INTRODUCTION — This monograph summarizes the interpretation of germline testing of the STK11 (LKB1) gene. It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or in the clinical care of the individual who was tested. These subjects are discussed separately .
How to read the report — An approach to reviewing a genetic test report is summarized in the checklist (table 1).
Testing involves two steps: determining the genotype and interpreting the pathogenicity of the variant(s).
●Genotype – Identifies the variants in the gene(s) tested. Should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory if the results were obtained by direct-to-consumer testing or a research study and would impact clinical care (eg, positive finding, negative finding in an individual with a suspected cancer syndrome).
●Interpretation – Determines pathogenicity of the variants identified. May require updating, especially for variants of unknown significance (VUS). (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management", section on 'Epidemiology and genetics'.)
The table provides a glossary of genetic testing terms (table 2).
STK11 (LKB1) gene — Pathogenic and likely pathogenic variants in STK11 are associated with Peutz-Jeghers syndrome (PJS). PJS is an autosomal dominant disorder that is most often due to germline pathogenic variants in the STK11 (LKB1) gene encoding a serine threonine kinase mapped to chromosome 19p13.3. Pathogenic variants in STK11, a designated tumor suppressor gene, in combination with an acquired genetic defect of the second STK11 allele in somatic cells, are responsible for the clinical manifestations of PJS.
Disease associations — The two characteristic manifestations of PJS are pigmented mucocutaneous macules and multiple hamartomatous gastrointestinal polyps. Individuals with PJS are also at an increased risk for both gastrointestinal and extraintestinal cancers.
●Gastrointestinal hamartomatous polyps are present in most patients with PJS. Although polyps most commonly occur in the small bowel (60 to 90 percent) and more specifically in the jejunum, they can be found throughout the gastrointestinal tract including the stomach (15 to 30 percent) and colon (50 to 64 percent).
●Polyps develop in the first decade of life, and symptoms usually begin between the ages of 10 and 30 years. Individuals with PJS can present with obstruction caused by intussusception or occlusion of the gastrointestinal lumen by the polyp, abdominal pain caused by infarction, anemia from acute or chronic bleeding, or extrusion of the polyp through the rectum.
●Hamartomatous polyps may also occur in the renal pelvis, urinary bladder, lungs, and nasopharynx.
Mucocutaneous pigmentation — Mucocutaneous pigmented macules (melanin spots) are present in more than 95 percent of individuals with PJS. These pigmented macules commonly occur on the lips and perioral region, palms of the hands, buccal mucosa, and soles of the feet. Mucocutaneous pigmentation usually occurs during the first one to two years of life, increases in size and number over the ensuing years, and finally fades after puberty except those on the buccal mucosa.
Gastrointestinal — Individuals with PJS have an increased risk of colorectal (39 percent), gastric (29 percent), small bowel (13 percent), and pancreatic cancer (11 to 36 percent). Other gastrointestinal cancers associated with PJS include cancers of the biliary tree, gallbladder, and esophagus.
Extraintestinal — Women with PJS have an increased risk of breast, ovarian (sex cord tumor with annular tubules, 20 percent of which may become malignant), endometrial, and a rare subtype of cervical (adenoma malignum) cancer. Men with PJS are at increased risk of testicular tumors (Sertoli cell tumors). Individuals with PJS are also at increased risk for lung cancer and possibly thyroid cancer.
INDIVIDUALS WITHOUT CANCER
Implications of a pathogenic or likely pathogenic variant — We consider all variants in STK11 that are pathogenic or likely pathogenic the same for purposes of counseling and cancer risk reduction, regardless of the initial reason for testing and the family history.
Discussion should include the range of cancer risks, possible interventions for surveillance or risk reduction, and implications for at-risk family members. (See 'At-risk relatives' below.)
Counseling may require additional visits or referral to a genetic counselor, clinical geneticist, or oncologist. Acting upon genetic test results is usually not an emergency; the individual can be reassured that management decisions can be deferred until questions have been answered.
Our recommendations are largely consistent with the American College of Gastroenterology (ACG) and the National Comprehensive Cancer Network (NCCN) guidelines for surveillance and risk reduction [2,3]. The type of cancer and age of onset in a family member may also inform screening (eg, screening at an earlier age if a family member has an earlier age of onset).
In addition to an annual physical examination with a complete blood count to detect iron deficiency anemia due to occult bleeding from gastrointestinal tract polyps or cancer, several evaluations and interventions are recommended to reduce the risk of Peutz-Jeghers syndrome (PJS)-associated cancers. Use of these strategies depends on the patient's age, values, and preferences (algorithm 1 and table 3).
●Gastrointestinal tract cancer
•Baseline screening of the stomach and colon with upper endoscopy and colonoscopy at ages eight to ten years. The interval for follow-up is based on the findings. However, in the absence of polyps, follow-up screening is recommended at 18 years and then repeated every two to three years.
•Baseline endoscopic screening of the small intestine with video capsule endoscopy (VCE) beginning at ages eight to ten years. The interval for follow-up is based on the findings. However, in the absence of polyps, follow-up screening is recommended at 18 years and then repeated every two to three years. Computed tomography enterography (CTE) or magnetic resonance enterography (MRE) are alternative imaging modalities for individuals with PJS in whom capsule endoscopy cannot be performed.
