Reviewing the occurrence of large genomic rearrangements in patients with inherited cancer predisposing syndromes: importance of a comprehensive molecular diagnosis

ABSTRACT

Introduction

Hereditary cancer predisposition syndromes are caused by germline pathogenic or likely pathogenic variants in cancer predisposition genes (CPG). The majority of pathogenic variants in CPGs are point mutations, but large gene rearrangements (LGRs) are present in several CPGs. LGRs can be much more difficult to characterize and perhaps they may have been neglected in molecular diagnoses.

Areas covered

We aimed to evaluate the frequencies of germline LGRs in studies conducted in different populations worldwide through a qualitative systematic review based on an online literature research in PubMed. Two reviewers independently extracted data from published studies between 2009 and 2020. In total, 126 studies from 37 countries and 5 continents were included in the analysis. The number of studies in different continents ranged from 3 to 48 and for several countries there was an absolute lack of information. Asia and Europe represented most of the studies, and LGR frequencies varied from 3.04 to 15.06% in different continents. MLPA was one of the methods of choice in most studies (93%).

Expert opinion

The LGR frequencies found in this review reinforce the need for comprehensive molecular testing regardless of the population of origin and should be considered by genetic counseling providers.

KEYWORDS:

• Cancer predisposition genes
• cancer predisposition syndromes
• large gene rearrangements
• molecular diagnosis
• molecular techniques

Article highlights

• Large gene rearrangements may have been underestimated in molecular diagnoses of cancer predisposition syndromes in routine clinical practice for a long time, which can lead to underdiagnoses

• In many countries, studies focusing on molecular diagnosis of cancer predisposition syndromes do not search for large gene rearrangements

• Our review found that Multiplex Ligation-dependent Probe Amplification (MLPA) was the most used technique to detect large gene rearrangements in cancer predisposition genes around the world

• The frequencies of large gene rearrangements in different populations reinforce the need for comprehensive molecular testing whenever a cancer predisposition syndrome is suspected and point mutations are excluded

Acknowledgments

The authors would like to thank Fundo de Incentivo à Pesquisa (FIPE) of Hospital de Clínicas de Porto Alegre and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Authors’ contributions

D.L.R.: formal analysis; investigation; methodology; writing – original draft; writing-review & editing, P.A-P.: conceptualization; project administration; writing – original draft; writing-review & editing. C.R.: conceptualization; data curation; formal analysis; investigation; methodology; writing – original draft; writing-review & editing.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed here

Additional information

Funding

This work was supported by Fundo de Incentivo à Pesquisa (FIPE) of Hospital de Clínicas de Porto Alegre and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).