The "extreme phenotype approach" applied to male breast cancer allows the identification of rare variants of ATR as potential breast cancer susceptibility alleles.
The "extreme phenotype approach" applied to male breast cancer allows the identification of rare variants of ATR as potential breast cancer susceptibility alleles.
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在肿瘤遗传学中，一些患者可以被认为是“极端表型”，例如具有非常早的发病表现或多个原发性恶性肿瘤的患者，在同一亲本分支中具有异常高数量的相同谱的癌症或罕见癌症类型的患者。对于这些情况，遗传易感性是非常可能的，但经典的候选基因面板分析往往和令人沮丧的仍然是负面的。在EX 2 TRICAN项目的框架下，探索未解决的极端癌症表型，我们对罕见的男性乳腺癌家族病例进行外显子组测序，鉴定了ATR的一种新的致病性变体（p.Leu1808*）。ATR已经被怀疑是女性乳腺癌的易感基因。我们接下来在患有早发性和家族性乳腺癌的男性和女性的群组中鉴定了3种另外的ATR变体（c.7762-2A>C; c.2078+1G>A; c.1A>G）。进一步的分子和细胞研究表明，影响剪接位点的变体对转录本的影响，ATR表达的减少和ATR底物CHEK 1的磷酸化。这项工作进一步证明了扩展的遗传分析（如外显子组测序）的兴趣，以确定非常罕见的变异，这些变异在经典癌症基因组测试无法解释的极端表型癌症病例中可能在癌症易感性中发挥作用。
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.