Common genetic variants contribute to incomplete penetrance

evidence from cancer-free BRCA1 mutation carriers

Bradley Downs, Simon Sherman, Jian Cui, Yeong C. Kim, Carrie Snyder, Maria Christensen, Jiangtao Luo, Henry T. Lynch, San Ming Wang

Research output: Contribution to journalArticle

Abstract

Purpose: The presence of pathogenic germline mutation in BRCA1 gene is considered as the most penetrant genetic predisposition for breast cancer. However, a portion of BRCA1 mutation carriers never develops breast cancer throughout their lifetime. This phenomenon is called incomplete penetrance. Genetic factor is proposed to contribute to this phenomenon, but the details regarding the genetic factor remain elusive. BRCA1 mutations were inherited from the ancestors of the mutation carrier families during human evolution, and their presence is a consistent threat to the survival of the mutation carrier population. In the present study, we hypothesize that evolution could positively select genetic components in the mutation carrier population to suppress the oncogenesis imposed by the predisposition. Experimental design: To test our hypothesis, we used whole exome sequencing to compare germline variation of all genes in pairs of breast cancer–unaffected and breast cancer–affected BRCA1 mutation carriers, each pair was from the same family carrying the same BRCA1 mutation. Results: We identified a group of ‘beneficial’ variants enriched in the breast cancer–unaffected carrier group. These were the common variants in human population distributed in multiple genes involved in multiple functionally important pathways. We found a single-nucleotide polymorphism, rs3735400 located in ANLN gene, which plays an essential role in controlling cytokinesis and is often found to be overexpressed in cancer. The carriers of this variant had lower cumulative risk of developing breast cancer; overexpression of the variant-containing ANLN decreased ANLN nuclear localization suppressed expression of the variant-containing ANLN, and decreased the cellular proliferation respectively. Conclusion: Our findings support our hypothesis that common genetic variants can be evolutionarily selected in BRCA1 mutation carrier population to counterpart the oncogenic effects imposed by mutation predisposition in BRCA1, contributing to the incomplete penetrance.

Original languageEnglish (US)
Pages (from-to)68-78
Number of pages11
JournalEuropean Journal of Cancer
Volume107
DOIs
StatePublished - Jan 1 2019

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Penetrance
Mutation
Neoplasms
Breast
Breast Neoplasms
Population
BRCA1 Gene
Genes
Exome
Cytokinesis
Germ-Line Mutation
Genetic Predisposition to Disease
Single Nucleotide Polymorphism
Carcinogenesis
Research Design
Cell Proliferation
Survival

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Common genetic variants contribute to incomplete penetrance : evidence from cancer-free BRCA1 mutation carriers. / Downs, Bradley; Sherman, Simon; Cui, Jian; Kim, Yeong C.; Snyder, Carrie; Christensen, Maria; Luo, Jiangtao; Lynch, Henry T.; Wang, San Ming.

In: European Journal of Cancer, Vol. 107, 01.01.2019, p. 68-78.

Research output: Contribution to journalArticle

Downs, Bradley ; Sherman, Simon ; Cui, Jian ; Kim, Yeong C. ; Snyder, Carrie ; Christensen, Maria ; Luo, Jiangtao ; Lynch, Henry T. ; Wang, San Ming. / Common genetic variants contribute to incomplete penetrance : evidence from cancer-free BRCA1 mutation carriers. In: European Journal of Cancer. 2019 ; Vol. 107. pp. 68-78.
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abstract = "Purpose: The presence of pathogenic germline mutation in BRCA1 gene is considered as the most penetrant genetic predisposition for breast cancer. However, a portion of BRCA1 mutation carriers never develops breast cancer throughout their lifetime. This phenomenon is called incomplete penetrance. Genetic factor is proposed to contribute to this phenomenon, but the details regarding the genetic factor remain elusive. BRCA1 mutations were inherited from the ancestors of the mutation carrier families during human evolution, and their presence is a consistent threat to the survival of the mutation carrier population. In the present study, we hypothesize that evolution could positively select genetic components in the mutation carrier population to suppress the oncogenesis imposed by the predisposition. Experimental design: To test our hypothesis, we used whole exome sequencing to compare germline variation of all genes in pairs of breast cancer–unaffected and breast cancer–affected BRCA1 mutation carriers, each pair was from the same family carrying the same BRCA1 mutation. Results: We identified a group of ‘beneficial’ variants enriched in the breast cancer–unaffected carrier group. These were the common variants in human population distributed in multiple genes involved in multiple functionally important pathways. We found a single-nucleotide polymorphism, rs3735400 located in ANLN gene, which plays an essential role in controlling cytokinesis and is often found to be overexpressed in cancer. The carriers of this variant had lower cumulative risk of developing breast cancer; overexpression of the variant-containing ANLN decreased ANLN nuclear localization suppressed expression of the variant-containing ANLN, and decreased the cellular proliferation respectively. Conclusion: Our findings support our hypothesis that common genetic variants can be evolutionarily selected in BRCA1 mutation carrier population to counterpart the oncogenic effects imposed by mutation predisposition in BRCA1, contributing to the incomplete penetrance.",
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