TY - JOUR
T1 - Genetic variation and recurrent haplotypes on chromosome 6q23-25 risk locus in familial lung cancer
AU - Musolf, Anthony M.
AU - Simpson, Claire L.
AU - Moiz, Bilal A.
AU - Pikielny, Claudio W.
AU - Middlebrooks, Candace D.
AU - Mandal, Diptasri
AU - De Andrade, Mariza
AU - Cole, Michael D.
AU - Gaba, Colette
AU - Yang, Ping
AU - You, Ming
AU - Li, Yafang
AU - Kupert, Elena Y.
AU - Anderson, Marshall W.
AU - Schwartz, Ann G.
AU - Pinney, Susan M.
AU - Amos, Christopher I.
AU - Bailey-Wilson, Joan E.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/6
Y1 - 2021/6
N2 - Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains understudied. We previously identified a lung cancer risk locus on 6q23-25 using microsatellite data in families with a history of lung cancer. To further elucidate that signal, we performed targeted sequencing on nine of our most strongly linked families. Two-point linkage analysis of the sequencing data revealed that the signal was heterogeneous and that different families likely had different risk variants. Three specific haplotypes were shared by some of the families: 6q25.3-26 in families 42 and 44, 6q25.2-25.3 in families 47 and 59, and 6q24.2-25.1 in families 30, 33, and 35. Region-based logarithm of the odds scores and expression data identified the likely candidate genes for each haplotype overlap: ARID1B at 6q25.3, MAP3K4 at 6q26, and UTRN (6q24.1) and PHACTR2 (6q24.2). Further annotation was used to zero in on potential risk variants in those genes. All four genes are good candidate genes for lung cancer risk, having been linked to either lung cancer specifically or other cancers. However, this is the first time any of these genes has been implicated in germline risk. Functional analysis of these four genes is planned for future work.
AB - Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains understudied. We previously identified a lung cancer risk locus on 6q23-25 using microsatellite data in families with a history of lung cancer. To further elucidate that signal, we performed targeted sequencing on nine of our most strongly linked families. Two-point linkage analysis of the sequencing data revealed that the signal was heterogeneous and that different families likely had different risk variants. Three specific haplotypes were shared by some of the families: 6q25.3-26 in families 42 and 44, 6q25.2-25.3 in families 47 and 59, and 6q24.2-25.1 in families 30, 33, and 35. Region-based logarithm of the odds scores and expression data identified the likely candidate genes for each haplotype overlap: ARID1B at 6q25.3, MAP3K4 at 6q26, and UTRN (6q24.1) and PHACTR2 (6q24.2). Further annotation was used to zero in on potential risk variants in those genes. All four genes are good candidate genes for lung cancer risk, having been linked to either lung cancer specifically or other cancers. However, this is the first time any of these genes has been implicated in germline risk. Functional analysis of these four genes is planned for future work.
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U2 - 10.1158/0008-5472.CAN-20-3196
DO - 10.1158/0008-5472.CAN-20-3196
M3 - Article
C2 - 33853833
AN - SCOPUS:85108097814
SN - 0008-5472
VL - 81
SP - 3162
EP - 3173
JO - Cancer research
JF - Cancer research
IS - 12
ER -