Wallander Karin, Thutkawkorapin Jessada, Sahlin Ellika, Lindblom Annika, Lagerstedt-Robinson Kristina
Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Solna, Stockholm, Sweden.
Hered Cancer Clin Pract. 2021 Apr 7;19(1):23. doi: 10.1186/s13053-021-00181-2.
We have previously reported a family with a suspected autosomal dominant rectal and gastric cancer syndrome without any obvious causative genetic variant. Here, we focused the study on a potentially isolated rectal cancer syndrome in this family.
We included seven family members (six obligate carriers). Whole-exome sequencing and whole-genome sequencing data were analyzed and filtered for shared coding and splicing sequence and structural variants among the affected individuals.
When considering family members with rectal cancer or advanced adenomas as affected, we found six new potentially cancer-associated variants in the genes CENPB, ZBTB20, CLINK, LRRC26, TRPM1, and NPEPL1. All variants were missense variants and none of the genes have previously been linked to inherited rectal cancer. No structural variant was found.
By massive parallel sequencing in a family suspected of carrying a highly penetrant rectal cancer predisposing genetic variant, we found six genetic missense variants with a potential connection to the rectal cancer in this family. One of them could be a high-risk genetic variant, or one or more of them could be low risk variants. The p.(Glu438Lys) variant in the CENPB gene was found to be of particular interest. The CENPB protein binds DNA and helps form centromeres during mitosis. It is involved in the WNT signaling pathway, which is critical for colorectal cancer development and its role in inherited rectal cancer needs to be further examined.
我们之前报道过一个疑似常染色体显性遗传的直肠癌和胃癌综合征家族，但未发现任何明显的致病基因变异。在此，我们聚焦于该家族中一种可能孤立存在的直肠癌综合征展开研究。
我们纳入了7名家族成员（6名必然携带者）。对全外显子组测序和全基因组测序数据进行分析，并筛选出受影响个体之间共享的编码和剪接序列以及结构变异。
将患有直肠癌或晚期腺瘤的家族成员视为受影响个体时，我们在CENPB、ZBTB20、CLINK、LRRC26、TRPM1和NPEPL1基因中发现了6个新的潜在癌症相关变异。所有变异均为错义变异，且此前没有一个基因与遗传性直肠癌相关联。未发现结构变异。
通过对一个疑似携带高 penetrance直肠癌易感基因变异的家族进行大规模平行测序，我们发现了6个与该家族直肠癌可能相关的基因错义变异。其中一个可能是高风险基因变异，或者其中一个或多个可能是低风险变异。CENPB基因中的p.(Glu438Lys)变异尤其值得关注。CENPB蛋白结合DNA并在有丝分裂期间帮助形成着丝粒。它参与WNT信号通路，而WNT信号通路对结直肠癌的发展至关重要，其在遗传性直肠癌中的作用有待进一步研究。
