Human Cancer Genetics Programme

Human Genetics Group

Group Leader:  Javier Benítez
Research highlights
Deciphering the role of rare variants in breast cancer

We are participating in an H2020 project funded by the EU with the main objective of clarifying the role of some rare variants and genes in breast cancer development. The study includes, in a first step, the Next Generation Sequencing (NGS) of 35 genes already known as candidates in a set of 40,000 breast cancer cases and 40,000 controls from more than 50 countries. In a second step, we will sequence, in the same group of samples, a new set of > 30 genes. The third step will include the selection of the best and already confirmed genes in order to build a new diagnostic gene panel ready to be used in clinical practice. Our Group is coordinating the WP2 that is comprised of Cambridge University, Lund University and our Centre as partners. We are responsible for gene selection, sample management from the different groups, library preparation, sequencing and variant calling.

Breast and ovarian cancer susceptibility genes

By performing whole exome sequencing (WES) in 4 BRCAX families, we have found a set of new candidate breast cancer genes. We have identified a deleterious mutation in the known breast cancer susceptibility gene ATM in 1 family and, by extending the study to a larger series, we have established that 2% of Spanish breast cancer families are explained by germline mutations in this gene (Tavera et al., Br Cancer Res Treat 2017). In a second family, we have found a deleterious mutation in an excellent candidate gene from a family of DNA helicases that have a role in the Homologous Recombination (HR) DNA repair pathway. The high interest of this finding has prompted us to start a screening of the gene by targeted NGS in a series of 700 BRCAX families and 700 controls. We have found at least 3 additional deleterious mutations among the cases, suggesting that the gene could actually explain a small percentage of the BRCAX families. Other candidate genes, some of them direct interactors of BRCA1 and BRCA2, have been selected for further analysis in larger series of cases and controls in order to establish their role in the disease.

Ovarian cancer families are rare. We performed WES in 5 families and identified novel missense variants in the known ovarian cancer susceptibility gene RAD51C, among other candidates. Through functional studies, we were able to determine its pathogeny and its possible involvement in ovarian cancer risk. Because there are many variants in RAD51C with no clear implication in the disease, we have developed an algorithm based on different predictors that permit a good classification of RAD51C variants and their implication in ovarian families (Gayarre et al., Br J Cancer 2017).

Familial cancer exome project

In 2015, we published the identification by NGS of a new gene, POT1, as being responsible for families with multiple tumours including cardiac angiosarcomas (CAS). We extended our study to a large series of families with angiosarcomas, sporadic CAS and sarcomas in order to elucidate the role of POT1 in cancer development. Our results have led us to the indication of testing for POT1 mutations in families with angiosarcomas with or without CAS (25% with mutations), sporadic CAS, and cardiac sarcomas (10% with mutations). (Calvete et al., Eur J Hum Genet 2017).

In 2015, we also published the identification of a gene, ATP4A, responsible for a recessive family with gastric neuroendocrine tumours (Calvete et al., Hum Mol Genet 2015). By analysing additional families, we have identified a second gene PTHR1 that, combined with ATP4A, explains a second family based on a digenic model. Carriers of ATP4A present megaloblastic anaemia and low ferritin levels, PTHR1 carriers hypothyroidism and rheumatoid arthritis, while only those members carrying mutations in both genes develop gastric carcinoid (FIGURE). It also suggests the genetic heterogeneity of this disease (Calvete et al., Gastric Cancer 2017).

We have identified the NHEJ1 gene as being responsible for a family with a child that developed severe pancytopenia and bone marrow aplasia correlated with the presence of short telomeres (Carrillo et al., Hum Mol Genet 2017). We downregulated NHEJ1 expression in 293T and CD34 cells and we found increased p21 expression, reduced telomerase activity and decreased expression of several telomerase/shelterin genes. Because the decrease in expression of telomerase/shelterin genes did not occur when we inhibited expression of other NHEJ genes mutated in SCID patients − DNA-PK, Artemis or LigaseIV − we propose that NHEJ1 is responsible for the inhibition of telomerase activity.

Over the last 3 years, we have started to work with families with testicular cancer thanks to a collaboration that we established with the Spanish Germ-Cell Cancer Group and several institutions that are dedicated to the follow-up and treatment of patients with testicular cancer, for which the genetic bases are poorly known. We have already collected 21 families with at least 2 first-degree affected members who have been sequenced and analysed using bioinformatics tools (a total of 71 exomes). We are using different statistical and bioinformatics approaches (family based association tests, based on Kernel and burden tests) to identify candidate genes and variants for validation.

SNPs and the BER pathway

We have studied 3 genes from the BER pathway (OGG1, NEIL2 and UNG) containing SNPs that modify cancer risk in BRCA1/2 mutation carriers and are modifiers of Telomere Length (TL) (Benítez-Buelga et al., Oncotarget, second review; Baquero JM et al., Int J Cancer, submitted). We want to evaluate the global effect of endogenous factors (represented by the 3 genes) on TL. On the other hand, this pathway seems to be an excellent model for new treatments based in OGG1 and NEIL2 inhibitors. Our collaboration with Helleday’s group (Karolinska Institute) will permit us to explore new drugs in specific situations (BRCA carriers) and in different types of tumours (breast and ovarian).