PALB2: research reaching to clinical outcomes for women with breast cancer

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Abstract

PALB2 has taken its place with bona fide breast cancer susceptibility genes. It is now well established that women who carry loss-of-function mutations in the PALB2 gene are at similarly elevated breast cancer risks to those who carry mutations in BRCA2. Information about PALB2 is now being used in breast cancer clinical genetics practice and is routinely included in breast cancer predisposition gene panel tests. Tens of thousands of women worldwide have now had genetic tests for PALB2 mutations in the context of breast cancer susceptibility. However, prospective data related to the clinical outcomes of PALB2 mutation carriers is lacking and very little information (beyond mutation penetrance) is available to guide current clinical management for carriers (affected and unaffected by cancer). In addition, clinical classification of the vast array of non-loss-of-function genetic variants identified in PALB2 is in its infancy. These are key areas of current research efforts and are important foundations on which to move information about PALB2 into the precision public health arena.

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Most cited references 41

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Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment.

Allison Kurian, Emily Hare, Meredith Mills … (2014)

Multiple-gene sequencing is entering practice, but its clinical value is unknown. We evaluated the performance of a customized germline-DNA sequencing panel for cancer-risk assessment in a representative clinical sample. Patients referred for clinical BRCA1/2 testing from 2002 to 2012 were invited to donate a research blood sample. Samples were frozen at -80° C, and DNA was extracted from them after 1 to 10 years. The entire coding region, exon-intron boundaries, and all known pathogenic variants in other regions were sequenced for 42 genes that had cancer risk associations. Potentially actionable results were disclosed to participants. In total, 198 women participated in the study: 174 had breast cancer and 57 carried germline BRCA1/2 mutations. BRCA1/2 analysis was fully concordant with prior testing. Sixteen pathogenic variants were identified in ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4 among 141 women without BRCA1/2 mutations. Fourteen participants carried 15 pathogenic variants, warranting a possible change in care; they were invited for targeted screening recommendations, enabling early detection and removal of a tubular adenoma by colonoscopy. Participants carried an average of 2.1 variants of uncertain significance among 42 genes. Among women testing negative for BRCA1/2 mutations, multiple-gene sequencing identified 16 potentially pathogenic mutations in other genes (11.4%; 95% CI, 7.0% to 17.7%), of which 15 (10.6%; 95% CI, 6.5% to 16.9%) prompted consideration of a change in care, enabling early detection of a precancerous colon polyp. Additional studies are required to quantify the penetrance of identified mutations and determine clinical utility. However, these results suggest that multiple-gene sequencing may benefit appropriately selected patients. © 2014 by American Society of Clinical Oncology.

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ENIGMA--evidence-based network for the interpretation of germline mutant alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes.

Fergus Couch, Sue Healey, Katherine Nathanson … (2012)

As genetic testing for predisposition to human diseases has become an increasingly common practice in medicine, the need for clear interpretation of the test results is apparent. However, for many disease genes, including the breast cancer susceptibility genes BRCA1 and BRCA2, a significant fraction of tests results in the detection of a genetic variant for which disease association is not known. The finding of an "unclassified" variant (UV)/variant of uncertain significance (VUS) complicates genetic test reporting and counseling. As these variants are individually rare, a large collaboration of researchers and clinicians will facilitate studies to assess their association with cancer predisposition. It was with this in mind that the ENIGMA consortium (www.enigmaconsortium.org) was initiated in 2009. The membership is both international and interdisciplinary, and currently includes more than 100 research scientists and clinicians from 19 countries. Within ENIGMA, there are presently six working groups focused on the following topics: analysis, clinical, database, functional, tumor histopathology, and mRNA splicing. ENIGMA provides a mechanism to pool resources, exchange methods and data, and coordinately develop and apply algorithms for classification of variants in BRCA1 and BRCA2. It is envisaged that the research and clinical application of models developed by ENIGMA will be relevant to the interpretation of sequence variants in other disease genes. © 2011 Wiley Periodicals, Inc.

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A recurrent mutation in PALB2 in Finnish cancer families.

Vesa Kataja, Mervi Grip, W. H. Bell … (2007)

BRCA1, BRCA2 and other known susceptibility genes account for less than half of the detectable hereditary predisposition to breast cancer. Other relevant genes therefore remain to be discovered. Recently a new BRCA2-binding protein, PALB2, was identified. The BRCA2-PALB2 interaction is crucial for certain key BRCA2 DNA damage response functions as well as its tumour suppression activity. Here we show, by screening for PALB2 mutations in Finland that a frameshift mutation, c.1592delT, is present at significantly elevated frequency in familial breast cancer cases compared with ancestry-matched population controls. The truncated PALB2 protein caused by this mutation retained little BRCA2-binding capacity and was deficient in homologous recombination and crosslink repair. Further screening of c.1592delT in unselected breast cancer individuals revealed a roughly fourfold enrichment of this mutation in patients compared with controls. Most of the mutation-positive unselected cases had a familial pattern of disease development. In addition, one multigenerational prostate cancer family that segregated the c.1592delT truncation allele was observed. These results indicate that PALB2 is a breast cancer susceptibility gene that, in a suitably mutant form, may also contribute to familial prostate cancer development.

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Author and article information

Contributors

Melissa C. Southey: msouthey@unimelb.edu.au

Journal

Journal ID (nlm-ta): Hered Cancer Clin Pract

Journal ID (iso-abbrev): Hered Cancer Clin Pract

Title: Hereditary Cancer in Clinical Practice

Publisher: BioMed Central (London )

ISSN (Print): 1731-2302

ISSN (Electronic): 1897-4287

Publication date (Electronic): 19 April 2016

Publication date PMC-release: 19 April 2016

Publication date Collection: 2016

Volume: 14

Electronic Location Identifier: 9

Affiliations

[ ]Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC 3010 Australia

[ ]Department of Medicine, The University of Melbourne, Parkville, VIC 3010 Australia

[ ]The Royal Melbourne Hospital, Parkville, VIC 3050 Australia

Article

Publisher ID: 49

DOI: 10.1186/s13053-016-0049-2

PMC ID: 4837522

PubMed ID: 27099641

SO-VID: 72f712a3-042d-4c97-a728-e37d12d247cb

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 7 February 2016

Date accepted : 11 April 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;

Award ID: APP1061177

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: palb2,breast cancer susceptibility,cancer susceptibility,familial cancer

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: palb2, breast cancer susceptibility, cancer susceptibility, familial cancer

PALB2: research reaching to clinical outcomes for women with breast cancer

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Karger: Oncology

Most cited references 41

Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment.

ENIGMA--evidence-based network for the interpretation of germline mutant alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes.

A recurrent mutation in PALB2 in Finnish cancer families.

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