TY - JOUR
T1 - Variation in cancer risk among families with genetic susceptibility
AU - Huang, Theodore
AU - Braun, Danielle
AU - Lynch, Henry T.
AU - Parmigiani, Giovanni
N1 - Publisher Copyright:
© 2020 Wiley Periodicals LLC
PY - 2021/3
Y1 - 2021/3
N2 - Germline mutations in many genes have been shown to increase the risk of developing cancer. This risk can vary across families who carry mutations in the same gene due to differences in the specific variants, gene–gene interactions, other susceptibility mutations, environmental factors, and behavioral factors. We develop an analytic tool to explore this heterogeneity using family history data. We propose to evaluate the ratio between the number of observed cancer cases in a family and the number of expected cases under a model where risk is assumed to be the same across families. We perform this analysis for both carriers and noncarriers in each family, using carrier probabilities when carrier statuses are unknown, and visualize the results. We first illustrate the approach in simulated data and then apply it to data on colorectal cancer risk in families carrying mutations in Lynch syndrome genes from Creighton University's Hereditary Cancer Center. We show that colorectal cancer risk in carriers can vary widely across families, and that this variation is not matched by a corresponding variation in the noncarriers from the same families. This suggests that the sources of variation in these families are to be found predominantly in variants harbored in the mutated MMR genes considered, or in variants interacting with them.
AB - Germline mutations in many genes have been shown to increase the risk of developing cancer. This risk can vary across families who carry mutations in the same gene due to differences in the specific variants, gene–gene interactions, other susceptibility mutations, environmental factors, and behavioral factors. We develop an analytic tool to explore this heterogeneity using family history data. We propose to evaluate the ratio between the number of observed cancer cases in a family and the number of expected cases under a model where risk is assumed to be the same across families. We perform this analysis for both carriers and noncarriers in each family, using carrier probabilities when carrier statuses are unknown, and visualize the results. We first illustrate the approach in simulated data and then apply it to data on colorectal cancer risk in families carrying mutations in Lynch syndrome genes from Creighton University's Hereditary Cancer Center. We show that colorectal cancer risk in carriers can vary widely across families, and that this variation is not matched by a corresponding variation in the noncarriers from the same families. This suggests that the sources of variation in these families are to be found predominantly in variants harbored in the mutated MMR genes considered, or in variants interacting with them.
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U2 - 10.1002/gepi.22366
DO - 10.1002/gepi.22366
M3 - Article
C2 - 33030277
AN - SCOPUS:85092188498
VL - 45
SP - 209
EP - 221
JO - Genetic Epidemiology
JF - Genetic Epidemiology
SN - 0741-0395
IS - 2
ER -