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New basal cell carcinoma susceptibility loci.

Stacey SN, Helgason H, Gudjonsson SA, Thorleifsson G, Zink F, Sigurdsson A, Kehr B, Gudmundsson J, Sulem P, Sigurgeirsson B, Benediktsdottir KR, Thorisdottir K, Ragnarsson R, Fuentelsaz V, Corredera C, Gilaberte Y, Grasa M, Planelles D, Sanmartin O, Rudnai P, Gurzau E, Koppova K, Nexø BA, Tjønneland A, Overvad K, Jonasson JG, Tryggvadottir L, Johannsdottir H, Kristinsdottir AM, Stefansson H, Masson G, Magnusson OT, Halldorsson BV, Kong A, Rafnar T, Thorsteinsdottir U, Vogel U, Kumar R, Nagore E, Mayordomo JI, Gudbjartsson DF, Olafsson JH, Stefansson K - Nat Commun (2015)

Bottom Line: Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)).Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor.In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.

View Article: PubMed Central - PubMed

Affiliation: deCODE Genetics/AMGEN, Sturlugata 8, Reykjavik 101, Iceland.

ABSTRACT
In an ongoing screen for DNA sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conduct a genome-wide association study (GWAS) of 24,988,228 SNPs and small indels detected through whole-genome sequencing of 2,636 Icelanders and imputed into 4,572 BCC patients and 266,358 controls. Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)). Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor. In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.

No MeSH data available.


Related in: MedlinePlus

CASP8-coding exons, protein domains and locations of probes.(a) Coding exons of the major transcript variants. The positions of exon 8 and exon 8L are indicated. The transcript variant containing exon 8L is designated ‘NR_' because the exon 8L sequence contains a stop codon that may render this RNA species susceptible to nonsense-mediated decay. (b) Procaspase-8 protein domains corresponding to exons, from pfam: IPR001875-DED are the DED; IPR011600-Pept_C14_cat corresponds to the peptidase catalytic domains. (c) Location of the probe sequences used on the expression microarrays. The height of the bars corresponds to the relative levels of expression in blood. (d) Location of primer-amplicons used in RT–PCR.
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f2: CASP8-coding exons, protein domains and locations of probes.(a) Coding exons of the major transcript variants. The positions of exon 8 and exon 8L are indicated. The transcript variant containing exon 8L is designated ‘NR_' because the exon 8L sequence contains a stop codon that may render this RNA species susceptible to nonsense-mediated decay. (b) Procaspase-8 protein domains corresponding to exons, from pfam: IPR001875-DED are the DED; IPR011600-Pept_C14_cat corresponds to the peptidase catalytic domains. (c) Location of the probe sequences used on the expression microarrays. The height of the bars corresponds to the relative levels of expression in blood. (d) Location of primer-amplicons used in RT–PCR.

Mentions: We determined whether any of the BCC risk variants were associated with local differences in gene expression (cis-expression quantitative trait loci (eQTL)) by cross-referencing genotypes to RNA expression microarray data that we had derived previously from 1,001 blood and 673 adipose tissue samples26. No significant associations were seen for 2p24 MYCN, 8q21 ZFHX4 or 10p14 GATA3. At 2q33, CASP8 generates numerous splice variants (Fig. 2a). One probe on the microarrays, designated NM_033355, is in the 3′ UTR and captures all major CASP8 isoform transcripts (Fig. 2c). A second probe, designated NM_033358, is unique to a small exon located between exons 8 and 9 of the major transcripts (exon numbering is based on NM_001228). The NM_033358 transcript encodes caspase-8 isoform E, which contains the death effector domains (DED) but lacks the catalytic domains of caspase-8 (Fig. 2b). A transcript with an extended exon 8, called exon 8L (NR_111983) has the capacity to encode a similar DED-only isoform because the 8L extension contains an in-frame stop codon. However, splicing of exon 8L to downstream exons may target the transcript for nonsense-mediated decay27282930. Evidence for the existence in vivo of DED-only caspase-8 isoforms and their potential inhibitory effects on apoptosis has been controversial282931323334.


New basal cell carcinoma susceptibility loci.

Stacey SN, Helgason H, Gudjonsson SA, Thorleifsson G, Zink F, Sigurdsson A, Kehr B, Gudmundsson J, Sulem P, Sigurgeirsson B, Benediktsdottir KR, Thorisdottir K, Ragnarsson R, Fuentelsaz V, Corredera C, Gilaberte Y, Grasa M, Planelles D, Sanmartin O, Rudnai P, Gurzau E, Koppova K, Nexø BA, Tjønneland A, Overvad K, Jonasson JG, Tryggvadottir L, Johannsdottir H, Kristinsdottir AM, Stefansson H, Masson G, Magnusson OT, Halldorsson BV, Kong A, Rafnar T, Thorsteinsdottir U, Vogel U, Kumar R, Nagore E, Mayordomo JI, Gudbjartsson DF, Olafsson JH, Stefansson K - Nat Commun (2015)

CASP8-coding exons, protein domains and locations of probes.(a) Coding exons of the major transcript variants. The positions of exon 8 and exon 8L are indicated. The transcript variant containing exon 8L is designated ‘NR_' because the exon 8L sequence contains a stop codon that may render this RNA species susceptible to nonsense-mediated decay. (b) Procaspase-8 protein domains corresponding to exons, from pfam: IPR001875-DED are the DED; IPR011600-Pept_C14_cat corresponds to the peptidase catalytic domains. (c) Location of the probe sequences used on the expression microarrays. The height of the bars corresponds to the relative levels of expression in blood. (d) Location of primer-amplicons used in RT–PCR.
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Related In: Results  -  Collection

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f2: CASP8-coding exons, protein domains and locations of probes.(a) Coding exons of the major transcript variants. The positions of exon 8 and exon 8L are indicated. The transcript variant containing exon 8L is designated ‘NR_' because the exon 8L sequence contains a stop codon that may render this RNA species susceptible to nonsense-mediated decay. (b) Procaspase-8 protein domains corresponding to exons, from pfam: IPR001875-DED are the DED; IPR011600-Pept_C14_cat corresponds to the peptidase catalytic domains. (c) Location of the probe sequences used on the expression microarrays. The height of the bars corresponds to the relative levels of expression in blood. (d) Location of primer-amplicons used in RT–PCR.
Mentions: We determined whether any of the BCC risk variants were associated with local differences in gene expression (cis-expression quantitative trait loci (eQTL)) by cross-referencing genotypes to RNA expression microarray data that we had derived previously from 1,001 blood and 673 adipose tissue samples26. No significant associations were seen for 2p24 MYCN, 8q21 ZFHX4 or 10p14 GATA3. At 2q33, CASP8 generates numerous splice variants (Fig. 2a). One probe on the microarrays, designated NM_033355, is in the 3′ UTR and captures all major CASP8 isoform transcripts (Fig. 2c). A second probe, designated NM_033358, is unique to a small exon located between exons 8 and 9 of the major transcripts (exon numbering is based on NM_001228). The NM_033358 transcript encodes caspase-8 isoform E, which contains the death effector domains (DED) but lacks the catalytic domains of caspase-8 (Fig. 2b). A transcript with an extended exon 8, called exon 8L (NR_111983) has the capacity to encode a similar DED-only isoform because the 8L extension contains an in-frame stop codon. However, splicing of exon 8L to downstream exons may target the transcript for nonsense-mediated decay27282930. Evidence for the existence in vivo of DED-only caspase-8 isoforms and their potential inhibitory effects on apoptosis has been controversial282931323334.

Bottom Line: Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)).Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor.In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.

View Article: PubMed Central - PubMed

Affiliation: deCODE Genetics/AMGEN, Sturlugata 8, Reykjavik 101, Iceland.

ABSTRACT
In an ongoing screen for DNA sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conduct a genome-wide association study (GWAS) of 24,988,228 SNPs and small indels detected through whole-genome sequencing of 2,636 Icelanders and imputed into 4,572 BCC patients and 266,358 controls. Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)). Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor. In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.

No MeSH data available.


Related in: MedlinePlus