Dear PJS friends,
It's been just five years since the PJS gene was officially found. Since then
there's been plenty of research into PJS and during the past 3 1/2 years much
of it has been reported to this group. I continue to send updates and
patient-view reports on research and Andrew & I both send medical journal
titles.
I thought we could have a fifth anniversary celebration and update to help us see just what's been discovered about PJS during the past five years. This is
from a patient-view and incorporates both a timeline and key thoughts from PJS
research. I can go into more detail on any point and have already done
patient-view reports on many of these topics. I can also provide references to
articles and dates. This seems complicated enough without going into any more detail,
so I'm sticking to the main stories.
Background
PJS is caused by a single gene and autosomal dominant. Autosomal means that
it isn't sex-linked. Dominant is used in contrast to a recessive trait. It
doesn't take two parents with the same mutation to have a PJS child. Each child
of a PJS parent has a 50% risk of having PJS.
Three hallmarks: spots, GI polyps (hamartomas and small intestine) and
increased risk of cancer
Unresolved questions about connection between polyps and cancers
Sporadic/familial PJS - about half the people with PJS have new mutations
or sporadic PJS, the other half got it from a parent or familial PJS.
Pedigree studies (family trees) of PJS families by doctors and genetic
counselors are valuable research tools.
How many of us are there? Frequency of PJS in general population
Upgrading PJS to a Hereditary Cancer Syndrome
Estimates of cancer risk rise to alarming levels
Screening guidelines for PJS polyps and cancers increase in number and
frequency
News from UK that PJS folks with mutation at chromosome 19p13.3 have a
higher lifetime risk of cancer (47%) than those without the mutation.
Elevated levels of COX-2 found in polyps from PJS folks, COX-2 inhibitors
to reduce polyps and cancer risk a possibility. Trial already underway in
Finland.
PJS Gene Found
Described
a mutation on chromosome 19
a serine-threonine kinase
normally occurs throughout the human body, including in embryonic stages
similar (homologous) genes in many animals including frogs, mice, fish, flies which are used for research (see below)
PJS folks checked for gene mutations (germline mutations)
polyps, cancers and blood tested for the mutation
many types of mutations
not all PJS folks have mutation at chromosome 19p13.3
the roles of genetic testing, genetic counseling and screening for familial PJS
Second gene for PJS sought
Role of PJS Gene in Humans and Animals
PJS-related cancers from non-PJS folks checked for gene mutation (somatic
mutations)
somatic mutations infrequent in most cancers, surprisingly common in others
the role of single gene disorders (cancer syndromes) in understanding cancer
The role of the PJS gene LKB1/STK11 in humans and animals
in embryonic development
in polyps and spots
in cancer development
in metabolism
in cell signaling
The importance of LOH or Loss of Heterozygosity in PJS polyps and cancers: each person with PJS has one mutated PJS gene and one "good gene",
loss of the good gene or loss of heterozygosity is tied to development of cancer
The various functions of LKB1 and theories on how its loss might cause
polyps and cancer
LKB1 has many roles at a cellular level
some researchers approach LKB1 from an interest in PJS
many researchers find LKB1 from their interest in other biological processes
cell signaling studies suggest importance of LKB1 in many pathways - phosphorylation and auto-phosphorylation
Researchers ask, what does LKB1 do when it's functioning correctly (so far
most research has focussed on it not working correctly): possibly protects against small bowel cancer
Animal Experiments
Mice
mouse LKB1 found
LKB1-null mice developed (those mice died before birth which shows
role of LKB1 in mouse embryonic development)
mice with one working copy of LKB1 get polyps similar to ours -- a
theory of halploinsufficiency described.
Halploinsufficiency theory contrasts with LOH theory in stating that a
reduced amount of LKB1 rather than no LKB1 leads to polyps.
polyps from PJS mice overexpress COX-2 or cyclooxygenase-2, a
potential target for COX-2 inhibitors which are used in another hereditary
polyposis/cancer syndrome (FAP) to reduce polyps and cancer risk.
LKB1-null mouse experiment suggests that while the mutation leads to
overgrowth of benign tissue, it resists transformation to cancer by Ras, a
common cancer promoter. This suggests a unique PJS-cancer pathway.
Flies
Flies don't fly. lkb1-null flies like LKB1-null mice don't survive.
Problems seem to be primarily in anterior-prosterior axis formation and
epithelial polarity.
Yeast
LKB1 links metabolism with cancer through AMPK regulation.
Frogs
Inhibition of XEEK1, the frog equivalent to LKB1, led to developmental abnormalities -- shortened body axis and defective dorso-anterior patterning
associated with Wnt signaling which is involved in both development and cancer.
Okay, there are lots of ideas here and more questions than answers I think. Still, an overview of the research literature might help us see what's happened and what's coming next. Hope this is helpful, not confusing. Be sure to ask questions.
