DISEASE INFORMATION
Peutz-Jeghers Syndrome (PJS) is an autosomal dominant disorder characterized by the development of gastrointestinal hamartomatous polyps and melanin hyperpigmentation of the skin and mucous membranes. The gastrointestinal (GI) polyps, while benign, can result in chronic bleeding, secondary anemia, and contribute to recurrent obstruction and intussusceptions, often requiring surgical intervention. In addition to polypsis and mucocutaneous pigmentation, PJS patients are predisposed to a variety of tumors, most commonly gastroesophageal, small bowel, colorectal, and pancreatic.¹ With an estimated incidence of 1 in 120,000 births, individuals affected by PJS are also at increased risk for developing breast, ovarian, uterine, cervical, testicular, and lung cancer.^2,3 Overall, individuals affected with PJS have an 81% risk of developing cancer by age of 70, with GI and breast cancers being the most common.^4,5,6

PJS is caused by mutations in the STK11 gene (previously known as LKB1). Located on chromosome 19p13.3, STK11 is comprised of 10 exons, only nine of which code for the serine threonine protein kinase-11.⁷ STK11 is a tumor suppressor gene that helps in cell cycle arrest and growth suppression.⁸ STK11 also interacts with the p53 tumor suppressor to regulate apoptosis. Polyps in PJS have been shown to have reduced numbers of apoptotic cells and lack STK11 protein expression.⁹ Mutations in STK11 result in a truncated protein that causes an inactivation of kinase domains.^10,11

TESTING BENEFITS & INDICATIONS
Treatment options are available for disease management, including removal of polyps, as well as preventative screening and standard treatments for the associated cancers. Genetic testing enables identification of individuals who are at increased risk of cancers associated with STK11 mutations.¹²

TEST DESCRIPTION
This Ambry Test: Peutz-Jeghers AMPLIFIED includes concurrent gene sequence analysis and gross deletion/duplication analysis of the STK11 gene. PCR-based double-stranded automated sequencing in the sense and antisense directions for exons 1-9 of the STK11 gene, plus at least 20 bases into the 5’ and 3’ ends of all the introns and analysis for gross deletions/duplications of the STK11 gene is performed by the Multiplex Ligation-Dependent Probe Amplification (MLPA) kit, developed by MRC Holland. Specific mutation analysis for individual STK11 mutations known to be in the family is also available.

MUTATION DETECTION RATE
Mutations in STK11 have been identified in 100% of individuals with a family history of PJS, and 91% of those with a negative family history.¹¹ The Ambry Test: Peutz-Jeghers AMPLIFIED is capable of detecting >99% of identified mutations in STK11.

SPECIMEN REQUIREMENTS
Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Blood Spot: Call for availability.
Saliva: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature.
DNA: Send 20 µg in TE at 50-100 ng/µl. Store frozen and ship on ice or dry ice.
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.

REFERENCES
¹ Westerman AM et al. Scand J Gastroenterol Suppl. 1999; 230: 64-70.
² Giardiello FM et al. Gastroenterology. 2000; 119(6): 1447-53.
³ Marignani PA. J Clin Pathol. 2005; 58(1): 15-9.
⁴ Boardman LA et al. Human Mutation. 2000; 16(1): 23-30.
⁵ Spigelman AD et al. Gut.1989; 30:1588-1590.
⁶ Lim W et al. Gastroenterology. 2004; 126:1788-1794.
⁷ Jenne DE et al. Nat Genet. 1998; 18(1): 38-43.
⁸ Tiainen M et al. Hum. Mol. Genet. 2002; 11(13): 1497-1504.
⁹ Karuman P et al. Molecular Cell. 2001; 7(6): 1307-1319.
¹⁰ Ylikorkala A et al. Hum Mol Genet. 1999; 8(1): 45-51.
¹¹ Aretz S et al. Human Mutation. 2005;26(6): 513-519.
¹² Hemminki A. CLMS. 1999; 55: 735-750.  

DISCLAIMER
This test was developed and its performance characteristics were determined by Ambry Genetics Corporation. The laboratory is regulated under the Clinical Laboratory Improvement Amendments 2003 as qualified to perform nonwaived testing. The Ambry Test: Peutz-Jeghers AMPLIFIED analyzes the following types of mutations: nucleotide substitutions, small deletions, small insertions (including small repeat expansion), small indels and gross deletions/duplications. It is not intended to analyze the following types of mutations: gross rearrangements, deep intronic variations, and other unknown abnormalities. The pattern of mutation types varies with the gene tested and the Ambry Test detects a high but variable percentage of known and unknown mutants of the classes stated. A negative result from the analysis cannot rule out the possibility that the tested individual carries a rare unexamined mutation or mutation in the undetectable group. The Ambry Test: Peutz-Jeghers AMPLIFIED is designed and validated to be capable of detecting >99% of described mutations in STK11 (considering less than 1% to be the other types of mutations). Peutz-Jeghers Syndrome is a complex clinical disorder, which in most cases, >94%, is due to alterations in STK11 generally detected by the Ambry Test: Peutz-Jeghers AMPLIFIED except as noted above. Mutations in other genes or the regions not tested by the Ambry Test: Peutz-Jeghers AMPLIFIED can also give rise to clinical conditions similar to PJS. Although molecular tests are highly accurate, rare diagnostic errors may occur. Possible diagnostic errors include sample mix-up, erroneous paternity identification, technical errors, clerical errors, and genotyping errors. Genotyping errors can result from trace contamination of PCR reactions, from maternal cell contamination in fetal samples, from rare genetic variants, which interfere with analysis, or from other sources. This report does not represent medical advice. Any questions, suggestions, or concerns regarding interpretation of results should be forwarded to a genetic counselor, medical geneticist, or physician skilled in interpretation of the relevant medical literature. References are available upon request.