A few years ago, Javier Benítez, director of the Human Genetics Group at the CNIO, received a call from Pablo García Pavía, from the Cardiology Unit of the Puerta de Hierro University Hospital. This cardiologist was treating two brothers with a rare form of cancer, cardiac angiosarcoma (CAS). Could the experts in genetics do something? “At that time we tried a few ideas, but unsuccessfully,”says Benítez. We have had to wait for modern genome analysis techniques to discover the brothers’ genetic problem. The finding opens a way to identify CAS families who are carriers of a mutation in the gene
responsible for the disease. Family members could then benefit from an early diagnosis and the appropriate treatment.
Researchers in Benítez’s group recently revaluated the case of the
brothers with CAS. After sequencing their exome — the part of the
genome that is translated into protein and therefore the one that most
influences the state of the organism, they found that the cause of the
illness was a mutation in a gene called POT1.
The identification of this gene led them directly to another CNIO group,
the Telomere and Telomerase Group, headed by María Blasco. POT1 is
one of the proteins that comprise the protective shield around telomeres
— the structures that protect the tips of chromosomes — and it has
recently been identified as responsible for other forms of hereditary
cancer: melanoma and familial glioma. Blasco’s group is not only one of
the leading groups in the field of telomeres, but has also participated —
together with the groups headed by Carlos López-Otín and Elías Campo —
in the first description of the mutation of this gene in human cancer
(chronic lymphocytic leukaemia).
Cardiac angiosarcoma is a rare but malignant disease. In the case of
hereditary CAS, the median survival expectancy is only four months
because the disease is diagnosed at an advanced stage. Until now, no
related gene has been identified.
CNIO researchers also observed that hereditary CAS occurs in families with
a high incidence of other types of cancer. This is similar to what is
observed in people affected by the so-called Li-Fraumeni syndrome, which
is caused by a mutation in the tumour suppressor gene — nicknamed the
genome guardian — P53. However, POT1, but not P53, was found
mutated in the families affected by CAS.
The discovery of the new mutation proved to be even more significant
from a clinical perspective, given that it identified carriers at risk of
developing cardiac angiosarcoma and possibly other tumours.
As Benítez explained, “in the past, we simply didn’t have anything that
could help in identifying these people at risk, because there were no
markers for familial CAS or for families with a syndrome similar to Li-
Fraumeni without P53 mutations. This study uncovers one of the genes
that explains the high incidence of cancer in some of them.”
“The translation of these results into the clinic is immediate,” says Blasco.
“In fact, we are already helping families that carry this mutation.” CNIO