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Article

Cancer Predisposition Genes in Cancer-Free Families

1
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany
2
Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany
3
Hopp Children’s Cancer Center (KiTZ), 69120 Heidelberg, Germany
4
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
5
Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany
6
Computational Oncology, Molecular Diagnostics Program, National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
7
Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
8
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
9
Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland
10
Comprehensive Cancer Center, Helsinki University Hospital, 00290 Helsinki, Finland
11
Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland
12
Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, 30605 Pilsen, Czech Republic
13
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
The authors shared senior authorship.
Cancers 2020, 12(10), 2770; https://doi.org/10.3390/cancers12102770
Received: 10 August 2020 / Revised: 21 September 2020 / Accepted: 24 September 2020 / Published: 27 September 2020
(This article belongs to the Special Issue Functional Genomics of Cancer)
Familial clustering of cancer and identification of high- and low-risk cancer predisposition gene variants implicate that there are families that are at a high to moderate excess risk of cancer. We wanted to test genetically whether there are families protected from cancer. We whole-genome sequenced 51 elderly individuals without any personal or family history of cancer. We identified less high-risk loss-of-function variants in known and suggested cancer predisposition genes in these cancer-free individuals than in the general population. However, our results for low-risk variants were not conclusive. Our study suggests that random environmental causes of cancer are so dominant that a clear demarcation of cancer-free populations using genetic data may not be feasible. However, carrier identification of and counseling about prevalent high-risk cancer predisposition genes is useful.
Familial clustering, twin concordance, and identification of high- and low-penetrance cancer predisposition variants support the idea that there are families that are at a high to moderate excess risk of cancer. To what extent there may be families that are protected from cancer is unknown. We wanted to test genetically whether cancer-free families share fewer breast, colorectal, and prostate cancer risk alleles than the population at large. We addressed this question by whole-genome sequencing (WGS) of 51 elderly cancer-free individuals whose numerous (ca. 1000) family members were found to be cancer-free (‘cancer-free families’, CFFs) based on face-to-face interviews. The average coverage of the 51 samples in the WGS was 42x. We compared cancer risk allele frequencies in cancer-free individuals with those in the general population available in public databases. The CFF members had fewer loss-of-function variants in suggested cancer predisposition genes compared to the ExAC data, and for high-risk cancer predisposition genes, no pathogenic variants were found in CFFs. For common low-penetrance breast, colorectal, and prostate cancer risk alleles, the results were not conclusive. The results suggest that, in line with twin and family studies, random environmental causes are so dominant that a clear demarcation of cancer-free populations using genetic data may not be feasible. View Full-Text
Keywords: predisposing genes; high-risk genes; polygenic risk; random environment predisposing genes; high-risk genes; polygenic risk; random environment
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Figure 1

MDPI and ACS Style

Zheng, G.; Catalano, C.; Bandapalli, O.R.; Paramasivam, N.; Chattopadhyay, S.; Schlesner, M.; Sijmons, R.; Hemminki, A.; Dymerska, D.; Lubinski, J.; Hemminki, K.; Försti, A. Cancer Predisposition Genes in Cancer-Free Families. Cancers 2020, 12, 2770. https://doi.org/10.3390/cancers12102770

AMA Style

Zheng G, Catalano C, Bandapalli OR, Paramasivam N, Chattopadhyay S, Schlesner M, Sijmons R, Hemminki A, Dymerska D, Lubinski J, Hemminki K, Försti A. Cancer Predisposition Genes in Cancer-Free Families. Cancers. 2020; 12(10):2770. https://doi.org/10.3390/cancers12102770

Chicago/Turabian Style

Zheng, Guoqiao, Calogerina Catalano, Obul R. Bandapalli, Nagarajan Paramasivam, Subhayan Chattopadhyay, Matthias Schlesner, Rolf Sijmons, Akseli Hemminki, Dagmara Dymerska, Jan Lubinski, Kari Hemminki, and Asta Försti. 2020. "Cancer Predisposition Genes in Cancer-Free Families" Cancers 12, no. 10: 2770. https://doi.org/10.3390/cancers12102770

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