasma storage. Circulating AMH was measured for 172 carriers and 216 non-carriers from families carrying ITALIC! BRCA1 mutations, and 147 carriers and 158 non-carriers from families carrying ITALIC! BRCA2 mutations. Associations between plasma AMH concentration and carrier status were tested by linear regression, adjusted for age at plasma storage, oral contraceptive use, body mass index and cigarette smoking.


RESULTS
Mean AMH concentration was negatively associated with age ( ITALIC! P < 0.001). Mutation carriers were younger at blood draw than non-carriers ( ITALIC! P ≤ 0.031). ITALIC! BRCA1 mutation carriers had, on average, 25% (95% CI: 5%-41%, ITALIC! P = 0.02) lower AMH concentrations than non-carriers and were more likely to have AMH concentrations in the lowest quartile for age (OR 1.84, 95% CI: 1.11-303, ITALIC! P = 0.02). There was no evidence of an association between AMH concentration and ITALIC! BRCA2 mutation status ( ITALIC! P = 0.94).


CONCLUSIONS
AMH does not directly measure the primordial follicle pool. The clinical implications of the lower AMH concentrations seen in ITALIC! BRCA1 mutation carriers cannot be assessed by this study design.


CONCLUSIONS
Women with a germline mutation in ITALIC! BRCA1 may have reduced ovarian reserve. This is consistent with other smaller studies in the literature and has potential implications for fertility and reproductive lifespan.


BACKGROUND
kConFab is supported by a grant from the Australian National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. K.A.P. is an Australian National Breast Cancer Foundation Practitioner Fellow. J.L.H. is a NHMRC Senior Principal Research Fellow. M.H. is a NHMRC Practitioner Fellow. R.A.A. reports personal fees from Roche Diagnostics & Beckman Coulter outside the submitted work and C.S. reports other earnings from Melbourne IVF outside the submitted work. The remaining authors have nothing to declare and no conflicts of interest.
Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia Sir Peter MacCallum Dep. of Oncology, The University of Melbourne, Parkville 3053, Australia Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Parkville 3053, Australia Department of Medicine, St Vincent's Hospital, The University of Melbourne, Parkville 3053, Australia kelly.phillips@petermac.org.
Kelly-Anne
KA
Phillips
Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia School of Medicine, Faculty of Health, Deakin University, Geelong 3220, Australia.
Ian M
IM
Collins
Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Parkville 3053, Australia Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne 3004, Australia.
Roger L
RL
Milne
Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia Department of Medicine, St Vincent's Hospital, The University of Melbourne, Parkville 3053, Australia Department of Medical Oncology, St Vincent's Hospital, Fitzroy 3065, Australia.
Sue Anne
SA
McLachlan
Prince of Wales Clinical School, University of New South Wales, Sydney 2052, Australia Department of Medical Oncology, Prince of Wales Hospital, Randwick 2031, Australia.
Michael
M
Friedlander
Department of Obstetrics and Gynaecology, the Royal Women's Hospital, Parkville 3053, Australia.
Martha
M
Hickey
Department of Obstetrics and Gynaecology, the Royal Women's Hospital, Parkville 3053, Australia Melbourne IVF, East Melbourne 3002, Australia.
Catharyn
C
Stern
Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Parkville 3053, Australia.
John L
JL
Hopper
Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia.
Richard
R
Fisher
Melbourne IVF, East Melbourne 3002, Australia.
Gordon
G
Kannemeyer
Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia.
Sandra
S
Picken
Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia.
Charmaine D
CD
Smith
School of Computer Science, University of St Andrews, Fife KY16 9AJ, UK.
Thomas W
TW
Kelsey
Medical Research Council Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH8 9YL, UK.
Richard A
RA
Anderson
D000328:Adult; D054304:Anti-Mullerian Hormone / Q000097:blood*; D001315:Australia; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004260:DNA Repair; D005260:Female; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D009520:New Zealand; D065851:Ovarian Reserve / Q000235:genetics*
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D015415:Biomarkers; D054304:Anti-Mullerian Hormone
BRCA1; BRCA2; DNA repair; anti-Müllerian hormone; fertility; ovarian reserve; reproduction