Study Identifies Familial Risk Patterns of Several Hematologic Malignancies

People who have a first-degree relative diagnosed with a hematologic malignancy have a higher risk of developing a blood cancer, according to an analysis of the Swedish Family-Center Database published in Blood. Researchers found that age at diagnosis, patient-relative relationship, and the number of affected first-degree relatives also appeared to determine an individual’s risk of developing certain blood cancers.

“These findings may help identify individuals who may benefit from counseling and germline genetic testing, although most germline testing is on a research basis,” lead author Amit Sud, PhD, of the Institute of Cancer Research in London, told ASH Clinical News. “Also, in individuals in whom a germline genetic mutation is identified, this may influence treatment and donor selection in patients who need a [hematopoietic cell] transplant.”

This study updates and expands an earlier report from the database, which identified familial risks for myeloid malignancies, to include an estimate of familial risk for lymphoid malignancies.

In this analysis, Dr. Sud and investigators reviewed data from more than 16 million individuals registered in the Swedish Family-Center Database, which was established in 1958.

The researchers identified a total of 153,115 people in the database who were diagnosed with a major classifiable primary hematologic malignancy between 1958 and 2015. Next, they quantified familial relative risks (FRRs) by calculating standardized incident ratios (SIRs) of hematologic malignancies in a total of 391,131 first-degree relatives (i.e., parent, sibling, or child) and comparing SIRs with the expected number of cases.

Among all cancers diagnosed in the registry, cases with a familial link represented 4.1% of all hematologic malignancy diagnoses, “which is higher than cancers of the nervous system (1.8%), kidney (2.8%), and pancreas (3.0%) but lower than those of the breast (8.5%), colorectum (10.1%), and prostate (15.3%),” the authors reported.

Compared with the general population, individuals with a first-degree relative diagnosed with a hematologic malignancy were at a greater risk for developing the same malignancy. For example, among those with a familial link, risks increased:

  • 1.5-fold for acute myeloid leukemia
  • 6.8-fold for essential thrombocythemia
  • 6.9-fold for myelodysplastic syndromes
  • 7.7-fold for polycythemia vera
  • 5.6-fold for chronic lymphocytic leukemia
  • 8.3-fold for hairy cell leukemia
  • 9.8-fold for nodular sclerosis Hodgkin lymphoma
  • 13.3-fold for mantle cell lymphoma
  • 15.8-fold for lymphoplasmacytic lymphoma/Waldenström macroglobulinemia
  • 16.7-fold for mixed-cellularity Hodgkin lymphoma

There also were twofold increases in FRRs for diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma. However, there was no evidence of familial clustering of chronic myeloid leukemia, myelofibrosis, or T-cell neoplasms.

Next, the investigators examined FRRs of lymphoid malignancies by patient characteristics, finding that FRRs increased for some blood cancers according to age at diagnosis, sex, and type of familial relationship. For example, in Hodgkin lymphoma (HL) and chronic lymphocytic leukemia (CLL), FFRs were significantly higher for first-degree relatives of patients diagnosed at a younger age (5.76 vs. 3.36 for HL; 6.99 vs. 4.83 for CLL; p<0.007 for both).

Risk also differed according to patient relationship: The FRRs appeared to be higher in siblings compared with parent-offspring relationships for non-Hodgkin lymphoma (NHL; 1.97 vs. 1.69), HL (7.45 vs. 3.09), and CLL (7.80 vs. 5.36; p values not reported). However, there was no apparent relationship between sex and FRRs.

FRRs were significantly higher for individuals with two or more affected first-degree relatives, compared with individuals with one affected first-degree relative, across all hematologic malignancies (TABLE). These increased FFRs translated to higher lifetime cumulative risks for developing all types of primary hematologic malignancies (4.3%), followed by NHL (2.2%) and CLL (2.3%).

Although this study included a large patient population spanning several decades, the reliance on data from one geographic area limits the findings’ generalizability. The authors suggest that these findings may not be applicable to patients in economically developing countries, who may have different tumor incidence rates and potentially different environmental and genetic risk factors. Also, the researchers point to the possibility of misclassification of cancer outcomes in the registry.

In future investigations, Dr. Sud said the research team is going “to ask whether these data can inform population-based screening initiatives in hematologic malignancies.” Additional questions include how asymptomatic relatives should be managed and what unknown genetic risk factors may predispose individuals to developing a blood cancer. Dr. Sud added that the study results may inform future research initiatives, particularly gene discovery initiatives, for identifying etiological risk factors for lymphomas.

The authors report no relevant conflicts of interest.

References

Sud A, Chattopadhyay S, Thomsen H, et al. Analysis of 153,115 patients with hematological malignancies refines the spectrum of familial risk. Blood. 2019 Aug 8. [Epub ahead of print]

Perspectives

A sizable study evaluating relatively comprehensive registry information from a single country (Sweden) encompassed a sample size large enough to enable dissection of familial risks to hematologic malignancy and the results are striking. The authors showed that the presence of a malignancy in a family increased risk to relatives in a manner that increased with the number of relatives affected. For example, if one relative is affected, then the cumulative lifetime risk increased by 1% to 2%, particularly for non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). If at least two relatives were affected, the risk is much greater, at three- or fourfold.

A striking finding is that many hematologic malignancies exhibit familial predisposition, but for some, no increased risk was seen – such as chronic myeloid leukemia and myelofibrosis. This in itself is interesting, as some other malignancies within the same disease type did show an increased risk (e.g., polycythemia vera, but not myelofibrosis).
The authors also found that the risk differed according to tumor type; for example, CLL was associated with an increased risk of B lineage tumors, but predisposition also was seen across lymphoid and myeloid tumors.

The findings add weight to recent discoveries that have shown that germline predisposition plays a role in multiple hematologic malignancies. Importantly, there is evidence for germline predisposition in familial hematologic malignancies, as well as presumed sporadic cases. This should prompt clinicians to take a careful family history for all newly diagnosed patients. However, the genes responsible were not examined in this study, so these results do not in themselves identify additional gene-disease testing opportunities.

The study is limited by the reliance on data from only one population, and prior studies have established clearly ancestry-determined variations in susceptibility to hematologic malignancies. Most genomic studies of hematologic malignancies have examined only a minority of individuals who develop these malignancies (whites in particular), and multi-ethnic studies are needed.

The findings strongly support the need to ascertain families with hematologic malignancies for discovery research to identify the drivers of germline predisposition – and to accompany this with parallel genomic analysis of the tumors to examine the interaction of germline and somatic variants in tumor development and behavior.

Charles Mullighan, MBBS (Hons), MSc, MD
St. Jude Children’s Research Hospital
Memphis, TN