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. 2023 Feb 7:14:111-125.
doi: 10.18632/oncotarget.28358.

The "extreme phenotype approach" applied to male breast cancer allows the identification of rare variants of ATR as potential breast cancer susceptibility alleles

Martin Chevarin  1   2 , Diana Alcantara  3 , Juliette Albuisson  4   5 , Marie-Agnès Collonge-Rame  6 , Céline Populaire  6 , Zohair Selmani  6 , Amandine Baurand  4   7 , Caroline Sawka  7 , Geoffrey Bertolone  7 , Patrick Callier  1   2   8 , Yannis Duffourd  1   8 , Philippe Jonveaux  9 , Yves-Jean Bignon  10 , Isabelle Coupier  11 , François Cornelis  12   13 , Christophe Cordier  14 , Monique Mozelle-Nivoix  15 , Jean-Baptiste Rivière  1   7   8 , Paul Kuentz  1   6   8 , Christel Thauvin  1   7 , Romain Boidot  5 , François Ghiringhelli  16 , Marc O'Driscoll  3 , Laurence Faivre  1   4   7   8 , Sophie Nambot  1   4   7   8
Affiliations

The "extreme phenotype approach" applied to male breast cancer allows the identification of rare variants of ATR as potential breast cancer susceptibility alleles

Martin Chevarin et al. Oncotarget. .

Abstract

In oncogenetics, some patients could be considered as "extreme phenotypes", such as those with very early onset presentation or multiple primary malignancies, unusually high numbers of cancers of the same spectrum or rare cancer types in the same parental branch. For these cases, a genetic predisposition is very likely, but classical candidate gene panel analyses often and frustratingly remains negative. In the framework of the EX2TRICAN project, exploring unresolved extreme cancer phenotypes, we applied exome sequencing on rare familial cases with male breast cancer, identifying a novel pathogenic variant of ATR (p.Leu1808*). ATR has already been suspected as being a predisposing gene to breast cancer in women. We next identified 3 additional ATR variants in a cohort of both male and female with early onset and familial breast cancers (c.7762-2A>C; c.2078+1G>A; c.1A>G). Further molecular and cellular investigations showed impacts on transcripts for variants affecting splicing sites and reduction of ATR expression and phosphorylation of the ATR substrate CHEK1. This work further demonstrates the interest of an extended genetic analysis such as exome sequencing to identify very rare variants that can play a role in cancer predisposition in extreme phenotype cancer cases unexplained by classical cancer gene panels testing.

Keywords: ATR; exome sequencing; extreme phenotype; genetic predisposition to cancer; male breast cancer.

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Conflict of interest statement

CONFLICTS OF INTEREST

Authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1. Sequencing of ATR cDNA.
(A) IGV visualization of a subset of reads encompassing the last two exons of ATR cDNA for PED3315.1 carrying c.7762-2A>C variant. (B) IGV visualization of a subset of reads encompassing exons 8 to 10 of ATR cDNA for PED7847.1 carrying c.2078+1G>A variant.
Figure 2
Figure 2. Impact of mutations on ATR expression and intra S phase checkpoint.
(A) Western blotting of ATR expression in LCLs from patient PED2361.1 (p.Leu1808*) and patient PED9445.1 (p.Met1?). The Seckel control LCLs are from the ATR-Seckel patient described by Ogi T el al60 (p.M1159I and p.V2300Gfs*75). (B) Impact of variant of PED2361.1 on CHEK1 phosphorylation (Unt: without hydroxyurea treatment, HU: with hydroxyurea treatment).
Figure 3
Figure 3. Impact of splicing variants.
(A) Layout of C-terminal extremity of ATR. (B) Skipping of exon 9 creates a premature stop codon (Yellow: end of exon 8, green: exon 9, blue: beginning of exon 10).
See this image and copyright information in PMC

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