Abstract P4-12-16: Teasing out the PALB2 phenotype
Authors: Dalton Emily K , McFarland Rachel , Laduca Holly , Li Shuwei , Gau Chia-Ling 
Published: May 2015

Abstract
Background: Biallelic mutations in PALB2 (Partner and Localizer of BRCA2) are known to cause Fanconi Anemia Type N. Multiple reports have demonstrated an increased risk for cancer in individuals heterozygous for PALB2 mutations. For example, a recent study by Antoniou et al reported a 33-58% lifetime risk for breast cancer in PALB2 mutation carriers, with 30% of carriers reporting triple negative breast cancer (TNBC). Other studies have suggested associations between PALB2 heterozygosity and pancreatic cancer, ovarian cancer, male breast cancer, and prostate cancer as well. We aimed to better define PALB2 phenotypes by assessing clinical history of TNBC, pancreatic, ovarian, and prostate cancers amongst PALB2 mutation carriers identified via multigene panel testing.
Methods: We reviewed clinical histories of 11,007 individuals who underwent PALB2 sequence and deletion/duplication analysis as part of a multigene hereditary cancer panel. Descriptive statistics were utilized for clinical histories of PALB2 carriers, and chi square analysis was used to compare clinical histories of PALB2 mutation carriers to mutation-negative controls. Individuals with mutations in other cancer susceptibility genes were excluded from analysis.
Results: A total of 98 PALB2 mutation carriers identified among 9610 individuals were included in our analysis. The majority of mutation carriers were Caucasian (80%) and female (92.8%). All identified mutations were truncating (nonsense, frameshift, or gross deletions). No pathogenic missense mutations were identified in this cohort. 77.6% (n=76) of mutation carriers had breast cancer, diagnosed at a mean age of 48. Hormone receptor status was available for 48 mutation carriers and 2469 controls. 37.5% (18/48) of breast cancers in mutation carriers were reported as triple negative, compared to 17.1% (423/2469) of breast cancers in controls (OR: 2.9 ; p= 0.0002). 7.8% (n= 8) of PALB2 mutation carriers had ovarian cancer. There was no significant difference in the incidence of ovarian cancer between PALB2 mutation carriers and controls (OR: 0.65 ; p= 0.25). Additionally, mutation carriers were significantly less likely to have a family history of ovarian cancer than controls (OR: 0.5; p= 0.02). 5.9% (n=6) of mutation carriers had pancreatic cancer, diagnosed at a mean age of 57.8, compared to 61 for controls. PALB2 mutation carriers were 1.3 times more likely to have personal and/or family history of pancreatic cancer, although this was not statistically significant (p= 0.22). Similarly, PALB2 mutation carriers were 1.5 times more likely to have a family history of prostate cancer, although this was not statistically significant (p= 0.09).
Conclusions: Our data supports existing literature associating PALB2 mutations with TNBC. We did not observe significant associations between PALB2 carrier status and a clinical history of pancreatic, prostate, or ovarian cancers. However, this data should be interpreted with caution, as it is possible that unidentified genetic factors contributed to the clinical history of cancer in our mutation-negative controls. Investigation of PALB2-associated cancer risks in an unselected prospective cohort would help to further elucidate the PALB2 phenotype.
Citation Format: Emily K Dalton, Rachel McFarland, Holly Laduca, Shuwei Li, Chia-Ling Gau. Teasing out the PALB2 phenotype [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-16.