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Novel candidates in early-onset familial colorectal cancer

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Abstract

In 20–30% of patients suspected of a familial colorectal cancer (CRC) syndrome, no underlying genetic cause is detected. Recent advances in whole exome sequencing have generated evidence for new CRC-susceptibility genes including POLE, POLD1 and NTHL1¸ but many patients remain unexplained. Whole exome sequencing was performed on DNA from nine patients from five different families with familial clusters of CRC in which traditional genetic testing failed to yield a diagnosis. Variants were filtered by minor allele frequencies, followed by prioritization based on in silico prediction tools, and the presence in cancer susceptibility genes or genes in cancer-associated pathways. Effects of frameshift variants on protein structure were modeled using I-Tasser. One known pathogenic variant in POLD1 was detected (p.S478N), together with variants in 17 candidate genes not previously associated with CRC. Additional in silico analysis using SIFT, PROVEAN and PolyPhen on the 14 missense variants indicated a possible damaging effect in nine of 14 variants. Modeling of the insertions/deletions showed a damaging effect of two variants in NOTCH2 and CYP1B1. One family was explained by a mutation in a known familial CRC gene. In the remaining four families, the most promising candidates found are a frameshift NOTCH2 and a missense RAB25 variant. This study provides potential novel candidate variants in unexplained familial CRC patients, however, functional validation is imperative to confirm the role of these variants in CRC tumorigenesis. Additionally, while whole exome sequencing enables detection of variants throughout the exome, other causes explaining the familial phenotype such as multiple single nucleotide polymorphisms accumulating to a polygenic risk or epigenetic events, might be missed with this approach.

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Funding

The present work was supported by the CA72851, CA184792, CA187956 and CA202797 grants from the National Cancer Institute, National Institute of Health; grants from the Sammons Cancer Center and Baylor Foundation, as well as funds from the Baylor Scott & White Research Institute, Dallas, TX, USA to AG. This work was also supported by grant CA160911 from the NIH to PG.

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Authors and Affiliations

  1. Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Dallas, TX, USA

    Anne M. L. Jansen & Ajay Goel

  2. Departments of Medicine and Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA

    Pradipta Ghosh & C. Richard Boland

  3. Department of Biotechnology, Mohanlal Sukhadia University, Udaipur, Rajasthan, 313001, India

    Tikam C. Dakal

  4. Division of Clinical Cancer Genomics City of Hope, Department of Medical Oncology, National Medical Center, Duarte, CA, USA

    Thomas P. Slavin

  5. Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, 91016, USA

    Ajay Goel

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  1. Anne M. L. Jansen
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  3. Tikam C. Dakal
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Contributions

AMLJ: conceived and designed the study, collected the data, performed the analysis, drafting the manuscript, PG and TCD: Performed analysis, drafting the manuscript, critical reviewing of the manuscript, TPS: critical reviewing of the manuscript, CRB: critical reviewing of the manuscript, funding acquisition AG: Conceived and designed the study, critical reviewing of the manuscript, funding acquisition, supervision

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Correspondence to Ajay Goel.

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The authors have no conflicts to disclose.

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Supplementary material 1 (DOCX 25 kb)

Supplementary Figure 1:

Pedigree of family F. Squares represent males, circles represent females and diamonds is undisclosed gender. Phenotype is shown as tumor type followed by age of onset. Patients presented with colorectal cancer (CRC; fully filled symbol) or polyps (pol, right top corner). Arrows indicate patient sequenced with whole exome sequencing.*DNA available for co-segregation study. Supplementary Figure 2: Enriched terms of familial and sporadic CRC TCGA cohort.Enriched terms comparing the familial cohort (this study) with the sporadic CRC TCGA data are represented as scatterplots in a two dimensional space to summarize GO terms'semantic similarities (using REVIGO). Sematic space X and Y are used to be able to show distance between dots, but have no intrinsic meaning. The size of the dots indicates the frequency of the GO terms in the underlying GOA database. Distance of the dots from each other indicate the relatedness of the GO terms. Color of the dots indicates the p-value for false discovery rates. P-value is the enrichment p-value computed according to the mHG or HG model. This p-value is not corrected for multiple testing of 15413 GO terms. The most significant changes in the familiar cohort are seen in cell-cell adhesion pathways—Supplementary material 2 (PPTX 239 kb)

Supplementary material 3 (XLSX 577 kb)

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Jansen, A.M.L., Ghosh, P., Dakal, T.C. et al. Novel candidates in early-onset familial colorectal cancer. Familial Cancer 19, 1–10 (2020). https://doi.org/10.1007/s10689-019-00145-5

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