Abstract
BackgroundWe 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.MethodsWe 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.ResultsWhen 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.ConclusionBy 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.
Highlights
We have previously reported a family with a suspected autosomal dominant rectal and gastric cancer syndrome without any obvious causative genetic variant
The family was included in the study after one of the family members was referred to the Department of Clinical Genetics, Karolinska University Hospital, Solna, Stockholm, Sweden, for genetic counselling
Sequencing The six family members with rectal cancer or advanced adenomas of the rectum were considered obligate carriers of a variant associated with a rectal cancer syndrome
Summary
We have previously reported a family with a suspected autosomal dominant rectal and gastric cancer syndrome without any obvious causative genetic variant. With improving techniques for massive parallel sequencing, knowledge on the genetics behind colorectal cancer is believed to increase. We have previously published results from linkage and exome analyses in a family with multiple cases of rectal and gastric cancer [3, 4]. The family pedigree clearly indicates an autosomal dominant, highly penetrant disease, and since the previous study one additional individual has been diagnosed with rectal cancer. This prompted us to re-analyze the family and to focus on rectal cancer as a separate entity.
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