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Segregation analysis of 17,425 population-based breast cancer families: Evidence for genetic susceptibility and risk prediction.

Accepted version
Peer-reviewed

Type

Article

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Authors

Li, Shuai 
MacInnis, Robert J 
Lee, Andrew 
Nguyen-Dumont, Tu 
Dorling, Leila 

Abstract

Rare pathogenic variants in known breast cancer-susceptibility genes and known common susceptibility variants do not fully explain the familial aggregation of breast cancer. To investigate plausible genetic models for the residual familial aggregation, we studied 17,425 families ascertained through population-based probands, 86% of whom were screened for pathogenic variants in BRCA1, BRCA2, PALB2, CHEK2, ATM, and TP53 via gene-panel sequencing. We conducted complex segregation analyses and fitted genetic models in which breast cancer incidence depended on the effects of known susceptibility genes and other unidentified major genes and a normally distributed polygenic component. The proportion of familial variance explained by the six genes was 46% at age 20-29 years and decreased steadily with age thereafter. After allowing for these genes, the best fitting model for the residual familial variance included a recessive risk component with a combined genotype frequency of 1.7% (95% CI: 0.3%-5.4%) and a penetrance to age 80 years of 69% (95% CI: 38%-95%) for homozygotes, which may reflect the combined effects of multiple variants acting in a recessive manner, and a polygenic variance of 1.27 (95% CI: 0.94%-1.65), which did not vary with age. The proportion of the residual familial variance explained by the recessive risk component was 40% at age 20-29 years and decreased with age thereafter. The model predicted age-specific familial relative risks consistent with those observed by large epidemiological studies. The findings have implications for strategies to identify new breast cancer-susceptibility genes and improve disease-risk prediction, especially at a young age.

Description

Keywords

ATM, BOADICEA, BRCA1, BRCA2, CHEK2, PALB2, TP53, breast cancer, familial aggregation, familial risk, missing heritability, segregation analysis, Adult, Aged, 80 and over, Breast Neoplasms, Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Multifactorial Inheritance, Penetrance, Young Adult

Journal Title

Am J Hum Genet

Conference Name

Journal ISSN

0002-9297
1537-6605

Volume Title

Publisher

Elsevier BV
Sponsorship
Cancer Research UK (C12292/A31369)
EPSRC (EP/T022159/1)
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