Broad therapeutic applications
The cure for PJS will lead the way to effective treatments for many other life-threatening health issues where LKB1 (STK11) gene mutation is at the center stage. Other diseases linked to LKB1 (STK11) gene mutations include but are not limited to Lung Cancer ("According to the American Cancer Society, an estimated 606,520 Americans will die from cancer in 2020. This equates to 1,680 people dying of cancer each day in 2020, and 70 dying each hour."), Tuberous Sclerosis, Pancreatic Cancer, Breast Cancer, Stomach Cancer, Small intestine Cancer, Cervical Cancer, Uterine Cancer, Testicular Cancer, Esophageal Cancer, Alzheimer's disease, Cowden Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, Lhermitte-Duclos disease, Proteus Syndrome, Polycystic Kidney disease, Obesity & Type 2 Diabetes, Cardiac Hypertrophy, Cardiovascular disease, Proteus Syndrome.
Peutz-Jeghers Syndrome (PJS) is a genetic disorder characterized by the development of uncontrolled polyp formation and proliferation, including pigmentations on the mouth and lips, and predisposition to cancer of all types.
Patients with PJS have higher risk of developing cancer of the GI tract, liver, pancreas, lungs, breast, stomach, cervical, colon, ovaries, uterus, testes, and other organs. Patients also endure consistent medical procedures, polyps, intussusception, internal bleeding, and GI blockages that are life threatening if not operated on immediately
PJS is caused by mutation of the LKB1 (STK11) master tumor suppressor gene. The mutation is the direct cause for inappropriate expansion of epithelial cells resulting in inflammation, polyps, and tumors.
Polyps form within the gastrointestinal tract frequently causing bowel obstruction, chronic bleeding, vomiting, abdominal pain and intussusception requiring emergency surgical intervention. Patients also develop dark blue or brown freckles, known as pigmentations, in the areas of the mouth, lips, fingers and toes. Freckles generally appear in childhood and often fade with age thereby often not visible on an adult which can make later diagnosis difficult since they are not aware they were born with PJS.
Repeated surgical intervention results in Small Bowel Syndrome (SBS) which significantly decreases the possibility of future surgical intervention. Surgical interventions also result in bowel perforation, hospitalization, and high medical expenses. Repeated general anesthesia and surgical complications also present great risks.
There are no approved therapies, and the standard of care is “watch and wait” with invasive screening and surgical polyp and tumor removal every 6-24 months.
LKB1 (also known as seine-threonine kinase 11, “STK11”) is a regulator of cell polarity, energy metabolism and cell proliferation. It brings its growth suppressing effect by activating a group of kinases, including adenine monophosphate-activated protein (AMPK) and related kinases. AMPK is a necessary element in cell metabolism that is required for maintaining energy homeostasis.
LKB1 tumor suppressor activity depends on the regulation of AMPK signaling and cell polarization. It is proven that activation of AMPK by LKB1 suppresses growth and proliferation when energy and nutrient levels are imbalanced and insufficient for demand. So, when LKB1 is mutated, it may not activate AMPK properly.
Since LKB1 is meant to regularly prevent cells from growing and dividing too rapidly, its mutation alters its function and ability to restrain cell growth. This coupled with the fact that LKB1 and its associated molecular pathways are sensitive to the environment opens the door for cancer to develop.
Research of the molecular mechanism responsible for Peutz-Jeghers Syndrome (PJS) has revealed important insight into cancer development in the larger population.
The cure for PJS will lead the way to effective treatments for many other life-threatening health issues where LKB1 (STK11) gene mutation is at the center stage. Other diseases linked to LKB1 (STK11) gene mutations include but are not limited to Lung Cancer ("According to the American Cancer Society, an estimated 606,520 Americans will die from cancer in 2020. This equates to 1,680 people dying of cancer each day in 2020, and 70 dying each hour."), Tuberous Sclerosis, Pancreatic Cancer, Breast Cancer, Stomach Cancer, Small intestine Cancer, Cervical Cancer, Uterine Cancer, Testicular Cancer, Esophageal Cancer, Alzheimer's disease, Cowden Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, Lhermitte-Duclos disease, Proteus Syndrome, Polycystic Kidney disease, Obesity & Type 2 Diabetes, Cardiac Hypertrophy, Cardiovascular disease, Proteus Syndrome.
The STK11 gene is located on chromosome 19 and codes for serine/threonine kinase 11 (STK11) also known as live kinase B1 (LKB1).
STK11 kinase functions as a master tumor suppressor.
PJS is caused by mutation of STK11/LKB1 gene which leads to formation and proliferation of polyps and tumors that place 93% increase in lifetime risk of cancer.
Polyp formation and proliferation are the characteristic symptoms of PJS.
Polyps are most often hamartomatous, growing in a disorganized manner and frequently leading to many serious complications. Adenocarcinoma may also develop.
Associated cancers include, but are not limited to, lung, breast, colon, pancreatic, esophagus, stomach, ovaries, cervix, testicles and gastrointestinal tract.
The cumulative lifetime cancer risk begins to rise in middle age.
Literature does describe the disease to be life shortening and patients do experience an increased rate of cancer formation. Lifespan could likely be prolonged with efficacious therapy.
A Dutch study followed 133 patients for 14 years. The cumulative risk for cancer was 40% and 76% at ages 40 and 70, respectively. 42 (32%) of the patients died during the study, of which 28 (67%) were cancer related. They died at a median age of 45. In this study, mortality was increased compared with the general population.
Over 90% of patients with clinical diagnosis of PJS have a mutation in the STK11/LKB1 gene.
Main criteria for clinical diagnosis are: family history, mucocutaneous lesions with characteristic hyperpigmentation in the mouth and on the hands and feet, and or polyps in the GI tract.
During the first year of life, most patients will develop hyperpigmentation in the mouth, hands or feet. First bowel obstruction due to intussusception typically occurs between the ages of 3 and 18 years.
Genetic testing for this PJS is commercially available to physicians and hospitals through manufacturers such as Ambry, GeneDx and Invitae.
Despite increased awareness and genetic testing, the disorder remains underdiagnosed or misdiagnosed. Common misdiagnoses include disorders characterized by nonspecific GI discomfort.
At present the average age of diagnosis is in the second decade of life unless a crisis develops earlier.
PJS is currently classified as an orphan disease with an estimated incidence of 1:25,000
PJS may be caused by hereditable or de novo mutation. Literature suggests an even split between inherited and de novo mutation. The heritable form of this disorder is dominant.
PJS is underdiagnosed. While many patients exhibit symptoms of PJS, they remain undiagnosed until the emergence of a crises.
Patients have been identified world-wide with no racial, ethnic, geographic or gender bias.
In addition to classical PJS, mutation in STK11/LKB1 has been implicated in other polyposis syndromes and cancers including non-small cell lung cancer where nearly half of the tumors harbor mutation in STK11/LKB1.
There are no approved drugs for the treatment of PJS and current standard of care is inefficient and unacceptable.
Current treatment paradigm is “watch and wait,” with surgical intervention as necessary.
Based on polyp growth, invasive surgical intervention may be required every 6-24 months.
Repeated invasive screening and surgical interventions can result in Small Bowel Syndrome which significantly decreases success rate for future polyp removal procedures.
Current treatment costs associated with screening and surgical intervention can range between $25k and $200k annually.
The “wait and see” approach does not treat the underlying disorder and exposes patients to serious health risks as well as poor quality of life.
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