Fernandez-Rozadilla Ceres, Alvarez-Barona Miriam, Schamschula Esther, Bodo Sahra, Lopez-Novo Anael, Dacal Andres, Calviño-Costas Consuelo, Lancho Angel, Amigo Jorge, Bello Xabier, Cameselle-Teijeiro Jose Manuel, Carracedo Angel, Colas Chrystelle, Muleris Martine, Wimmer Katharina, Ruiz-Ponte Clara
Fundación Pública Galega de Medicina Xenómica SERGAS, Grupo de Medicina Xenómica_USC, IDIS, 15706 Santiago de Compostela, Spain.
Division of Human Genetics, Medical University Innsbruck, 6020 Innsbruck, Austria.
Cancers (Basel). 2019 Jul 30;11(8):1081. doi: 10.3390/cancers11081081.
Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, caused by heterozygous mutations in the mismatch repair (MMR) genes. Biallelic mutations in these genes lead however, to constitutive mismatch repair deficiency (CMMRD). In this study, we follow the diagnostic journey of a 12-year old patient with CRC, with a clinical phenotype overlapping CMMRD. We perform molecular and functional assays to discard a CMMRD diagnosis then identify by exome sequencing and validation in a cohort of 134 LS patients, a candidate variant in the UTR region in homozygosis. We propose that this variant, together with other candidates, could be responsible for age-of-onset modulation. Our data support the idea that low-risk modifier alleles may influence early development of cancer in LS leading to a LS-to-CMMRD phenotypic continuum. Therefore, it is essential that larger efforts are directed to the identification and study of these genetic modifiers, in order to provide optimal cancer prevention strategies to these patients.
林奇综合征（LS）是最常见的遗传性结直肠癌（CRC）综合征，由错配修复（MMR）基因的杂合突变引起。然而，这些基因的双等位基因突变会导致组成型错配修复缺陷（CMMRD）。在本研究中，我们追踪了一名12岁结直肠癌患者的诊断过程，其临床表型与CMMRD重叠。我们进行了分子和功能检测以排除CMMRD诊断，然后通过外显子测序并在134名LS患者队列中进行验证，确定了一个纯合状态下位于UTR区域的候选变异。我们提出，这个变异与其他候选变异可能共同导致发病年龄的改变。我们的数据支持这样一种观点，即低风险修饰等位基因可能影响LS患者癌症的早期发生，从而导致从LS到CMMRD的表型连续变化。因此，必须加大力度识别和研究这些基因修饰因子，以便为这些患者提供最佳的癌症预防策略。
