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Am J Hum Genet. 2018 Mar 1;102(3):401-414. doi: 10.1016/j.ajhg.2018.01.018. Epub 2018 Feb 22.

Inherited DNA-Repair Defects in Colorectal Cancer.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
2
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
3
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Indiana University School of Medicine, Indianapolis, IN 46202, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
4
Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
5
Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
6
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
7
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
8
Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
9
Yale Cancer Center, Yale School of Medicine, New Haven, CT 06510, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
10
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: eliezerm_vanallen@dfci.harvard.edu.

Abstract

Colorectal cancer (CRC) heritability has been estimated to be around 30%. However, mutations in the known CRC-susceptibility genes explain CRC risk in fewer than 10% of affected individuals. Germline mutations in DNA-repair genes (DRGs) have recently been reported in CRC, but their contribution to CRC risk is largely unknown. We evaluated the gene-level germline mutation enrichment of 40 DRGs in 680 unselected CRC individuals and 27,728 ancestry-matched cancer-free adults. Significant findings were then examined in independent cohorts of 1,661 unselected CRC individuals and 1,456 individuals with early-onset CRC. Of the 680 individuals in the discovery set, 31 (4.56%) individuals harbored germline pathogenic mutations in known CRC-susceptibility genes, and another 33 (4.85%) individuals had DRG mutations that have not been previously associated with CRC risk. Germline pathogenic mutations in ATM and PALB2 were enriched in both the discovery (OR = 2.81 and p = 0.035 for ATM and OR = 4.91 and p = 0.024 for PALB2) and validation (OR = 2.97 and adjusted p = 0.0013 for ATM and OR = 3.42 and adjusted p = 0.034 for PALB2) sets. Biallelic loss of ATM was evident in all individuals with matched tumor profiling. CRC individuals also had higher rates of actionable mutations in the HR pathway, which can substantially increase the risk of developing cancers other than CRC. Our analysis provides evidence for ATM and PALB2 as CRC-risk genes, underscoring the importance of the homologous recombination pathway in CRC. In addition, we identified frequent complete homologous recombination deficiency in CRC tumors, representing a unique opportunity to explore targeted therapeutic interventions such as poly-ADP ribose polymerase inhibitor (PARPi).

KEYWORDS:

ATM mutations; CRC; DNA-repair deficiency; PALB2 mutations; actionable mutations; cancer heritability; colorectal cancer genetics; germline genetics; homologous recombination

PMID:
29478780
PMCID:
PMC5985280
DOI:
10.1016/j.ajhg.2018.01.018
[Indexed for MEDLINE]
Free PMC Article

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