Stubbins and colleagues sought to evaluate whether individuals with germline BRCA1 or BRCA2 (gBRCA1/2) pathogenic variants (PV) have an independent risk of developing de novo hematologic malignancies (HM) in addition to therapy-related neoplasms.1 In this single-institution retrospective study, the authors identified 25 patients with gBRCA1 (n=14) or gBRCA2 (n=11) PV concurrent with a HM diagnosis. Eight of 14 (BRCA1) and eight of 11 (BRCA2) patients had de novo HM, rather than therapy-related HM. These patients constituted 1.1% of patients with HM seen over 8 years. Leukemic cells from three of 14 (21%) patients with BRCA1/2 PV had loss of heterozygosity (LoH) of the wildtype allele. In addition to therapy-related HM in BRCA1/2 carriers,2 patients with BRCA1/2 PV developed de novo HM of various types. Most literature examining BRCA1/2 and HM focuses on therapy-related neoplasms, so the characterization of de novo HM is of interest. The study by Stubbins and colleagues ascertained patients based on the presence of a HM providing a valuable perspective on gBRCA1/2-associated cancers. The development of HM in patients with PV in gBRCA1/2 could be either incidental, with a risk similar to that in the general population,3 or causal, based on the gBRCA1/2 PV. Differentiating between these two possibilities is the greatest clinical concern to patients and providers, but the study by Stubbins et al. is neither designed nor powered to address this issue.
The authors suggest that the relative frequency of gBRCA1/2 PV is enriched in their HM population compared to a reference (gnomAD) population. However, without ancestry matching, it is impossible to accurately determine whether it is truly higher, as the frequency of gBRCA1/2 PV varies among populations; 1:175 individuals in non-Finnish Europeans (0.6%)4 and 1:40 in Ashkenazi Jews (2.5%).5 The report of a 1.1% rate of gBRCA1/2 PV in HM could be based on representation of individuals from both populations, and enriched due to referral bias.
In a significant proportion of tumors occurring in patients with BRCA1/2 PV, the mutant BRCA protein is biologically neutral, with tumor pathogenesis occurring independently of, rather than driven by, gBRCA1/2. In an analysis evaluating germline blood and matched tumor tissue from over 17,000 cancer patients among whom 472 harbored a gBRCA1/2 PV, selective pressure for biallelic inactivation, zygosity-dependent phenotype penetrance, and poly-ADP ribose polymerase inhibitor (PARPi) sensitivity were only observed in tumor types classically associated with BRCA1/2, i.e., breast, ovary, prostate or pancreas cancers.3 Arguing against BRCA as a major driver of the observed de novo HM is the presence of LoH in only three of 14 evaluated samples in the study cohort. It is known that classically BRCA1/2-associated solid tumors often (though not always) demonstrate LoH, whereas solid tumors occurring with, but not driven by, BRCA do not.6 The level of LoH observed in this study is consistent with chance, being similar to the level observed with benign gBRCA1/2 variants in a larger dataset.3 As noted by the authors, both determining whether this level is higher than observed in HM with benign gBRCA1/2 variants and evaluating the role of epigenetic silencing should be done. In classically BRCA1/2-associated tumors with and without LoH, additional factors often support BRCA as a driver of tumor pathogenesis, such as vertical transmission, early age of onset, and phenotypic tumor characteristics including homologous recombination deficiency or PARPi sensitivity. The manuscript by Stubbins et al. does not report whether the study cohort or the observed de novo HM display these features.
