Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls.
BACKGROUND
PALB2 is emerging as a high-penetrance breast cancer predisposition gene in the order of BRCA1 and BRCA2. However, large studies that have evaluated the full gene rather than just the most common variants in both cases and controls are required before all truncating variants can be included in familial breast cancer variant testing.


METHODS
In this study we analyse almost 2000 breast cancer cases sourced from individuals referred to familial cancer clinics, thus representing typical cases presenting in clinical practice. These cases were compared to a similar number of population-based cancer-free controls.


RESULTS
We identified a significant excess of truncating variants in cases (1.3 %) versus controls (0.2 %), including six novel variants (p = 0.0001; odds ratio (OR) 6.58, 95 % confidence interval (CI) 2.3-18.9). Three of the four control individuals carrying truncating variants had at least one relative with breast cancer. There was no excess of missense variants in cases overall, but the common c.1676A > G variant (rs152451) was significantly enriched in cases and may represent a low-penetrance polymorphism (p = 0.002; OR 1.24 (95 % CI 1.09-1.47).


CONCLUSIONS
Our findings support truncating variants in PALB2 as high-penetrance breast cancer susceptibility alleles, and suggest that a common missense variant may also lead to a low level of increased breast cancer risk.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, East Melbourne, VIC, 8006, Australia. ella.thompson@petermac.org.|The Sir Peter MacCallum Department of Oncology, St Andrews Place, East Melbourne, VIC, 3002, Australia. ella.thompson@petermac.org.
Ella R
ER
Thompson
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, East Melbourne, VIC, 8006, Australia. kylie.gorringe@petermac.org.|The Sir Peter MacCallum Department of Oncology, St Andrews Place, East Melbourne, VIC, 3002, Australia. kylie.gorringe@petermac.org.|Department of Pathology, University of Melbourne, Corner GrattonStree and Royal Parade, Melbourne, VIC, 3010, Australia. kylie.gorringe@petermac.org.
Kylie L
KL
Gorringe
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, East Melbourne, VIC, 8006, Australia. simone.rowley@petermac.org.
Simone M
SM
Rowley
Discipline of Medical Genetics and Centre for Information-Based Medicine, The University of Newcastle and Hunter Medical Research Institute, 1 Kookaburra Circuit, Newcastle, NSW, 2305, Australia. michelle.wong-brown@newcastle.edu.au.
Michelle W
MW
Wong-Brown
Familial Cancer Centre, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia. simone.mcinerny@petermac.org.
Simone
S
McInerny
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, East Melbourne, VIC, 8006, Australia. na.li@petermac.org.|Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan, Hubei, China. na.li@petermac.org.
Na
N
Li
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, East Melbourne, VIC, 8006, Australia. Alison.trainer@petermac.org.|Familial Cancer Centre, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia. Alison.trainer@petermac.org.
Alison H
AH
Trainer
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, East Melbourne, VIC, 8006, Australia. lisa.devereux@petermac.org.|LifePool, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia. lisa.devereux@petermac.org.
Lisa
L
Devereux
Bioinformatics Core Facility, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia. maria.doyle@petermac.org.
Maria A
MA
Doyle
Bioinformatics Core Facility, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia. Jason.li@petermac.org.
Jason
J
Li
Bioinformatics Core Facility, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia. Richard.lupat@petermac.org.
Richard
R
Lupat
Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia. martin.delatycki@ghsv.org.au.
Martin B
MB
Delatycki
The Sir Peter MacCallum Department of Oncology, St Andrews Place, East Melbourne, VIC, 3002, Australia. Gillian.mitchell@petermac.org.|Familial Cancer Centre, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia. Gillian.mitchell@petermac.org.|Hereditary Cancer Program, BC Cancer Agency, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada. Gillian.mitchell@petermac.org.
Gillian
G
Mitchell
The Sir Peter MacCallum Department of Oncology, St Andrews Place, East Melbourne, VIC, 3002, Australia. paul.james@petermac.org.|Department of Pathology, University of Melbourne, Corner GrattonStree and Royal Parade, Melbourne, VIC, 3010, Australia. paul.james@petermac.org.|Familial Cancer Centre, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia. paul.james@petermac.org.
Paul A
PA
James
Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan, Hubei, China. rodney.scott@newcastle.edu.au.|Division of Genetics, Hunter Area Pathology Service, Lookout Road, Newcastle, NSW, 2305, Australia. rodney.scott@newcastle.edu.au.
Rodney J
RJ
Scott
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, East Melbourne, VIC, 8006, Australia. ian.campbell@petermac.org.|The Sir Peter MacCallum Department of Oncology, St Andrews Place, East Melbourne, VIC, 3002, Australia. ian.campbell@petermac.org.|Department of Pathology, University of Melbourne, Corner GrattonStree and Royal Parade, Melbourne, VIC, 3010, Australia. ian.campbell@petermac.org.
Ian G
IG
Campbell
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001315:Australia; D001943:Breast Neoplasms / Q000235:genetics; D016022:Case-Control Studies; D000076164:Fanconi Anemia Complementation Group N Protein; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D015995:Prevalence; D012306:Risk; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins