Fanconi anaemia,BRCA2mutations and childhood cancer: a developmental perspective from clinical and epidemiological observations with implications for genetic counselling

Abstract

Fanconi anaemia (FA) is an inherited condition characterised by congenital and developmental abnormalities and a strong cancer predisposition. In around 3-5% of cases FA is caused by biallelic mutations in the BRCA2 gene. Individuals heterozygous for BRCA2 mutations have an increased risk of inherited breast and ovarian cancer. We reviewed the mutation spectrum in BRCA2-associated FA, and the spectrum and frequency of BRCA2 mutations in distinct populations. The rarity of FA due to biallelic BRCA2 mutations supports a fundamental role of BRCA2 for prevention of malignant transformation during development. The spectrum of malignancies seen associated with FA support the concept of a tissue selectivity of BRCA2 mutations for development of FA-associated cancers. This specificity is illustrated by the distinct FA-associated BRCA2 mutations that appear to predispose to specific brain or haematological malignancies. For some populations, the number of FA-patients with biallelic BRCA2 disruption is smaller than that expected from the carrier frequency, and this implies that some pregnancies with biallelic BRCA2 mutations do not go to term. The apparent discrepancy between expected and observed incidence of BRCA2 mutation-associated FA in high-frequency carrier populations has important implications for the genetic counselling of couples with recurrent miscarriages from high-risk populations.

Central nervous system abnormalities in Fanconi anaemia: patterns and frequency on magnetic resonance imaging

“…8 In addition to microcephaly, the central nervous system (CNS) in FA can be affected by structural abnormalities and also malignancies, which in most cases are medulloblastoma. 2,9 Non-malignant CNS abnormalities have been reported to occur in FA with a frequency of approximately 8% according to published data. 5,10,11 Imaging of the CNS of individuals with FA has mostly been carried out as part of an endocrine workup from the investigations of growth failure, and hence mainly concentrated on pituitary assessment, 12 often using CT.…”

“…FA results from the disruption of a DNA damage response pathway in which proteins encoded by at least 16 FA genes that have been identified to date (FANCA, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q). 1 Mutations in FANCD1/BRCA2 cause FA in 3-5% of cases 2 and link FA to inherited breast and ovarian cancer. 3 On a cellular level, FA is characterized by hypersensitivity to cross-linking agents, such as mitomycin C (MMC), hypersensitivity to cytokines and a typical G2 arrest in the cell cycle, particularly in response to genotoxic stress.…”

X-linked recessive VACTERL-H due to a mutation in FANCB in a preterm boy

“…In addition to that, the presence of a different type of FA should be considered in children or fetuses with renal and limb anomalies (especially hypoplasia of the radial ray) and growth retardation. The recurrent miscarriges of the described family in mind and the presence of a carrier status for FA should be considered in couples with recurrent miscarriges of unknown cause in high-risk populations for FA (Meyer et al, 2014).…”

Synthetic lethality: the road to novel therapies for breast cancer

“…Other types of cancers also found in BRCA1 and BRCA2 mutation carriers include pancreatic and prostate cancers (Ozcelik et al 1997, Breast Cancer Linkage Consortium 1999, Antoniou et al 2003, Edwards et al 2003, King et al 2003, van Asperen et al 2005. Although most familial BRCA1 or BRCA2 mutations are inherited as heterozygous mutations, rare, biallelic germ-line mutations do occur in patients with Fanconi anaemia (Howlett et al 2002, Domchek et al 2013, Meyer et al 2014, Sawyer et al 2015. Furthermore, in addition to germ-line mutations in these genes, somatic BRCA1 and BRCA2 mutations are also found in breast, prostate, ovarian and pancreatic cancers, as is somatic hypermethylation of the BRCA1 gene promoter.…”