Integrated Analysis of Germline and Tumor DNA Identifies New Candidate Genes Involved in Familial Colorectal Cancer.

Marcos Díaz‐Gay ,Anna Gratacós-Mulleras ,Coral Arnau‐Collell ,Francesc Balaguer ,Míriam Cuatrecasas ,Sebastià Franch‐Expósito ,Solip Park ,Fran Supek ,Clara Esteban-Jurado ,Antoni Castells ,Teresa Ocaña ,Juan José Lozano ,María Vila-Casadesús ,Sergi Beltrán ,Paula A Sánchez-Rojas ,Luís Bujanda ,Genı́s Parra ,Laia Bonjoch ,Joaquín Cubiella ,Jenifer Muñoz ,Steve Laurie ,Sergi Castellví–Bel

doi:10.3390/cancers11030362

Abstract

Colorectal cancer (CRC) shows aggregation in some families but no alterations in the known hereditary CRC genes. We aimed to identify new candidate genes which are potentially involved in germline predisposition to familial CRC. An integrated analysis of germline and tumor whole-exome sequencing data was performed in 18 unrelated CRC families. Deleterious single nucleotide variants (SNV), short insertions and deletions (indels), copy number variants (CNVs) and loss of heterozygosity (LOH) were assessed as candidates for first germline or second somatic hits. Candidate tumor suppressor genes were selected when alterations were detected in both germline and somatic DNA, fulfilling Knudson’s two-hit hypothesis. Somatic mutational profiling and signature analysis were also performed. A series of germline-somatic variant pairs were detected. In all cases, the first hit was presented as a rare SNV/indel, whereas the second hit was either a different SNV (3 genes) or LOH affecting the same gene (141 genes). BRCA2, BLM, ERCC2, RECQL, REV3L and RIF1 were among the most promising candidate genes for germline CRC predisposition. The identification of new candidate genes involved in familial CRC could be achieved by our integrated analysis. Further functional studies and replication in additional cohorts are required to confirm the selected candidates.

Highlights

Colorectal cancer (CRC) is one of the most common and lethal malignant neoplasms worldwide, accounting for 8% of all cancer-related deaths [1]
A germline single nucleotide variants (SNV) and a tumor SNV were identified in ADCY8 and HSPG2 genes, whereas a germline SNV/indel and somatic loss of heterozygosity (LOH) of the wild-type allele was predicted for BRCA2, BLM, ERCC2, PARP2, RECQL, REV3L, RIF1, SEC23B, SMARCA4 and STK11IP
The cyclic AMP (cAMP) pathway was already found to be associated with cancer, with the overexpression of ADCY3 increasing oncogenic potential in gastric cancer cells [15] and ADCY8 acting itself as a risk modifier in glioma [16]

Summary

Introduction

Colorectal cancer (CRC) is one of the most common and lethal malignant neoplasms worldwide, accounting for 8% of all cancer-related deaths [1]. Developed countries are the most affected, with almost. Genetic and environmental factors are involved in CRC predisposition. Inherited genetic variation reaches 35% of susceptibility according to twin studies [4]. Predisposition can be classified according to population frequency and associated disease risk into high- and low-penetrant variants. High-penetrant variants are rare and have a large effect on the predisposition to the disease. Only 5% of CRC cases are explained by this kind of variation due to its low frequency in the population. Low-penetrance genetic variation, mainly identified in genome-wide association studies, is characterized by a high prevalence in the population and a weak deleterious effect. All identified low-penetrance variants contribute significantly to CRC susceptibility, accounting for 5–10% of the heritability to this disease [6]

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