Grant Details
Grant Number: |
5R01CA243483-04 Interpret this number |
Primary Investigator: |
Amos, Christopher |
Organization: |
Baylor College Of Medicine |
Project Title: |
Sequencing Familial Lung Cancer |
Fiscal Year: |
2023 |
Abstract
Lung cancer (LC) is the leading cause of cancer mortality in the U.S. Although tobacco smoking and some
environmental exposures contribute substantially to lung cancer risk, family studies show an additional strong
contribution from genetic factors. The Genetic Epidemiology of Lung Cancer Consortium (GELCC) has been
collecting samples and data from individuals with a strong family history of LC for the last 20 years, and has
assembled a unique resource of specimens and data. We have cancer phenotypes, smoking exposure data
and biological specimens available on multiple relatives in over 150 highly aggregated LC families (high-risk
familial lung cancer families, HRFLC cases/families) as well as phenotype, genotype and smoking data on
over 800 additional lung cancer cases who have a family history of at least one first or second degree relative
with lung cancer but for whom biospecimens were not available from additional relatives (familial cases from
biospecimen limited families, FLC cases). The goal of this research application is to identify genetic
factors that confer a high risk for lung cancer and to perform research to characterize further the
mechanisms by which these factors influence lung cancer risk. Identifying genetic factors for lung cancer
provides insight into the specific causes and pathways underlying its development. In addition, if high-risk
individuals can be identified they will reap the greatest benefit from screening modalities.
We propose three aims. In aim 1 we will identify genetic factors conferring a high-risk of lung
cancer development.. In this aim, we will complete analyses of WES data from 33 HRFLC families
comprising 291 individuals along with 114 FLC cases and case/control analyses of 1084 lung cancer cases
compared with 919 controls. We will use these data along with linkage analysis to prioritize uncommon variants
that have a strong effect on lung cancer risk. In Aim 2 we will extend and validate findings to a broader
population. We will also collect additional samples from LC cases in HRLFC. We will sequence the most
strongly associated variants and genes from Aim 1 in additional affected and unaffected individuals in the
sequenced families and an additional set of FLC cases and frequency matched controls. This aim will allow us
to a) validate findings from aim 1 using a larger collection of cases with a family history of lung cancer and
controls and b) assess the impact on risk in families according to smoking behavior and genetic contributions.
In Aim 3 we will study the impact that variants found in aims 1 and 2 have on cellular biology. We will
study the effect that specific mutations have on cellular phenotypes identified in aims 1 and 2 using CRISPR
technology. We will begin by studying mutations in PARK2 that we recently identified in 5 HRLFC families and
in E2A we previously studied. The proposed research will bring new insights into the etiology of lung cancer.
Publications
Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes.
Authors: Long E.
, Yin J.
, Shin J.H.
, Li Y.
, Li B.
, Kane A.
, Patel H.
, Sun X.
, Wang C.
, Luong T.
, et al.
.
Source: Nature Communications, 2024-09-12 00:00:00.0; 15(1), p. 7995.
EPub date: 2024-09-12 00:00:00.0.
PMID: 39266564
Related Citations
High-throughput characterization of functional variants highlights heterogeneity and polygenicity underlying lung cancer susceptibility.
Authors: Long E.
, Patel H.
, Golden A.
, Antony M.
, Yin J.
, Funderburk K.
, Feng J.
, Song L.
, Hoskins J.W.
, Amundadottir L.T.
, et al.
.
Source: American Journal Of Human Genetics, 2024-07-11 00:00:00.0; 111(7), p. 1405-1419.
EPub date: 2024-06-20 00:00:00.0.
PMID: 38906146
Related Citations
Lung cancer in ever- and never-smokers: findings from multi-population GWAS studies.
Authors: Li Y.
, Xiao X.
, Li J.
, Han Y.
, Cheng C.
, Fernandes G.F.
, Slewitzke S.E.
, Rosenberg S.M.
, Zhu M.
, Byun J.
, et al.
.
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2024-01-05 00:00:00.0; , .
EPub date: 2024-01-05 00:00:00.0.
PMID: 38180474
Related Citations
Heritable Traits and Lung Cancer Risk: A Two-Sample Mendelian Randomization Study.
Authors: Pettit R.W.
, Byun J.
, Han Y.
, Ostrom Q.T.
, Coarfa C.
, Bondy M.L.
, Amos C.I.
.
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2023-10-02 00:00:00.0; 32(10), p. 1421-1435.
PMID: 37530747
Related Citations
A comprehensive analysis of lung cancer highlighting epidemiological factors and psychiatric comorbidities from the All of Us Research Program.
Authors: Shaw V.R.
, Byun J.
, Pettit R.W.
, Han Y.
, Hsiou D.A.
, Nordstrom L.A.
, Amos C.I.
.
Source: Scientific Reports, 2023-07-05 00:00:00.0; 13(1), p. 10852.
EPub date: 2023-07-05 00:00:00.0.
PMID: 37407606
Related Citations
p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study.
Authors: Köbel M.
, Kang E.Y.
, Weir A.
, Rambau P.F.
, Lee C.H.
, Nelson G.S.
, Ghatage P.
, Meagher N.S.
, Riggan M.J.
, Alsop J.
, et al.
.
Source: The Journal Of Pathology. Clinical Research, 2023-03-22 00:00:00.0; , .
EPub date: 2023-03-22 00:00:00.0.
PMID: 36948887
Related Citations
A rare FGF5 candidate variant (rs112475347) for predisposition to nonsquamous, nonsmall-cell lung cancer.
Authors: Cannon-Albright L.A.
, Teerlink C.C.
, Stevens J.
, Facelli J.C.
