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Hereditary breast and ovarian cancer: new genes in confined pathways

Key Points

  • Genetic abnormalities in BRCA1 and BRCA2 predispose to hereditary breast and ovarian cancer (HBOC). However, only approximately 25% of HBOC cases can be ascribed to BRCA1 and BRCA2 mutations.

  • Next-generation sequencing approaches are uncovering novel HBOC factors among affected families without BRCA1 or BRCA2 mutations; at present more than 25 have emerged. New factors generally function in the same genome maintenance pathways as established HBOC factors, indicating substantial locus heterogeneity.

  • Disabled pathways in HBOC are homologous recombination repair (HRR), protection of stalling DNA replication forks, mismatch repair, and cell cycle checkpoint and DNA damage checkpoint control pathways.

  • The new pathogenic variants are rare, which poses challenges to the estimation of risk attribution through patient cohorts. There is a risk that patients or healthy carriers exhibiting pathogenic variants in rare HBOC genes may be excluded from the best possible treatment or presymptomatic screening programmes.

  • Structural and functional analysis can support variant classification in the context of international collaboration and standardized guidelines. Functional approaches are aided by extensive locus heterogeneity, which converges on a relatively small number of genome maintenance pathways that may be reconciled in vitro.

Abstract

Genetic abnormalities in the DNA repair genes BRCA1 and BRCA2 predispose to hereditary breast and ovarian cancer (HBOC). However, only approximately 25% of cases of HBOC can be ascribed to BRCA1 and BRCA2 mutations. Recently, exome sequencing has uncovered substantial locus heterogeneity among affected families without BRCA1 or BRCA2 mutations. The new pathogenic variants are rare, posing challenges to estimation of risk attribution through patient cohorts. In this Review article, we examine HBOC genes, focusing on their role in genome maintenance, the possibilities for functional testing of putative causal variants and the clinical application of new HBOC genes in cancer risk management and treatment decision-making.

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Figure 1: Timeline of events important in HBOC discovery and the identification of predisposing HBOC genes.
Figure 2: Tumour suppression requires functional genome maintenance pathways to counteract genotoxic stress cues.
Figure 3: Genome stability pathways and genes in HBOC.
Figure 4: Proposed clinical management of breast and ovarian tumours.

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Acknowledgements

The authors thank K. Cimprich for communicating results prior to publication and B. Ejlertsen for helpful comments on the manuscript. The authors thank the Danish Cancer Society (C.S.S.), the Danish Medical Research Council (C.S.S.), the Neye Foundation (F.C.N.) and the Research Foundation for Health Research of the Capital Region of Denmark (F.C.N. and T.v.O.H.) for funding of their work.

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Correspondence to Claus Storgaard Sørensen.

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Glossary

Locus heterogeneity

A genetic term describing how variations in different genes cause the same disorder. The genes are not linked physically; examples are hereditary breast and ovarian cancer predisposition by BRCA1, BRCA2, partner and localizer of BRCA2 (PALB2) and TP53.

Homologous recombination repair

(HRR). A DNA repair pathway acting on DNA double-strand breaks that uses the undamaged sister chromatid as template for error-free repair. It is a multi-protein pathway involving a large number of factors, including BRCA1, BRCA2, partner and localizer of BRCA2 (PALB2) and RAD51 genes.

Mismatch repair

(MMR). A system for repairing erroneous insertion, deletion and misincorporation of bases arising during DNA replication. Mutations in MMR genes can result in microsatellite instability, which is implicated in most human cancers.

Interstrand DNA crosslink repair

Interstrand crosslinks (ICLs) occur through the covalent joining of opposite strands of the DNA helix. ICLs occur after reaction of DNA with natural products of metabolism or with chemotherapeutic reagents such as platinum compounds. ICL repair requires several DNA repair pathways including Fanconi anaemia and homologous recombination repair (HRR).

Fanconi anaemia

A bone marrow syndrome with enhanced predisposition to several cancers. It is a rare inherited disorder caused by mutations in several genes involved in the repair of DNA crosslinks, which includes the Fanconi anaemia factors FANCA and FANCE, BRCA1, BRCA2 and partner and localizer of BRCA2 (PALB2) genes.

Genotoxic stress

Cellular exposure to environmental and endogenous agents or conditions that can lead to genome alterations. If unrepaired as cells resume the cell division cycle, the altered genetic information leads to mutations, which may lead to cancer.

Cell cycle checkpoints

Signalling events during the cell cycle that prevent further progression.

Cyclin-dependent kinase

(CDK). Member of a class of kinases that associate with partner proteins termed cyclins. Specific CDKs are active at various phases of the cell cycle to promote cell cycle progression.

Platinum analogues

A class of chemotherapeutic agents, including cisplatin, oxaliplatin and carboplatin. Platinum compounds form intrastrand and interstrand crosslinks on DNA.

poly-(ADP-ribose) polymerase

(PARP). A class of enzymes involved in facilitating DNA repair.

Variant of unknown significance

(VUS). Variants in genes are classified according to their impact on the protein function. A variant with an unknown clinical function owing to lack of functional or clinical data is classified as a VUS.

Co-segregation

Genetic examination of several family members to clarify whether a specific variant is linked to a disease or not.

Mini-gene splicing analysis

A cell-based functional assay to establish whether a variant has an effect on splicing.

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Nielsen, F., van Overeem Hansen, T. & Sørensen, C. Hereditary breast and ovarian cancer: new genes in confined pathways. Nat Rev Cancer 16, 599–612 (2016). https://doi.org/10.1038/nrc.2016.72

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