•Endoscopic polypectomy for polyps larger than 0.5 cm that are detected during upper endoscopy and colonoscopy. All other small bowel polyps >1 cm in size should be resected to reduce the risk of polyp-related complications (eg, anemia, bleeding, obstruction, malignancy, and need for urgent surgery).
•Indications for surgery include the inability to achieve endoscopic polyp control either due to polyp size or number and the presence of neoplasia. Surgery may also be required in patients with small bowel obstruction or intussusception.
•Annual examinations of the testicles beginning around age 10. If abnormalities are detected on testicular examination or if patients have signs of feminization (eg, gynecomastia), additional evaluation (eg, testicular ultrasound) is warranted.
●Ovarian, endometrial, and cervical cancer
•Annual physical examination for observation of precocious puberty starting at age eight years
•Annual pelvic examination and Pap smear starting at age 18 to 20 years
•For women with PJS, starting at age 30 years:
-Clinical breast examinations and self-examinations every six months
-Breast magnetic resonance imaging (MRI) and mammography annually
•Magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasound (EUS) annually starting at age 30 to 35 years. Screening for pancreatic cancer should preferably be performed in the setting of a research protocol at an experienced center with a multidisciplinary team.
•Guidelines for screening for lung cancer do not differ from those in the general population.
Additional details and the supporting evidence are discussed separately. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management", section on 'Cancer screening'.)
Implications of a negative test — Negative testing means no pathogenic or likely pathogenic variants were identified (algorithm 1). However, some tests only evaluate a subset of variants; pathogenic variants might be present in other parts of the gene (if testing was not comprehensive) or in other genes.
●If the familial variant in STK11 is known and the tested individual does not have that variant, usually they can be reassured that they are not at high risk for PJS-associated cancers, with the caveats outlined above (see 'How to read the report' above). However, it is important to assess family history and other cancer risk factors to provide an individualized risk.
●If a familial variant in STK11 is not known and the results of genetic testing are negative, additional risk factors (genetic or acquired) may be present, and additional testing (with a gene panel that includes other colorectal cancer genes) and/or surveillance is based on family history and other risk factors. Referral to a clinical geneticist, oncologist, or genetic counselor may be helpful to determine optimal testing in those with a strong family history of cancer. (See 'Locating a genetics expert' below.)
Implications of a VUS — Individuals with a variant of uncertain significance (VUS) should be managed based on their personal and family history and not the VUS (algorithm 1).
New information may become available, and the testing laboratory or other resource should be consulted periodically for updates in the classification of the VUS (eg, annually).
PATIENTS WITH COLORECTAL CANCER — The implications of genetic test results should be discussed with the individual's oncologist or surgeon; in some cases, referral to a specialist in hereditary colorectal cancer syndromes may be appropriate.
The presence of a pathogenic or likely pathogenic variant in STK11 may impact several aspects of management, including the following:
●Additional surveillance and prophylactic measures. (See 'Implications of a pathogenic or likely pathogenic variant' above.)
●Counseling and testing of family members is also often appropriate. (See 'Considerations for family members' below.)
For individuals with a negative test or a variant of uncertain significance (VUS) for whom there are reasons to be concerned about a genetic cause, additional genetic testing may be appropriate. The need for additional testing may be discussed with a genetic counselor, the primary oncologist, or other specialists with expertise in managing hereditary colorectal cancer syndromes. (See 'Locating a genetics expert' below.)
CONSIDERATIONS FOR FAMILY MEMBERS
Preconception counseling — Preconception counseling is appropriate for individuals with a pathogenic or likely pathogenic variant in STK11 who are considering childbearing.
Some may elect to conceive using donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). (See "Preimplantation genetic testing", section on 'Patients known to be at increased risk of offspring with a specific medically actionable condition'.)
At-risk relatives — Individuals who test positive for a pathogenic variant or likely pathogenic variant should inform their at-risk relatives about the importance of genetic counseling and possible testing.
●The risk of having inherited the variant is 50 percent for first-degree relatives. Other at-risk relatives may include aunts, uncles, nieces, nephews, and cousins.
●Usually the variant segregates on the side of the family with a history of cancer; however, if possible, it is recommended to test a parent or other relative with cancer to determine the at-risk side of the family.
●Genetic testing for at-risk relatives may be considered as early as eight years. Age of polyposis onset for relatives may help guide the decision of when to test.
●Families facing decisions to test minors should meet with a certified genetic counselor or other health care provider with genetics expertise. If genetic testing is deferred in a child at 50 percent risk, Peutz-Jeghers syndrome (PJS) screening is recommended until informative genetic testing is obtained (algorithm 1 and table 3). (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues' and 'Implications of a pathogenic or likely pathogenic variant' above.)
●Peutz-Jeghers syndrome (PJS) and associated cancers:
•Manifestations and management – (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management".)
•Variant classification – (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Clinical classification of pathogenicity'.)
•Terminology – (See "Genetics: Glossary of terms".)
•Genetic testing – (See "Genetic testing".)
•Genetic counseling – (See "Genetic counseling: Family history interpretation and risk assessment".)
Locating a genetics expert
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
●Genetic counselors – National Society of Genetic Counselors (NSGC)
●National Institutes of Health (NIH) Cancer Genetics Services Directory
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