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Germline Variants in DNA Repair Pathway Genes May Trigger Familial MPNs

November 23, 2021

November 2021


Germline variants in DNA repair pathway genes, such as BRCA1/2, may trigger familial myeloproliferative neoplasms (MPNs), suggesting these variants should be incorporated in diagnostic workups, according to study findings published in Blood Advances.

“The occurrence of a rare cancer subtype in more than a single family member suggests that genetic factors play an important role in the pathogenesis of such a malignancy,” said corresponding study author Steffen Koschmieder, MD, PhD, of the RWTH Aachen University in Aachen, Germany.

Dr. Koschmieder and colleagues designed their study to identify additional predisposing germline variables in familial MPNs. To accomplish this goal, the researchers conducted whole-exome sequencing (WES) in a total of five families who were affected by MPNs and whose members carried a somatic JAK2 V617F (c.1849G.T) mutation.

The investigators carried out WES by evaluating DNA of peripheral blood samples. Target regions were enriched using a probe-based capture method, and an in-house method was used for alignment to the reference genome (hg19 or hg38) and variant calling. Sanger sequencing was used to confirm variants of interest.

Rare heterozygous germline variants were detected in known tumor predisposition genes of the DNA repair pathway in four families. These DNA repair pathway genes included the highly penetrant BRCA1 and BRCA2 genes. According to the investigators, the germline variants are associated with hereditary cancer predisposition syndromes, particularly hereditary breast and ovarian carcinomas.

In the first family, a brother and sister who had prefibrotic myelofibrosis both carried a heterozygous loss-of-function mutation in the BRCA1 gene. The sister, who received an index MPN diagnosis at 53 years of age, subsequently developed uterine cancer at age 61. Two family members died from colorectal cancer: the mother at age 65 and a brother at age 77. Additionally, one sister died from ovarian cancer at age 52 and one brother died from leukemia at age 5.

The second family included a father and his daughter who had essential thrombocythemia (ET). The father later progressed to acute myeloid leukemia (AML). Both father and daughter had a missense variant in the BRCA2 gene. The researchers noted that the father demonstrated an excellent response to decitabine monotherapy.

In the third family, the mother had ET, although the researchers noted that “prefibrotic myelofibrosis could not be completely ruled out,” while the daughter had polycythemia vera (PV). The researchers identified a pathogenic frameshift variant c.1100del (p. Thr367Metfs*15) in the CHEK2 (checkpoint kinase 2) gene (OMIM*604373, transcript NM_007194.4), which the investigators reported likely led to loss of protein function. The grandmother in this family died

from leukemia at age 46, while the grandfather died from bladder cancer at age 75. A cousin also died from ovarian cancer during young adulthood.

The fourth family included a father with prostate carcinoma, who was diagnosed at age 64 and treated by only surgery. The father received a PV diagnosis at age 69, which later progressed to AML by age 75. The daughter also experienced ET, which later progressed to PV. Both family members carried a heterozygous missense variant in the tumor predisposition gene ATM. The researchers also noted that the family history was conspicuous for breast cancer. One sister on the father’s side had bilateral breast cancer, while a different sister died from breast cancer at age 85. “The fact that two patients with ET or PV progressed to AML may suggest a high risk of leukemic transformation and the necessity for closer monitoring of clonal evolution,” said Dr. Koschmieder.

The fifth family included a mother and daughter who had ET, but the investigators did not find “any pathogenic or likely pathogenic variant in the applied WES approach or BRCA1/2 multiplex ligation-dependent probe amplification.”

Dr. Koschmieder explained that the detection of a pathogenic germline variant in high-penetrance genes, such as BRCA1 and BRCA2, should prompt the discussion of prophylactic surgery. “Germline mutations in DNA repair genes may also affect the type of cytoreductive therapy,” he said. “Additionally, these findings suggest that DNA repair gene haploinsufficiency may predispose individuals to acquire MPN-associated driver mutations.”

The study authors reported no relevant conflicts of interest.


Elbracht M, Meyer R, Kricheldorf K, et al. Germline variants in DNA repair genes, including BRCA1/2, may cause familial myeloproliferative neoplasms. Blood Adv. 2021;5(17):3373-3376.


  Mid-January 2022


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