The many HM types reported is inconsistent with BRCA as a major driver of pathogenesis. For solid tumors, BRCA1/2 PV are associated with very specific tumor types - for example, high-grade serous ovarian cancer and pancreatic ductal adenocarcinoma are BRCA1/2-associated neoplasms, whereas low-grade, borderline, and germ-cell ovarian and pancreatic neuroendocrine cancers are not. Furthermore, PV in BRCA1 and BRCA2 have non-identical cancer risk profiles. The lumping of ten different HM diagnoses and looking at gBRCA1/2 together are convenient, however, their consideration in aggregate detracts from the possibility of identifying a specific causal relationship. Previously published studies have rigorously examined qualitative and quantitative cancer risks conferred by gBRCA1/2 PV. A study including 3,184 BRCA1 and 2,157 BRCA2 families from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) estimated absolute risks for 22 first primary cancer types, adjusting for family ascertainment.7 No increased risk of leukemia (BRCA1: relative risk [RR]=0.90, 0.36-2.26, P=0.82; BRCA2: RR=0.91, 0.29-2.85, P=0.87), lymphoma (BRCA1: RR=1.03, 0.33-3.22, P=0.96; BRCA2: RR=0.97, 0.16-5.87, P=0.97), or multiple myeloma (BRCA1: RR=3.06, 0.83-11.26, P=0.09; BRCA2: RR=0.84, 0.10-7.31, P=0.87) was reported. Stubbins and colleagues note that this study ascertained patients based on known personal or family history of breast or ovarian cancer, with the possibility of pre-selection for a specific disease phenotype. Although bias is possible, it is extraordinarily unlikely that clinically meaningful risks of HM would have been undetected. Furthermore, characterization of cancers in a cohort of nearly 7,000 men with gBRCA1/2 PV showed 51 cases of HM (all subtypes) among 1,634 cancers noted (3.1%).8 By comparison, lymphoma, leukemia and multiple myeloma are estimated to account for 9.4% of new cancers in the USA in 2023.9 Therefore, even in a BRCA1/2 population without a risk of female breast or ovarian cancer, HM are not overrepresented. We therefore read this exploratory study with interest, but also with concern that its findings, based on 16 patients with de novo HM from a single institution, may be misinterpreted or extrapolated to indicate a causal relationship between gBRCA1/2 and HM in general. The preponderance of currently published data from rigorously conducted studies refutes such causality. The current report, while thought-provoking, does not provide the breadth or depth of evidence necessary to contradict existing data. We agree with the authors’ conclusion that examining study populations specifically ascertained to look at inherited predispositions to HM, and families with BRCA1/2 PV and multiple cases of HM, would be of interest. However, we wish to reassure readers and the BRCA1/2 community that although this paper by Stubbins and colleagues demonstrates that individuals with BRCA1/2 PV are not exempt from HM, it does not substantiate a BRCA1/2-associated general predisposition to HM.
Footnotes
- Received July 4, 2023
- Accepted July 10, 2023
Correspondence
Disclosures
No conflicts of interests to disclose.
Contributions
Both authors contributed equally.
References
- Stubbins RJ, Asom AS, Wang P, Lager AM, Gary A, Godley LA. Germline loss of function BRCA1 and BRCA2 mutations and risk of de novo hematopoetic malignancies. Haematologica. 2024; 109(1):351-356. Google Scholar
- Schulz E, Valentin A, Ulz P. Germline mutations in the DNA damage response genes BRCA1, BRCA2, BARD1 and TP53 in patients with therapy related myeloid neoplasms. J Med Genet. 2012; 49(7):422-428. Google Scholar
- Jonsson P, Bandlamudi C, Cheng ML. Tumour lineage shapes BRCA-mediated phenotypes. Nature. 2019; 571(7766):576-579. Google Scholar
- Karczewski KJ, Francioli LC, Tiao G. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020; 581(7809):434-443. Google Scholar
- Roa BB, Boyd AA, Volcik K, Richards CS. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet. 1996; 14(2):185-187. Google Scholar
- Sokol ES, Pavlick D, Khiabanian H. Pan-cancer analysis of BRCA1 and BRCA2 genomic alterations and their association with genomic Instability as measured by genome-wide loss of heterozygosity. JCO Precis Oncol. 2020; 4:442-465. Google Scholar
- Li S, Silvestri V, Leslie G. Cancer risks associated with BRCA1 and BRCA2 pathogenic variants. J Clin Oncol. 2022; 40(14):1529-1541. Google Scholar
- Silvestri V, Leslie G, Barnes DR. Characterization of the cancer spectrum in men with germline BRCA1 and BRCA2 pathogenic variants: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). JAMA Oncol. 2020; 6(8):1218-1230. Google Scholar
- Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023; 73(1):17-48. Google Scholar
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