BRCA1 & BRCA2 Germline Variants Are Enriched in MDS/AML and Portend Higher Average Mutational Burden
Authors: Williams Louis , Kuzmanovic Teodora , Hirsch Cassandra M. , Przychodzen Bartlomiej P. , Saunthararajah Yogenthiran , Awada Hassan , Adema Vera , Graham Amy C , Radivoyevitch Tomas , Carraway Hetty E. , Nazha Aziz , Sekeres Mikkael A. , Maciejewski Jaroslaw P. 
Published: October 2019

The homologous DNA repair pathway genes BRCA1 and BRCA2 are classically associated with increased susceptibility to hereditary breast and ovarian cancer due to increased vulnerability to double stranded DNA breaks (mutator phenotype). In addition to their role in breast/ovarian cancer, defects in these genes may predispose to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). For example, in large populations of breast cancer patients, those with inherited defects in homologous repair (HR) showed a propensity to therapy-related MDS and AML; however, a relationship between BRCA gene variants and spontaneous myeloid neoplasms has yet to be elucidated. Moreover, analyses are complicated by the large number of clinically uncharacterized single nucleotide variants (SNV) in BRCA gene loci.

We thus evaluated the relationship between germline BRCA variants (GLVs) and the risk of adult MDS or AML. We applied next generation sequencing to a large cohort of patients (N =463) presenting with MDS (402) and AML (61). In these analyses, all mutations with a variant allele frequency of less than 30% were considered somatic. We then identified alterations known to be linked with breast/ovarian cancer development by linkage analyses. These mutations (n=2), along with missense mutations with an allele frequency <.001% and previously unknown mutations with a CADD score >10, were considered Tier-1 mutations (n=37). Tier 2 mutations were defined as missense mutations with a population frequency >.01% or mutations in patients with incomplete clinical or sequencing data. After excluding Tier-2 variants, 39 of 88 GLVs were further analyzed.

BRCA Tier-1 GLV were significantly over-represented in the MDS/AML cohort compared to the general population, estimated via publically available exome aggregation databases (ExAC, 8% vs 0.1% p<.001). No biallelic mutations were detected. We compared the pattern of somatic mutation and cytogenetic alteration in patients with Tier-1 GLVs to those without these mutations. Patients carrying Tier-1 GLVs exhibited a significantly higher average mutational burden compared to those without GLVs, measured by an NGS panel including 186 genes (1.2 vs. 0.4, p<.005). The most common co-occurring mutations in BRCA GLV carriers affected DNMT3A(4), ASXL1(3), SF3B1(3), TET2(3), and TP53(3). Among these mutations, TP53 alterations were significantly enriched in BRCA GLV carriers (OR = 6.8, p = 0.003, Figure 1). There was no difference in complex karyotype, del5q, and del7 alterations in BRCA GLV carriers when compared to other MDS/AML patients. BRCA GLV carriers had a higher burden of familial cancer (41% vs. 19%, p<.001). There was no difference in gender, age-at-diagnosis of MDS/AML, or 10-year survival in carriers of BRCA 1/2 GLVs in comparison to the broader cohort (Figure 2).

BRCA GLVs (Tier-1) are over-represented in MDS/AML patients as compared to the general population, and linked with a higher rate of somatic point mutations but not common MDS/AML-associated cytogenetic abnormalities. This suggests the possibility that defects in HDR may facilitate the evolution of apparently spontaneous MDS/AML that is actually germline predisposed. As with breast and ovarian cancers, another possibility is that such variants could have implications in treatment selection, especially in the context of the evolution of PARP inhibition as a therapeutic modality in MDS/AML.

Disclosures

Saunthararajah: Novo Nordisk, A/S: Patents & Royalties; EpiDestiny, LLC: Patents & Royalties. Carraway:Jazz: Speakers Bureau; FibroGen: Consultancy; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Agios: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Nazha:MEI: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy.