Cancer risks in LKB1 germline mutation carriers

Hamid Mehenni ^1*, Nicoletta Resta ², Joe-Gahb Park ³, Michiko Miyaki ⁴, Genevra Guanti ² and Michael C Costanza ⁵

¹ Centre Medico-Chirurgical de Plainpalais, Switzerland
² Università di Bari, Italy
³ Seoul National University College of Medicine, Korea, Republic of
⁴ Tokyo Metropolitan Komagome Hospital, Japan
⁵ Geneva University Hospital, Switzerland

^* To whom correspondence should be addressed. E-mail: mehenni{at}cellbio.unige.ch.

Accepted 20 December 2005

Abstract

Background & Aims: Germ-line mutations in the LKB1 gene are known to cause Peutz-Jeghers syndrome (PJS), which is an autosomal dominant disorder characterized by hamartomatous polyposis and muco-cutaneous pigmentation. This syndrome is associated with an increased risk of malignancies in different organs but there is a lack of data on cancer range and risk in LKB1 germ-line mutation carriers.

Patients & Methods: The cumulative incidence of cancer in 149 PJS patients with germ-line mutation(s) in LKB1 was estimated with Kaplan-Meier time-to-cancer onset analyses and compared between relevant subgroups with log rank tests.

Results: 32 cancers were found in the LKB1 mutation carriers. Overall cancer risks at ages 30, 40, 50, 60, and 70 years, respectively, were 6%, 18%, 31%, 41%, and 67%. There were similar overall cancer risks between male and female carriers. However, there were overall cancer risk differences for exon 6 mutation carriers vs. non-exon 6 mutation carriers (log rank p = 0.022 overall, 0.56 in males, 0.0000084 in females). Most (22/32) of the cancers occurred in the gastrointestinal tract, and the overall gastrointestinal cancer risks at ages 40, 50, 60, and 70 years, respectively, were 12%, 24%, 34%, and 63%. In females the risks for developing gynecologic cancer at ages 40, and 50 years, respectively, were 13%, and 18%.

Conclusions: Mutations in exon 6 of LKB1 are associated with a higher cancer risk than mutations within other regions of the gene. Moreover, this study provides age-related cumulative risks of developing cancer in LKB1 mutation carriers that should be useful for developing a tailor-made cancer surveillance protocol for PJS patients.

Keywords: Exon specific risk, LKB1 gene mutations, Peutz-Jeghers syndrome, cumulative cancer risk, surveillance

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