Table 2 Independent evidence corroborating associations between a subset of hematologic cancers and mutations in BRCA pathway genes

Leukemia, NHL

ATM

56 patients with A-T have standardized incidence ratio for leukemia and NHL of 113 (CI = 41–246)

30

Thymomas, lymphoblastic lymphomas

ATM

Atm deficient mice are immunodeficient with a high incidence of thymomas or lymphoblastic lymphomas

30

PLL, ALL and B-CLL

ATM

PLL, ALL and B-CLL tumors have cytogenetic and immunologic similarities to MCL.

30, 31.

T-PLL

ATM

A-T patients have biallelic mutations in ATM and they develop stable clones that progress to T-PLL-like disease

32

B-CLL

ATM

ATM mutant B-CLL tumors have a proven defect in the repair of ionizing radiation induced damage, a function normally mediated by the BRCA pathway. ATM phosphorylates BRCA1 after gamma radiation induced DNA damage.

29

Myeloid leukemias

FANCD1

FANCD1 is the same as BRCA2 and a FANCD1/BRCA2 biallelic defect associates with leukemias that are much more likely to be myeloid than leukemias that develop in those with normal FANCD1/BRCA2. Myeloid leukemias have increased activity of the non-homologous end joining pathway, the less specific alternative to the BRCA pathway.

37

Double strand breaks

Fanconi anemia all types

All Fanconi anemia cells exhibit frequent spontaneous visible chromosome breaks

34–37

Gross chromosomal rearrangements

Brca2

Murine Brca2 is essential to suppress gross chromosomal rearrangements such as translocations after chromosome breakage. Mouse cells with truncated Brca2 accumulate chromosome breaks and aberrant chromatid exchanges.

15, 38

Homologous recombination repair

FANCJ (BRCA1)

BRCA1 interacts with FANCJ. Homologous recombination repair stimulated by double strand breaks is compromised both in FANCJ deficient cells and in cells with BRCA1 mutations that preclude FANCJ interaction.

39, 40

Acute promyelocytic leukemia

BRCA1

BRCA1 was found to co-localize with the promyelocytic leukemia protein (PML) in promyelocytic nuclear bodies that function in heterochromatin remodeling at the G2 phase and PML protein plays an essential role in the organization of the ionizing radiation induced DNA repair complex.

41, 42

Thymoma, T-cell development, chromosomal abnormalities

Brca2

Mice homozygous for a truncating mutation in Brca2 surviving to adulthood die from thymic lymphoma. BRCA2 regulates RAD51 recombinase which is essential in dividing cells. Mice carrying a T-cell specific disruption of the Brca1 gene display markedly impaired T-lymphocyte development and proliferation with increased chromosomal abnormalities.

43, 44