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Major Genetic Syndromes

Table 10. Cumulative Cancer Risks in Peutz-Jeghers Syndrome Up To Specified Agea continued...

Far more is known about the somatic molecular genetic alterations found in the colonic tumors occurring in HPPS patients. In a study of patients with either more than 20 HPs per colon, more than four HPs larger than 1 cm in diameter, or multiple (5–10) HPs per colon, a specific somatic BRAF mutation (V600E) was found in polyp tissue.[437] Fifty percent (20 of 40) of HPs from these patients demonstrated the V600E BRAF mutation. The HPs from these patients also demonstrated significantly higher CpG island methylation phenotypes (CIMP-high), and fewer KRAS mutations than left-sided sporadic HPs. In a previous study from this group, HPs from patients with HPPS showed a loss of chromosome 1p in 21% (16 of 76) versus 0% in HPs from patients with large HPs (>1 cm), or only five to ten HPs.[428]

Many of the genetic and histological alterations found in HPs of patients with HPPS are common with the recently defined CIMP pathway of colorectal adenocarcinoma. The CIMP pathway (identified molecularly by hypermethylation of specific genes such as CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1) is characterized histologically by a hyperplastic polyp-serrated adenoma-adenocarcinoma sequence.[438]BRAF mutations are more commonly associated with the right colon and methylation of p16INK and MINT31.[437]

Interventions/rare colon cancer syndromes

Individuals with Peutz-Jeghers and juvenile polyposis syndromes are at increased risk of CRC and extracolonic cancers. Because these syndromes are rare, there have been no evidence-based surveillance recommendations. Due to the markedly increased risk of colorectal and other cancers in these syndromes, a number of guidelines have been published based on retrospective and case series (i.e., based exclusively on expert opinion).[131,439,440,441,442] One's best clinical judgment must be used in making screening recommendations based on published guidelines.

Table 11. Clinical Practice Guidelines for the Diagnosis of Cancer in Peutz-Jeghers Syndrome

Organization/ AuthorSTK11Gene Testing RecommendedaAge Colon Screening InitiatedFrequencyMethodExtracolonic Screening RecommendationsComment
ACPGBI = Association of Coloproctology of Great Britain and Ireland; BE = barium enema; C = colonoscopy; FS = flexible sigmoidoscopy; NCCN = National Comprehensive Cancer Network.
a STK11mutation analysis includes sequencing followed by analysis for deletions (e.g., MLPA), if no mutation found by sequencing.
b Lung cancer risk is increased, but there are no recommendations beyond smoking cessation and heightened awareness of symptoms.
ACPGBI 18 y3 yC or FS + BENo mention of extracolonic screeningNo mention of genetic testing; need to considerSTK11/LKB1testing
Brosens et al.[442]Yes, age not specifiedLate teens or at symptoms3 yCBreast, Gynecologic (Cervix, Ovaries, Uterus), Pancreas, Small Intestine, Stomach, TestesGenetic testing at late teens or at symptoms
Giardiello and Trimbath[441]Yes, at age 8 y18 y2–3 yCBreast, Gynecologic (Cervix, Ovaries, Uterus), Pancreas, Small Intestine, Stomach, Testes 
NCCN[84]No specific recommendationLate teens2–3 yCBreast, Gynecologic (Cervix, Ovaries, Uterus), Lungb, Pancreas, Small Intestine, Stomach, TestesRefer to specialized team
van Lier et al.[405] 25–30 y CBreast, Gynecologic (Cervix, Ovaries, Uterus), Pancreas, Small Intestine, Stomach 
Zbuk and Eng[443] 18 y3 yCBreast, Gynecologic (Cervix, Ovaries), Pancreas, Small Intestine, Stomach, Testes 

Level of evidence: 5


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