Low prevalence of germline PALB2 mutations in Australian triple‐negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is a tumour classification that is defined by oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 receptor negativity. TNBCs share a similar gene expression profile to BRCAmutated tumours, have been shown to carry a high proportion of BRCA mutations and have a more adverse prognosis compared to other types of breast tumours. PALB2 has been shown to be a moderate-penetrance breast cancer susceptibility gene and is involved in the same DNA damage repair pathway as BRCA1 and BRCA2; this raises the possibility that germline PALB2 mutations may be involved in the pathogenesis of TNBCs. In our study, we sequenced the coding regions of PALB2 (including intron=exon boundaries) in genomic DNA from 347 patients diagnosed with TNBC to determine the prevalence of deleterious mutations in this population. Two novel truncating mutations (c.758dup and c.2390del) and one previously detected truncating mutation (c.311315G>C) were found. In addition, five variants predicted to be protein-affecting were also identified. Our study shows that the prevalence of PALB2 germline mutations in individuals with TNBC is~1%, similar to the prevalence of PALB2 germline mutation of 1% in familial non-BRCA1=2 breast cancer cohorts.Triple-negative breast cancer (TNBC) is a histological classification of breast cancer that is negative for the oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. TNBCs represent an important subtype of breast cancer as they have a lower recurrence-free and overall survival compared to receptor-positive disease, regardless of disease stage at time of diagnosis.

Prevalence of PALB2 mutations in Australian familial breast cancer cases and controls

“…This study screened Australian individuals with breast cancer who had been referred to a Familial Cancer Centre for genetic testing and in whom no pathogenic BRCA1 and BRCA2 variant could be identified. The frequency of PALB2 truncating variants in this cohort (1.1 %) is similar to other studies analysing high-risk breast cancer individuals (0.64–3.4 %, 1.35 % overall [ 3 , 6 – 9 , 26 – 41 ]) or triple-negative breast cancer (0.9–2.5 % [ 10 , 42 , 43 ]) but is the largest to include an analysis of the full gene in both cases and controls. However, we would not be able to detect any large deletions or rearrangements.…”

“…In Australia, early studies identified PALB2 c.3113G > A (p.Trp1038*) as a recurring truncating mutation among familial breast cancer index cases, and established the enrichment of c.3113G > A in cases compared to controls [ 6 ]. Further studies have identified a spectrum of truncating variants among breast cancer cases [ 7 – 10 ], the collective frequency of which has not been compared to Australian controls. Indeed few studies of PALB2 mutations have analysed significant numbers of family cancer clinic-ascertained cases or matched controls.…”

Prevalence of PALB2 Germline Mutations in Early-onset and Familial Breast/Ovarian Cancer Patients from Pakistan

“…In our study, the breast tumors associated with the PALB2 truncating (p.Y743*) and in silico -predicted potentially functional (p.D498Y, p.G644R, and p.E744K) mutations presented with high-grade tumors of IDC histology, which is consistent with previous studies conducted among Asian [13-15], European [24,25,48], and North-American patients [49]. In the Pakistani study, the breast tumor linked with the truncating mutation displayed the TNBC phenotype, in agreement with other studies from Europe, North-America and Australia [50-52]. Breast tumors associated with missense mutations were ER-positive, PR-positive, and HER2-negative.…”

A Review of the Hereditary Component of Triple Negative Breast Cancer: High- and Moderate-Penetrance Breast Cancer Genes, Low-Penetrance Loci, and the Role of Nontraditional Genetic Elements

“…In a similar cohort of 1,824 women with TNBC unselected for family history of cancer, deleterious mutations in PALB2 were detected in 1.2% of patients [41]. In a group of 347 Australian women with TNBC the prevalence of deleterious PALB2 germline mutations was ~1% [42]. A recent study of 10,901 women with TNBC (8,753 women with clinical test results and 2,148 tested in the research setting) found that germline mutations in PALB2 were associated with high-risk of TNBC (OR=14.41; 95%CI=9.27-22.60) and were enriched in patients with TNBC compared to non-TNBC tumors (OR2.12; 95% CI=1.63-2.74) [35].…”