Breast Cancer – 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
            • Environmental factors
        • To determine the family’s risk, models such as the family history score have been developed
  • Mutations in two high-penetrance tumor suppressor genes:
    • BRCA1 (17q21) and BRCA2 (13q13):
      • Whose proteins are involved in DNA repair through homologous repair
    • Show an autosomal-dominant inheritance pattern:
      • Loss of function greater than missense mutations
    • 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 harboring 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)
    • Germline BRCA testing will now be performed:
      • As a companion diagnostic in patients with metastatic breast cancer:
        • Given the availability of poly(ADP-ribose) 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 germ-line 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 (see table below)
      • 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

#Arrangoiz #CancerSurgeon #BreastSurgeon #BreastCancer #CASO #CenterforAdvancedSurgicalOncology #PalmettoGeneralHospital #SurgicalOncology

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