Cancer Predisposition Genes in Cancer-Free Families

Cancers

Matthias Schlesner¹  Akseli Hemminki²  Nagarajan Paramasivam³  Rolf Sijmons⁴  Kari Hemminki⁵  Subhayan Chattopadhyay⁵  Guoqiao Zheng⁵  Calogerina Catalano⁵  ObulReddy Bandapalli⁵  Asta Försti⁵  Jan Lubinski⁶  Dagmara Dymerska⁶ 

[1] Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland;Computational Oncology, Molecular Diagnostics Program, National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany;Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands;Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany;Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland;

关键词: predisposing genes;    high-risk genes;    polygenic risk;    random environment;   

DOI  :  10.3390/cancers12102770

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown