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Vice-Direction of Translational Research
HUMAN GENOTYPINGCEGEN UNIT
HUMAN CANCER GENETICS PROGRAMME | HUMAN GENOTYPING-CEGEN UNIT
Anna González Neira
Unit Head
Graduate Student
Sara Ruiz
Technicians
Charo Alonso, Núria Álvarez,
Belén Herráez, Tais Moreno ( TS )*,
Guillermo Pita ( TS )*
*Titulado Superior ( Advanced Degree )
further explored the joint effects of common and low-frequency
variants ( MAF<5%) on AIC, taking into account genes with at least
3 variants that were genotyped using a gene-based test ( SKAT ).
We identified a protein-coupled receptor ( p= 1.70x10-4 ) as the
most strongly associated gene. This study demonstrates that
both single-variant and gene-based tests – taking into account
the joint effects of common and low-frequency variants − can
elucidate genetic markers predictive of AIC in children.
p=6.681x10-05 ) . Recently, polymorphisms in ENOSF1 have been
reported to be associated with capecitabine-related severe toxicity,
mainly HFS. Remarkably, ENOSF1 has been proposed to regulate
TYMS ( one of the main targets of 5-FU ) expression through
degradation of TYMS mRNA via an antisense mechanism.
Identification of rare variants associated with
capecitabina-induced hand-foot syndrome ( HFS )
Ewing sarcoma ( ES ) is relatively uncommon, despite being the
second most frequent primary malignant bone tumour in children
and adolescents after osteosarcoma. Despite considerable
progress made during the past decades, many individuals still
relapse or suffer from adverse drug reactions ; this has motivated
the search for predictive factors. We selected 24 genes reported
to be involved in the biotransformation of the 6 agents used as the
standard chemotherapy regimen for ES, and a total of 384 SNPs
were selected across these candidate genes. We identified 3 SNPs
in the Spanish population − rs7190447, rs4148737 and rs11188147,
located in the ABCC6, ABCB1 and CYP2C8 genes, respectively
–that are significantly associated with overall survival. These
associations were confirmed in a large, independent, replication
cohort of 495 patients from 5 European countries. s
Replication analysis in Ewing’s sarcoma ( ES ) survival
genes
Capecitabine ( Xeloda ) is an oral prodrug of 5-fluouracil ( 5-FU )
that is used in the standard treatment of breast and colorectal
cancer. One of the most relevant dose-limiting adverse effects
of capecitabine is HFS, characterised by redness, tenderness,
and peeling of the palms and soles. With this study we aimed to
identify genetic variants associated with HFS. Using the Illumina
HumanExome Beadchip, we investigated 239,800 variants across
the genome in 636 Spanish and UK patients suffering from extreme
HFS toxicity grades ( grade 0 vs. grades 3 & 4 ) and diagnosed
with breast and colorectal cancer. We also found a new intronic
variant in ENOSF1 not previously associated with HFS ( OR=0.61,
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OVERVIEW
The most abundant types of genetic variation are single nucleotide
variants ( SNVs ) and copy number variants ( CNVs ). Association
studies involving the large-scale analysis of both SNVs and
CNVs in thousands of patients can help us to identify genes
underlying complex diseases, such as cancer, and drug response.
In this Unit we implement different high-throughput and costeffective methods to measure from one, to millions of SNV and
CNVs. In addition, epigenetic studies using whole-genome
methylation arrays are performed in the Unit. Complementarily,
research focused on the identification of predictive biomarkers
for personalised cancer therapy is also undertaken.
ANNUAL REPORT 2015
RESEARCH HIGHLIGHTS
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Exome array analysis identifies new loci and lowfrequency variants associated with anthracyclineinduced cardiotoxicity ( AIC ) in children
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Anthracycline chemotherapeutic agents are widely used to treat
childhood cancers. Their clinical use is limited due to dosedependent AIC, especially for late-onset manifestations such as
the observed dilated cardiomyopathy. We aimed to identify genetic
factors contributing to AIC in paediatric oncology patients. We
genotyped 93 DNAs from anthracycline-treated children, who
survived at least 5 years after the completion of therapy, for
247,870 variants on the Illumina HumanExome Beadchip. We
found a polymorphism in a gene encoding a cardiac transcription
factor that is involved in structural atrial remodelling, conferring
a risk of AIC ( OR= 8.61 ; 95%CI= 2.57-28.9 ; p= 4.86x10-4 ). We
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PUBLICATIONS
Day FR et al. ( incl. González-Neira A,
Benítez J ) ( 2015 ). Large-scale genomic analyses link reproductive aging to
hypothalamic signaling, breast cancer
susceptibility and BRCA1-mediated DNA
repair. Nat Genet 47, 1294-1303.