, Carr S.R.
, Allen-Brady K.
, Puri S.
, Bailey-Wilson J.E.
, Musolf A.M.
, Genetic Epidemiology of Lung Cancer Consortium
, et al.
.
Source: International Journal Of Cancer, 2023-03-14 00:00:00.0; , .
EPub date: 2023-03-14 00:00:00.0.
PMID: 36916144
Related Citations
Functional studies of lung cancer GWAS beyond association.
Authors: Long E.
, Patel H.
, Byun J.
, Amos C.I.
, Choi J.
.
Source: Human Molecular Genetics, 2022-10-20 00:00:00.0; 31(R1), p. R22-R36.
PMID: 35776125
Related Citations
Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer.
Authors: Byun J.
, Han Y.
, Li Y.
, Xia J.
, Long E.
, Choi J.
, Xiao X.
, Zhu M.
, Zhou W.
, Sun R.
, et al.
.
Source: Nature Genetics, 2022 Aug; 54(8), p. 1167-1177.
EPub date: 2022-08-01 00:00:00.0.
PMID: 35915169
Related Citations
Deep oncopanel sequencing reveals within block position-dependent quality degradation in FFPE processed samples.
Authors: Zhang Y.
, Blomquist T.M.
, Kusko R.
, Stetson D.
, Zhang Z.
, Yin L.
, Sebra R.
, Gong B.
, Lococo J.S.
, Mittal V.K.
, et al.
.
Source: Genome Biology, 2022-06-29 00:00:00.0; 23(1), p. 141.
EPub date: 2022-06-29 00:00:00.0.
PMID: 35768876
Related Citations
Genome-wide interaction analysis identified low-frequency variants with sex disparity in lung cancer risk.
Authors: Li Y.
, Xiao X.
, Li J.
, Byun J.
, Cheng C.
, Bossé Y.
, McKay J.
, Albanes D.
, Lam S.
, Tardon A.
, et al.
.
Source: Human Molecular Genetics, 2022-02-09 00:00:00.0; , .
EPub date: 2022-02-09 00:00:00.0.
PMID: 35138370
Related Citations
SNP characteristics and validation success in genome wide association studies.
Authors: Gorlova O.Y.
, Xiao X.
, Tsavachidis S.
, Amos C.I.
, Gorlov I.P.
.
Source: Human Genetics, 2022-01-04 00:00:00.0; , .
EPub date: 2022-01-04 00:00:00.0.
PMID: 34981173
Related Citations
Identification of lung cancer drivers by comparison of the observed and the expected numbers of missense and nonsense mutations in individual human genes.
Authors: Gorlova O.Y.
, Kimmel M.
, Tsavachidis S.
, Amos C.I.
, Gorlov I.P.
.
Source: Oncotarget, 2022; 13, p. 756-767.
EPub date: 2022-05-25 00:00:00.0.
PMID: 35634240
Related Citations
Advancing NGS quality control to enable measurement of actionable mutations in circulating tumor DNA.
Authors: Willey J.C.
, Morrison T.B.
, Austermiller B.
, Crawford E.L.
, Craig D.J.
, Blomquist T.M.
, Jones W.D.
, Wali A.
, Lococo J.S.
, Haseley N.
, et al.
.
Source: Cell Reports Methods, 2021-11-22 00:00:00.0; 1(7), p. 100106.
EPub date: 2021-11-03 00:00:00.0.
PMID: 35475002
Related Citations
Genetic Variation and Recurrent Haplotypes on Chromosome 6q23-25 Risk Locus in Familial Lung Cancer.
Authors: Musolf A.M.
, Simpson C.L.
, Moiz B.A.
, Pikielny C.W.
, Middlebrooks C.D.
, Mandal D.
, de Andrade M.
, Cole M.D.
, Gaba C.
, Yang P.
, et al.
.
Source: Cancer Research, 2021-06-15 00:00:00.0; 81(12), p. 3162-3173.
EPub date: 2021-04-14 00:00:00.0.
PMID: 33853833
Related Citations
Rare deleterious germline variants and risk of lung cancer.
Authors: Liu Y.
, Xia J.
, McKay J.
, Tsavachidis S.
, Xiao X.
, Spitz M.R.
, Cheng C.
, Byun J.
, Hong W.
, Li Y.
, et al.
.
Source: Npj Precision Oncology, 2021-02-16 00:00:00.0; 5(1), p. 12.
EPub date: 2021-02-16 00:00:00.0.
PMID: 33594163
Related Citations
Gene-Based Association Testing of Dichotomous Traits With Generalized Functional Linear Mixed Models Using Extended Pedigrees: Applications to Age-Related Macular Degeneration.
Authors: Jiang Y.
, Chiu C.Y.
, Yan Q.
, Chen W.
, Gorin M.B.
, Conley Y.P.
, Lakhal-Chaieb M.L.
, Cook R.J.
, Amos C.I.
, Wilson A.F.
, et al.
.
Source: Journal Of The American Statistical Association, 2021; 116(534), p. 531-545.
EPub date: 2020-07-28 00:00:00.0.
PMID: 34321704
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Whole Exome Sequencing of Highly Aggregated Lung Cancer Families Reveals Linked Loci for Increased Cancer Risk on Chromosomes 12q, 7p, and 4q.
Authors: Musolf A.M.
, Moiz B.A.
, Sun H.
, Pikielny C.W.
, Bossé Y.
, Mandal D.
, de Andrade M.
, Gaba C.
, Yang P.
, Li Y.
, et al.
.
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2020 Feb; 29(2), p. 434-442.
EPub date: 2019-12-11 00:00:00.0.
PMID: 31826912
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