On behalf of Dr Michael Mauro, it is my pleasure to introduce to our readers Therapeutic Advances in Hematology’s first themed issue, ‘Inherited predisposition to hematological malignancies’. Although the overwhelmingly majority of acute and chronic myeloid and lymphoid neoplasms are acquired disorders, with either direct or circumstantial evidence for their derivation from an early hematopoietic progenitor/stem cell, this very fact begs the question, often raised by newly diagnosed patients, ‘how did I get leukemia?’
As physicians, we attempt to couch our response to this question with language that we hope is more accessible than the following: that leukemia pathogenesis is due, at least in part, to one or more ‘driver’ mutations (often accompanied by neutral ‘passenger’ genetic changes) that contribute to the generation of a neoplastic disorder. However, this biologic narrative is superficial and ignores the proximal ‘why?’ Not asking about what factors contributed to the acquisition of somatic mutations in the first place is akin to asking a cosmogonist to unskeptically embrace the Big Bang Theory without delving into the primeval conditions that catalyzed the explosive origins of the universe. For patients trying to grasp why they have developed a hematologic cancer, pat explanations such as ‘bad luck’, ‘bad genes’ or ‘too much alcohol or smoking’ may have sufficed a generation ago, but are woefully inadequate in today’s genetic age. Increasingly sophisticated tools are now available to dissect the contributions of heritable variation, acquired mutations, epigenetics, and environmental factors/exposures in shaping disease phenotype.
In the last decade, despite several caveats, genome-wide association studies (GWASs) have been useful for uncovering single nucleotide polymorphisms (SNPs) and other inherited variants associated with complex diseases. Although most SNPs contribute a small component to the total heritable disease risk (expressed as an odds ratio compared with a control population), the identification of multiple predisposition alleles can provide a more complete picture of the molecular jigsaw puzzle that comprises susceptibility to diseases such as leukemia. The development of genotyping arrays, collaborative biobanks, and annotation of the most common SNPs by international efforts such as the HapMap project has facilitated this progress. While linkage studies in families have been fruitful in unmasking single-gene disorders exhibiting a Mendelian pattern of inheritance, these analyses are more relevant to less common familial diseases/syndromes with relatively high penetrance. With next-generation sequencing technologies already proving the aphorism ‘faster, deeper, cheaper’, it is the expectation that whole-genome/exome sequencing will quickly supplant both GWASs and traditional linkage studies to address questions related to inherited predisposition to pediatric and adult hematologic cancers.
For the practicing hematologist, it is not uncommon to see patients with hematologic malignancies where a compelling family history of similar diseases exists. For example, I am currently taking care of a 70-year-old man with chronic lymphocytic leukemia (CLL) (FISH positive for del (13q), negative for del (17p)) who also has a history of prostate cancer. I treated his active disease with 6 cycles of bendamustine and rituximab with excellent response; however, within 1.5 years, he developed myelodysplastic syndrome (MDS) with del (20q) and trisomy 8. Intriguingly, all three of his siblings have also been diagnosed with CLL. Does this patient harbor heritable genetic variation(s) that predispose him to develop certain malignancies? What is the genetic basis for strongly penetrant familial CLL? In lay terms, my patient and his siblings are asking the very same questions that I am. Odds are against one ‘smoking gun’ being the basis for familial CLL or inherited susceptibility to other hematologic neoplasms; instead, ‘private’ mutations unique to certain families or multiple risk loci will likely explain these patterns of disease heritability.
Moving forward, the challenge not only relates to the identification of inherited predisposition alleles, but how such information becomes incorporated into the diagnosis, risk stratification, and treatment algorithms for patients. In this regard, the tumor board of the future will likely include clinical genomicists and bioinformaticists who have waded through a sea of genetic data to produce a refined molecular risk calculation that complements traditional histopathology and clinical wisdom. It is incumbent that we clinicians become self-educated about the genetics and genomics of hematologic malignancies: from knowing chromosomal breakpoints associated with targetable lesions (e.g. rearranged PDGFRA/B or JAK2 just to name a few), to recognizing Fanconi’s anemia or familial MDS/acute myeloid leukemia (AML) in a timely manner, which carries implications for identifying a nonaffected sibling donor for transplant, or for women wishing to conceive who may consider pre-implantation diagnosis. Also, at least out here on the West coast of the USA, we are receiving an increasing number of referrals related to individuals who have signed up for Web-based personal genomic services with reports in hand that enumerate the increased risks associated with future development of certain nonhematologic and hematologic conditions. For example, the JAK2 46/1 haplotype is associated with a three- to four-fold increased risk of developing a JAK2 V617F-positive myeloproliferative neoplasm (MPN). Such testing is not available on a routine clinical basis, and in the case of the 46/1 haplotype, does not currently modify our management of MPN patients, nor individuals who have yet to develop an overt MPN. However, knowing how to interpret such data becomes increasingly important so we can inform patients without instilling undue fear.
We express deep gratitude to the following authors who have contributed to this comprehensive issue on inherited predisposition to hematological malignancies: Dr Nicholas Cross and Dr Amy Jones (MPNs); Dr Eric Nickels, Dr Jesse Soodalter, Dr Jane Churpek and Dr Lucy Godley (familial myeloid leukemia in adults); Dr Elliott Stieglitz and Dr Mignon Loh (childhood leukemias); Dr Divya Khoura and Dr Amelia Langston (multiple myeloma); and Dr Jennifer Brown (CLL). The information contained herein will serve as a valuable resource for physicians and scientists alike.