Michailidou K et al. ( incl. González-Neira A,
Benítez J ) ( 2015 ). Genome-wide association
analysis of more than 120,000 individuals
identifies 15 new susceptibility loci for breast
cancer. Nat Genet. PMID : 25751625.
Rosmarin D et al. ( incl. González-Neira
A ) ( 2015 ). A candidate gene study of
capecitabine-related toxicity in colorectal
cancer identifies new toxicity variants
at DPYD and a putative role for ENOSF1
rather than TYMS. Gut 64, 111-120.
Mavaddat N et al. ( incl. Benítez J,
González-Neira A ) ( 2015 ). Prediction of
breast cancer risk based on profiling with
common genetic variants. J Natl Cancer
I 107, djv036.
Zhang B et al. ( incl. Benítez J,
González-Neira A ) ( 2015 ). Height and
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Breast Cancer Risk : Evidence From Prospective Studies and Mendelian Randomization. J Natl Cancer I 107, djv219.
Glubb DM et al. ( incl. Benítez J,
González-Neira A ) ( 2015 ). Fine-Scale
Mapping of the 5q11.2 Breast Cancer Locus
Reveals at Least Three Independent Risk
Variants Regulating MAP3K1. Am J Hum
Genet 96, 5-20.
Darabi H et al. ( incl. González-Neira A,
Benítez J ) ( 2015 ). Polymorphisms in a
Putative Enhancer at the 10q21.2 Breast
Cancer Risk Locus Regulate NRBF2 Expression. Am J Hum Genet 97, 22-34.
Litchfield K et al. ( incl. González-Neira
A, Benítez J ) ( 2015 ). Multi-stage genome-wide association study identifies
new susceptibility locus for testicular germ
cell tumour on chromosome 3q25. Hum
Mol Genet 24, 1169-1176.
Orr N et al. ( incl. Benítez J, González-Neira
A ) ( 2015 ). Fine-mapping identifies two
additional breast cancer susceptibility loci
at 9q31.2. Hum Mol Genet 24, 2966-2984.
Lin WY et al. ( incl. Benítez J, González-Neira A ) ( 2015 ). Identification and character-
SPANISH NATIONAL CANCER RESEARCH CENTRE, CNIO
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ization of novel associations in the CASP8/
ALS2CR12 region on chromosome 2 with
breast cancer risk. Hum Mol Genet 24,
285-298.
Amin Al Olama A et al. ( incl. Benítez J,
González-Neira A ) ( 2015 ). Multiple novel prostate cancer susceptibility signals
identified by fine-mapping of known risk
loci among Europeans. Hum Mol Genet
24, 5889-602.
Kabisch M et al. ( incl. Benítez J,
González-Neira A ) ( 2015 ). Inherited
variants in the inner centromere protein
( INCENP ) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.
Carcinogenesis 36, 256-271.
Rudolph A et al. ( incl. Benítez J,
González-Neira A ) ( 2015 ). Investigation
of gene-environment interactions between 47 newly identified breast cancer
susceptibility loci and environmental risk
factors. Int J Cancer 136, E685-E696.
Fernandez-Navarro P, González-Neira A,
Pita G, Díaz-Uriarte R, Tais Moreno L, Ederra M, Pedraz-Pingarrón C, Sánchez-Con-
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tador C, Vázquez-Carrete JA, Moreo P,
Vidal C, Salas-Trejo D, Stone J, Southey
MC, Hopper JL, Pérez-Gómez B, Benitez
J, Pollan M ( 2015 ). Genome wide association study identifies a novel putative
mammographic density locus at 1q12-q21.
Int J Cancer 136, 2427-2436.
Martín M, Martínez N, Ramos M, Calvo L,
Lluch A, Zamora P, Muñoz M, Carrasco E, Caballero R, García-Sáenz JÁ, Guerra E, Caronia
D, Casado A, Ruíz-Borrego M, Hernando B,
Chacón JI, De la Torre-Montero JC, Jimeno
MÁ, Heras L, Alonso R, De la Haba J, Pita
G, Constenla M, González-Neira A ( 2015 ).
Standard versus continuous administration
of capecitabine in metastatic breast cancer ( GEICAM/2009-05 ): a randomized,
noninferiority phase II trial with a pharmacogenetic analysis. Oncologist 20, 111-112.
Sánchez-Tomé E, Rivera B, Perea J, Pita
G, Rueda D, Mercadillo F, Canal A, Gonzalez-Neira A, Benitez J, Urioste M ( 2015 ).
Genome-wide linkage analysis and tumoral characterization reveal heterogeneity
in familial colorectal cancer type X. J
Gastroenterol 50, 657-666.
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