PALB2 and breast cancer: ready for clinical translation!

Abstract

For almost two decades, breast cancer clinical genetics has operated in an environment where a heritable cause of breast cancer susceptibility is identified in the vast minority of women seeking advice about their personal and/or family history of breast and/or ovarian cancer. A new wave of genetic information is upon us that promises to provide an explanation for the greater proportion of current missing heritability of breast cancer. Whilst researchers refine bioinformatic and analytic methodology necessary to interpret the new genetic data, attention needs to be paid to defining appropriate and coordinated pathways for the translation of this information so that it can be applied in clinical genetic services for the benefit of the majority of women who currently have no explanation for their breast cancer susceptibility. The search for additional breast cancer susceptibility genes remains a very active area of research. Exhausting the power of linkage studies that identified BRCA1 and BRCA2, the research community moved to candidate gene studies that led to the identification of ATM, BRIP1, CHEK2, and PALB2 as so-called “moderate-risk” breast cancer susceptibility genes. Mutations in these genes are rare and although early reports suggested that, on average, they are associated with moderate risks of breast cancer; population-based studies have demonstrated that at least some mutations in these genes are associated with breast cancer risks that are comparable to the average risk associated with BRCA2 mutations. The search for additional breast cancer susceptibility genes has now moved onto research platforms applying massively parallel sequencing capable of sequencing whole human exomes and genomes in single instrument runs. These programs are identifying a large number of additional putative breast cancer susceptibility genes, many of which are currently undergoing validation. It is highly anticipated that the remaining missing heritability of breast cancer will be due to mutations in many different genes, each explaining a small proportion of the currently unexplained heritable breast cancer susceptibility. The characterization of PALB2 as a breast cancer susceptibility gene and subsequent research that has refined our understanding of the prevalence and penetrance of heritable mutations in PALB2 offers a precious opportunity to use the data as a model and develop modes of translation that would be appropriate for the anticipated volume of imminent new information.

PALB2 sequencing in Italian familial breast cancer cases reveals a high-risk mutation recurrent in the province of Bergamo

“…7 Additional studies found carriers of truncating mutations with a frequency of ~1−2% in Spanish, Chinese, South African, Russian, German, Italian, AfricanAmerican, Australasian, and Malaysian familial or early-onset breast cancer cases. 10,[20][21][22][23][24] A similar frequency was observed in population-based studies of Australians and mixed-ethnicity breast cancer cases. 20,25,26 A mutation-carrier frequency of 3.4% was reported in familial cases from the United States.…”

“…10,[20][21][22][23][24] A similar frequency was observed in population-based studies of Australians and mixed-ethnicity breast cancer cases. 20,25,26 A mutation-carrier frequency of 3.4% was reported in familial cases from the United States. This frequency, apparently higher as compared with that reported in other studies, might be due to the examined sample being enriched in a few founder mutations.…”

“…Of these 26 variants, 7 mutations (3 frameshift and 4 nonsense) introduced a premature termination codon and 1, c.3497delG, was a frameshift mutation that changed the last 21 amino acids of the protein's C terminus, causing the loss of the stop codon and the addition of three new residues ( Table 2). This change modifies the conserved WD40 protein domain interacting with BRCA2 20 and, therefore, is considered to be deleterious. Three of the deleterious mutations were previously described in a subanalysis of the same sample set.…”

“…18 The extent of the impact of this gene on breast cancer risk was questioned by a subsequent study. 19 The PALB2 (partner and localizer of BRCA2) gene, which encodes a direct interactor of BRCA2-namely, RAD51-and other proteins, 20 has been actively studied as a breast cancer risk factor, and sequencing of its coding regions revealed that deleterious mutations are present in several populations. The first study that indicated that PALB2 is a breast cancer gene reported germ-line truncating mutations in 10/923 (1.1%) English familial breast cancer cases.…”

“…Although initially these mutations were referred to as risk factors with moderate penetrance, several studies demonstrated that at least some of these mutations confer a much higher risk. 20 In the current study, we aimed to assess the involvement of PALB2 in Italian families with breast cancer by sequencing the entire gene-coding region in a large series of cases. In all, 575 probands were analyzed and 12 carriers of deleterious mutations were detected.…”