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.