Mutated gene in families with multiple tumours, including angiosarcoma

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