Mutations of HNRNPA0 and WIF1 predispose members of a large family to multiple cancers
We studied a large family that presented a strong familial susceptibility to multiple early onset cancers including prostate, breast, colon, and several other uncommon cancers. Through targeted gene, linkage, and whole genome sequencing analyses, we show that the presence of a variant in the regulat...
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Published in | Familial cancer Vol. 14; no. 2; pp. 297 - 306 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Dordrecht
Springer Netherlands
01.06.2015
Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Summary: | We studied a large family that presented a strong familial susceptibility to multiple early onset cancers including prostate, breast, colon, and several other uncommon cancers. Through targeted gene, linkage, and whole genome sequencing analyses, we show that the presence of a variant in the regulatory region of
HNRNPA0
associated with elevated cancer incidence in this family (Hazard ratio = 7.20,
p
= 0.0004). Whole genome sequencing identified a second rare protein changing mutation of
WIF1
that interacted with the
HNRNPA0
variant resulting in extremely high risk for cancer in carriers of mutations in both genes (
p
= 1.98 × 10
−13
). Analysis of downstream targets of the mutations in these two genes showed that the
HNRNPA0
mutation affected expression patterns in the PI3 kinase and ERK/MAPK signaling pathways, while the
WIF1
variant influenced expression of genes that play a role in NAD biosynthesis. This is a first report of variation in
HNRNPA0
influencing common cancers or of a striking interaction between rare variants coexisting in an extended pedigree and jointly affecting cancer risk. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Chongjuan Wei and Bo Peng have contributed equally to this work. |
ISSN: | 1389-9600 1573-7292 |
DOI: | 10.1007/s10689-014-9758-8 |