A novel germline PALB2 deletion in Polish breast and ovarian cancer patients

Abstract

BackgroundPALB2 protein was recently identified as a partner of BRCA1 and BRCA2 which determines their proper function in DNA repair.MethodsInitially, the entire coding sequence of the PALB2 gene with exon/intron boundaries was evaluated by the PCR-SSCP and direct sequencing methods on 70 ovarian carcinomas. Sequence variants of interest were further studied on enlarged groups of ovarian carcinomas (total 339 non-consecutive ovarian carcinomas), blood samples from 334 consecutive sporadic and 648 consecutive familial breast cancer patients, and 1310 healthy controls from central Poland.ResultsTen types of sequence variants were detected, and among them four novel polymorphisms: c.2996+58T>C in intron 9; c.505C>A (p.L169I), c.618T>G (p.L206L), both in exon 4; and c.2135C>T (A712V) in exon 5 of the PALB2 gene. Another two polymorphisms, c.212-58A>C and c.2014G>C (E672Q) were always detected together, both in cancer (7.5% of patients) and control samples (4.9% of controls, p = 0.2). A novel germline truncating mutation, c.509_510delGA (p.R170fs) was found in exon 4: in 2 of 339 (0.6%) unrelated ovarian cancer patients, in 4 of 648 (0.6%) unrelated familial breast cancer patients, and in 1 of 1310 controls (0.08%, p = 0.1, p = 0.044, respectively). One ovarian cancer patient with the PALB2 mutation had also a germline nonsense mutation of the BRCA2 gene.ConclusionsThe c.509_510delGA is a novel PALB2 mutation that increases the risk of familial breast cancer. Occurrence of the same PALB2 alteration in seven unrelated women suggests that c.509_510delGA (p.R170fs) is a recurrent mutation for Polish population.

The PALB2 Gene Is a Strong Candidate for Clinical Testing in BRCA1- and BRCA2-Negative Hereditary Breast Cancer

“…Similar to BRCA2, defects in the PALB2 gene are also associated with hereditary predisposition to male breast cancer (15,31) and pancreatic cancer (33)(34)(35) and according to some results they may also predispose to ovarian cancer (18,36). A comparison of cancer profiles in mutation-positive and -negative families in our study indicated only a weak association of PALB2 mutations with pancreatic and ovarian cancer.…”

“…A founder PALB2 c.1592delT mutation, associated with a roughly 4-fold increased hereditary propensity for female breast cancer, was detected in Finland in 3 of 113 (2.7%) patients with familial breast cancer and in 18 of 1,918 (0.9%) unselected breast cancer cases. Until now, about 50 truncating mutations have been detected in breast cancer families worldwide and mutations have also been reported in cases of inherited pancreatic (33)(34)(35) and ovarian cancer (18,36). Therefore, PALB2 has been considered a strong candidate breast cancer-susceptibility gene; however, due to the limited number of studies, estimation of penetrance of breast cancer associated with PALB2 mutation has not been precisely determined (37).…”

PALB2 analysis in BRCA2-like families

“…Our cohort included 53 familial ovarian cancer patients, but no mutation was found in PALB2 in any of these cases. Recently, a Polish study tested a set of sporadic 70 ovarian carcinomas for PALB2 mutations [27]. Remarkably they found the same mutation (c.509_510delGA) as we did.…”

Ovarian small cell carcinoma of hypercalcemic type – evidence of germline origin and smarca4 gene inactivation. a pilot study

“…Coding sequences of the SMARCA4 gene with intron/exon boundaries were PCR-amplified and sequenced as previously described [8]. Some primer sequences were taken from a publication by Medina et al [9], while others were designed using the free Table I.…”