Scientific Concept of the National Cohort (status ... - Nationale Kohorte

A.2
A.2. Scientific background and rationale for study elements
A.2.3.3 Cancer-related precursor stages
Precursor stages of hematologic malignancies: For most tumor types (organ sites) no
noninvasive methods are available for diagnosing premalignant phenotypes that can be applied
easily within very large cohort studies based on representative population samples.
One exception to this, however, is hematologic malignancies, for which premalignant states
can be diagnosed in blood samples using cellular and genetic and epigenetic markers. One
example is chronic lymphocytic leukemia, one of the most common types of adult leukemia
worldwide, which is usually diagnosed on the basis of the malignant B-cell phenotype, similar
to normal B1 lymphocytes that coexpress CD19/CD5 with dim surface immunoglobulin.
Recent studies have identified small B-cell clones using six-color flow cytometry with antibodies
against CD45, CD19, CD5, CD10, and kappa and lambda light chains in addition to
immunoglobulin heavy chain gene rearrangement in healthy individuals with no signs of a
lymphoproliferative disorder. This condition was termed monoclonal B-cell lymphocytosis and
has a population prevalence ranging from 3 to 5% in the general population 185 . A recent study
within the prospective PLCO cohort in the USA showed that malignant B-cell lymphoma is a
systematic precursor for chronic lymphocytic leukemia 186 and that malignant B-cell lymphoma
existed up to 77 months before chronic lymphocytic leukemia was diagnosed. Another example
is monoclonal gammopathy of undetermined significance, (MGUS), a premalignant plasma
cell proliferative disorder which is commonly found in older people (>50years), with an
average population prevalence of 3%. Again, a recent study within the PLCO cohort showed
that monoclonal gammopathy of undetermined significance is a precursor stage for multiple
myeloma 186 . The definition for MGUS requires the presence of serum M protein at a level of
less than 3 g/dl with fewer than 10% monoclonal plasma cells in the bone marrow. Affected
people have a lifelong elevated risk for the progression to multiple myeloma; however, in
only 1% of individuals with monoclonal gammopathy of undetermined significance does this
progress to multiple myeloma. There is now evidence in the literature that genetic factors or
possibly environmental factors may alter the risk of developing MGUS. Thus, understanding
these interactions of genetic and environmental factors will improve early detection so that
therapeutic regimens or even prevention strategies that will block the progression of MGUS
to the malignant stage can be developed and initiated early on. A third example of a bloodbased
marker related to development of hematologic malignancies involves specific chromosomal
translocations, such as the t(14;18)(q32;q21) translocation 187 . It is likely that further
precursor stages for hematologic malignancies can be identified and confirmed through prospective
cohort studies.
A prerequisite for studies on precursor stages of hematologic malignancies is that intact peripheral
blood lymphocytes are collected, which is indeed one component of the blood collection
protocol for the National Cohort. It thus will also be possible to explore the determinants
of progression of precursor stages to malignancy. Key hypotheses for such determinants
include respiratory infections and other environmental factors, which may drive chronic antigenic
stimulation 188-190 , nutrition-related lifestyle factors, and epigenetic alterations in different
blood cell populations.
Assessment of cancer-related precursor stages:
Level 3: Collection of intact peripheral (blood) lymphocytes, for future ascertainment
of hemataologic precursor stages (e.g., malignant B-cell lymphoma,
MGUS, chromosomal translocations)
38