Deleterious mutations in the PALB2 gene may account for the development of breast cancer in women with an elevated risk due to a family history of breast or ovarian cancer, but who test negative for the BRCA1 or BRCA2 genes.
Kelly Metcalfe, RN, PhD, FAAN
Deleterious mutations in the PALB2 gene may account for the development of breast cancer in women with an elevated risk due to a family history of breast or ovarian cancer, but who test negative for the BRCA1 or BRCA2 genes, researchers reported at the European Society of Gynaecological Oncology (ESGO) 2017 Congress.1
However, PALB2 mutation is unlikely to play a role in ovarian cancer in this high-risk cohort.
The PALB2 gene has been called the nuclear partner of the BRCA2 gene. PALB2 codes for a protein that works in tandem with the BRCA2 protein to repair damaged DNA and prevent tumor growth.
“It has been reported that women with mutations in the PALB2 gene have a 7-fold greater risk of cancer compared to the general population,” according to Kelly Metcalfe, RN, PhD, FAAN, University of Toronto in Toronto, Canada.
A recent case-control study of 65,057 patients with breast cancer determined that inherited pathogenic variants in PALB2 were associated with high risk of breast cancer (OR, 7.46; 95% CI, 5.12-11.19).2
“In Canada, genetic testing for BRCA1 and BRCA2 is available free of charge to women who meet eligibility criteria; however, less than 10% of women are identified with a BRCA mutation, despite features of hereditary cancer. PALB2 has been identified as a moderate penetrance gene in various populations,” she said.
Melcalfe and colleagues determined the frequency of PALB2 mutations in women with breast or ovarian cancer who tested negative for BRCA1 and BRCA2 despite meeting the criteria for genetic testing for these genes over a 7-year period beginning in 2007.
They amplified all 13 coding regions of PALB2 plus 20 base pairs using Wafergen SmartChip technology. The amplified DNAs were paired-end sequenced using an Illumina MiSeq sequencer. This probe was used on 2855 DNA samples from women with breast (n = 2225) or ovarian (n = 429) cancer to test for PALB2 mutations. In this cohort, 2133 women had unilateral, 270 had bilateral breast cancer, and 497 women had ovarian cancer. Of these, 45 patients had both breast and ovarian cancer. The mean age of the women at diagnosis was 57.1 years.1
“Genetic testing for PALB2 should be considered for high-risk women with breast cancer, especially those who present with bilateral breast cancer; 0.9% of women with breast cancer testing negative for BRCA1 or BRCA2 had a PALB2 mutation,” she said.
PALB2 mutations were detected in this series. Twenty (0.9%) deleterious PALB2 mutations were detected in women with breast cancer. The frequency of PALB2 mutations similar in regardless of the mean age of diagnosis (47.9 years versus 44.8 years; P = .35), but laterality showed a significant difference in frequency, which was higher in women with bilateral breast cancer (2.2%) compared to women with unilateral breast cancer (0.9%; P = .0081).1
No PALB2 mutations were found in women with ovarian cancer.
“PALB2 does not appear to contribute to ovarian cancer, which has implications for counselling women who are identified with a PALB2 mutation,” Metcalfe commented. “Findings from this study will serve to help establish clinical guidelines for the implementation of prevention, counseling, and treatment practices for women who face an elevated risk of breast cancer due to family history, but who do not carry a BRCA1/2 mutation.”
Metcalfe discussed future research, which will explore the treatment of PALB2-associated breast cancers, including characterizing the cancers, determining the lifetime risk of contralateral breast cancer and the impact of treatment on mortality.