Weeks Lab Research

A critical goal of cancer early detection is to identify individuals with pre-malignant states at greatest risk of progression. Clonal hematopoiesis (CH) is a premalignant expansion of hematopoietic stem cells possessing one or more somatic mutations in leukemia-associated driver genes. CH is a precursor to myeloid malignancies including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPNs). CH is being diagnosed at increased frequency due to widespread use of clinical next generation sequencing. However, as with other cancer precursors, most CH does not progress to overt malignancy. Thus, while detection of CH may be a first step, establishing a screening and prevention program for myeloid malignancies requires:

  1. Ability to identify populations enriched for high-risk CH 
  2. Strategies that estimate the risk of adverse outcomes for people with CH
  3. Interventions that prevent adverse outcomes and improve overall suvivial
  4. Study of cohorts that reflect the diversity of the population(s) at risk

 

 

Who To Screen? Currently CH is identified incidentally in patients undergoing next generation sequencing (NGS) in the workup of cytopenia or when sequencing is performed in patients with solid tumors or suspected hereditary cancer syndromes. Given the high prevalence of CH in older adults (CH subtypes CHIP and CCUS are present in >20% of adults ≥ 65 years of age) and the fact that the majority (>90%) of individuals with CH have a low risk of progressing to MDS or AML, focusing cancer prevention efforts on the highest risk populations is desirable. We have previously published on the increase prevalence of certain age-related inflammatory diseases in patients prior to diagnosis with MDS (Weeks et al. Blood 2021). Duplex sequencing of large populations is helping us determine the prevalence of CH in specific clinical contexts such as solid malignancy, sickle cell disease, and autoinflammatory diseases with a goal of designing algorithms to estimate the risk of having high-risk CH in these specific populations. 

 

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How do we risk stratify CH?  Individuals with CH are at increased risk for various inflammatory disease outcomes. We have demonstrated that CH is associated with an increased risk of gout, giant cell arteritis, cardiac arrythmias and cardiovascular disease-related death. 

 

Our group developed the clonal hematopoiesis risk score (CHRS), which is validated in population cohorts (UK Biobank) and hematology patient cohorts. We subsequently demonstrated that the CHRS risk groups correlate risk of inflammatory disease as well as myeloid malignancy. Present efforts are focused on development of clinical context-specific risk stratification tools using retrospective and prospective clinical-genomic databases.

 

What interventions prevent adverse outcomes? Clinical trials in clonal hematopoiesis are in the earliest stage of development. Clinical investigators in the Weeks lab participate in the design of these studies, including developing CHRS risk-informed eligibility criteria and designing translational correlatives. 

 

 

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Community outreach. The Weeks lab is committed to developing research databases that reflect the diversity of those at risk of myeloid malignancy. Our research, both interventional and observational studies, are open and available to Dana-Farber patients across the institute whether they receive their care at the Longwood Medical Area campus or in one of the regional campuses. We have worked to translate consent forms to the most commonly spoken languages in our region (English, Spanish, Haitian Creole, Mandarin). We have also partnered with the Cancer Care Access Program (CCAP) to develop a Hematology Referral Pathway (HRP) that triages hematologic concerns from primary care patients at federally qualified health centers creating a direct through line for hematologic care on the Dana-Farber Campuses. The HRP was established to counter the observed undercounting of individuals with lower risk myeloid malignancies, such as myelodysplastic syndrome (MDS) in patients of African descent and Hispanic heritage.