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. 2017 Jun 21;8(55):93450-93463.
doi: 10.18632/oncotarget.18596. eCollection 2017 Nov 7.

Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort

Leon Raskin  1 , Yan Guo  2 , Liping Du  2 , Mark Clendenning  3 , Christophe Rosty  3   4   5 ; Colon Cancer Family Registry (CCFR); Noralane M Lindor  6 , Stephen B Gruber  7   8 , Daniel D Buchanan  3   5   9
Affiliations

Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort

Leon Raskin et al. Oncotarget. .

Abstract

The underlying genetic cause of colorectal cancer (CRC) can be identified for 5-10% of all cases, while at least 20% of CRC cases are thought to be due to inherited genetic factors. Screening for highly penetrant mutations in genes associated with Mendelian cancer syndromes using next-generation sequencing (NGS) can be prohibitively expensive for studies requiring large samples sizes. The aim of the study was to identify rare single nucleotide variants and small indels in 40 established or candidate CRC susceptibility genes in 1,046 familial CRC cases (including both MSS and MSI-H tumor subtypes) and 1,006 unrelated controls from the Colon Cancer Family Registry Cohort using a robust and cost-effective DNA pooling NGS strategy. We identified 264 variants in 38 genes that were observed only in cases, comprising either very rare (minor allele frequency <0.001) or not previously reported (n=90, 34%) in reference databases, including six stop-gain, three frameshift, and 255 non-synonymous variants predicted to be damaging. We found novel germline mutations in established CRC genes MLH1, APC, and POLE, and likely pathogenic variants in cancer susceptibility genes BAP1, CDH1, CHEK2, ENG, and MSH3. For the candidate CRC genes, we identified likely pathogenic variants in the helicase domain of POLQ and in the LRIG1, SH2B3, and NOS1 genes and present their clinicopathological characteristics. Using a DNA pooling NGS strategy, we identified novel germline mutations in established CRC susceptibility genes in familial CRC cases. Further studies are required to support the role of POLQ, LRIG1, SH2B3 and NOS1 as CRC susceptibility genes.

Keywords: Colon Cancer Family Registry; DNA pooling; hereditary colorectal cancer; rare variants; targeted sequencing.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors have no conflict of interest to declare.

Figures

Figure 1
Figure 1. Distribution of 106 germline variants from 40 established and candidate CRC genes by case tiers
Figure 2
Figure 2. Targeted sequencing of pooled samples for identification of rare variants of large effect
See this image and copyright information in PMC

References

    1. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000;343:78–85. - PubMed
    1. Aaltonen L, Johns L, Jarvinen H, Mecklin JP, Houlston R. Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors. Clin Cancer Res. 2007;13:356–361. - PubMed
    1. Vasen HF. Clinical diagnosis and management of hereditary colorectal cancer syndromes. J Clin Oncol. 2000;18:81S–92S. - PubMed
    1. Fearnhead NS, Britton MP, Bodmer WF. The ABC of APC. Hum Mol Genet. 2001;10:721–733. - PubMed
    1. Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingston AL, Williams GT, Hodges AK, Davies DR, David SS, Sampson JR, Cheadle JP. Inherited variants of MYH associated with somatic G:C -->T:A mutations in colorectal tumors. Nat Genet. 2002;30:227. - PubMed

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