Genetic predisposition; Approximately 10% of breast cancers are inherited and associated with a family history, although this varies frequently by ethnicity and across countries in the context of early-onset, bilateral and/or TNBC. Individuals with a first-degree relative who had breast cancer have an elevated relative risk (RR) of 3 of early-onset breast cancer (before 35 years of age).
However, a family
history of breast cancer is associated with an ‘erratic’
individual risk of breast cancer composed of different
variables, including the size of the family and environmental factors. To determine the family’s risk, models
such as the family history score have been developed.
Mutations in two high-penetrance tumour suppressor genes, BRCA1 and BRCA2, whose
proteins are involved in DNA repair through homologous repair, show an autosomal-dominant inheritance
pattern (loss of function>missense). BRCA1 and BRCA2
mutations are associated with an average cumulative
risk of developing breast cancer by the age of 80 years
of 72% and 69%, respectively; the relative risk of breast
cancer in men harbouring BRCA2 mutations is
6%.
More than 2,000 BRCA gene alterations have
been described (mutations and large rearrangements),
but only few have been found repeatedly in unrelated
families, for example, founder mutations in Ashkenazi
Jewish families (BRCA1 185delAG or BRCA2 6174delT)
or Icelandic families (BRCA2 999del5).
The prevalence
of BRCA1 and BRCA2 mutations varies between ethnic
groups, being lower in the Asian group (0.5%) and higher in the Ashkenazi group (10.2%) in a US nationwide
study. Germline BRCA testing will now be performed
as a companion diagnostic in patients with metastatic
breast cancer given the availability of poly(ADPribose) polymerase (PARP) inhibitors, which prolong
progression-free survival (PFS) and improve quality of
life, as a targeted therapy for BRCA mutation carriers
in HER2-negative metastatic breast cancer.
Several syndromes related to germline mutations of
genes involved in DNA repair and maintaining genomic
integrity have been shown to be linked to, to a lesser
degree, the inherited breast cancer risk. Next-generation sequencing has enabled panels of genes to be
screened — beyond BRCA1 and BRCA2 — to determine
the inherited breast cancer risk, and include ATM,
CHEK2, PALB2, PTEN, STK11 and TP53.