Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome is caused by mutations in the STK11 gene.  It is characterized by multiple Peutz-Jeghers type hamartomatous gastrointestinal polyps, mucocutaneous hyperpigmentation, and an increased risk for multiple cancer types, primarily of the gastrointestinal tract.

 

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Peutz-Jeghers syndrome is caused by mutations in the STK11 gene.  It is characterized by multiple Peutz-Jeghers type hamartomatous gastrointestinal polyps, mucocutaneous hyperpigmentation, and an increased risk for multiple cancer types, primarily of the gastrointestinal tract.

 

Disease Name 
Peutz-Jeghers syndrome
Polyposis
Colorectal cancer
Disease Information 

Peutz-Jeghers syndrome (PJS) is an autosomal dominant cancer syndrome caused by pathogenic mutations in the STK11 gene (previously known as LKB1). STK11 is a tumor suppressor gene that helps in cell cycle arrest and growth suppression, and interacts with the p53 tumor suppressor to regulate apoptosis. 

Symptoms of PJS typically present in childhood with the development of hyperpigmented macules around the mouth, eyes, nostrils, perianal area, and buccal mucosa. This is often followed by, or in conjunction with, the development of PJS-type hamartomatous polyps. These occur most often in the small intestine, though they may also develop in the stomach, large bowel, and extraintestinal sites.1

Individuals with PJS are also at increased risk for a wide range of epithelial malignancies that can be either gastrointestinal or extraintestinal in nature. Though gastrointestinal and breast cancers are the most common, individuals are also at increased risk for pancreatic, lung, and gonadal cancers (specifically mucinous ovarian tumors and sex cord tumors with annular tubules in women, and Sertoli cell tumors in men). Overall, those with PJS have an ~85% risk of developing cancer by age of 70.2,3

The clinical diagnosis of PJS can be made when any of the following are present4:

  1. >2 histologically confirmed PJS-type hamartomatous polyps
  2. Any number of PJS-type polyps, with a family history of PJS in close relatives
  3. Characteristic mucocutaneous pigmentation, with a family history of PJS in close relatives
  4. Any number of PJS-type polyps, along with characteristic mucocutaneous pigmentation
Testing Benefits & Indication 

Genetic testing is useful to confirm a diagnosis of PJS in symptomatic individuals, and for testing of at-risk asymptomatic family members. Management options are available for those with PJS, including increased colonoscopy, high-risk breast cancer screening, and other screening techniques.  

STK11 genetic testing is indicated for individuals who meet any of the above clinical criteria.

Test Description 

STK11 coding exons 1-9 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-9. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by incorporating the gDNA onto a microfluidics chip, along with primer pairs followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing, or with insufficient read depth coverage for reliable heterozygous variant detection. Suspect variant calls are verified by Sanger sequencing.  Gross deletion/duplication analysis of STK11 using read-depth from NGS data is also performed. Any copy number changes detected by NGS are confirmed by targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification (MLPA).

Mutation Detection Rate 

Genetic testing detects a pathogenic mutation in 94% of individuals meeting the above clinical diagnostic criteria.5 Ambry’s STK11 testing is capable of detecting >99.9% of described mutations in the gene, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
TEST CODE TECHNIQUE CALENDAR DAYS
2766 STK11 Gene Sequence and Deletion/Duplication Analyses 10-21 
2762 STK11 Specific Site Analysis  7-14 

 

Specialty 
Genes 
STK11
References 
  1. Giardiello FM and Trimbath JD. Peutz-Jeghers syndrome and management recommendations. Clin Gastroenterol Hepatol. 2006; 4:408-415. 
  2. Hearle H, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res. 2006; 12:3209-15. 
  3. Lim W, et al. Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology. 2004; 126:1788-1794. 
  4. Beggs AD, et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut. 2010; 59:975-986. 
  5. Aretz S et al. High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome. Human Mutation. 2005;26(6): 513-519.