PALB2 mutations in male breast cancer: a population-based study in Central Italy

Abstract

To the Editor, Male breast cancer (MBC) is a rare disease compared to female breast cancer (FBC). However, MBC shares many similarities with FBC, including genetic predisposition factors such as BRCA1/2 mutations. The frequency of BRCA1/2 mutations is quite different in ethnically diverse populationand clinic-based MBC series, ranging between 4 and 40% for BRCA2 and up to 10% for BRCA1 [1]. In a population-based series of 108 MBCs from Central Italy, we reported that about 9% of MBCs were BRCA1/2 carriers [2], suggesting the contribution of additional susceptibility genes. Several studies identify PALB2 as a moderate-penetrance breast cancer (BC) susceptibility gene, accounting for about 1% of BRCA1/2 negative familial/early onset BCs [3, 4]. PALB2 mutations were found in families with both FBC and MBC cases, suggesting that PALB2 may be involved in MBC risk [3]. As for BRCA1/2, there are evidences that PALB2 might play a role in prostate cancer (PC) [5]. Interestingly, PC patients have an increased risk of BC [6] and, on the other hand, MBC patients show an increased risk of PC [7], suggesting that these tumours may share risk factors. The role of PALB2 in MBC predisposition is still largely unknown. An interesting evaluation about this latter is provided in the recent article by Sauty de Chalon et al. [8]. Yet in the above mentioned study PALB2 pathogenic mutations were not found in 25 MBCs belonging to 25 BRCA1/2 negative families and, based on PALB2 mutation frequency (*1%), it cannot be excluded that these findings may indeed be due to the small series analysed. By using direct sequencing, we performed a screen for germline mutations of PALB2 coding region and intron– exon boundaries in 97 BRCA1/2 negative MBCs, previously identified in a population-based series of 108 MBCs [2]. Age at first BC diagnosis ranged between 35 and 90 years (mean 63.9 years), 25.8% of the patients reported a first-degree family history (FH) of breast/ovarian cancer and 14.4% had a personal history of cancer(s) at sites other than breast. In particular, prostate (28.5%) and bladder (28.5%) carcinomas were the most frequently observed metachronous cancers. Table 1 shows all the PALB2 variants identified in our study. No truncating mutations were found. A novel missense variant, I1180T, was identified in a young man diagnosed with BC at 42 years of age and with negative FH. In silico analysis (PolyPhen, SIFT, Align-GVGD and Pmut) showed that I1180T is likely to be deleterious, since it occurs in the WD40-4 conserved domain that regulates PALB2 interaction with BRCA2. This variant was not found in 90 male population controls analysed (Table 1). Three additional missense variants (Q559R, E672Q and G998E) and one synonymous (T1100T) variant, all previously Valentina Silvestri and Piera Rizzolo equally contributed to the work.