Oncology
Cancer risk associated with STK11/LKB1 germline mutations in Peutz–Jeghers syndrome patients: Results of an Italian multicenter study

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Abstract

Background

Germline mutations in the STK11/LKB1 gene cause Peutz–Jeghers syndrome, an autosomal-dominantly inherited condition characterized by mucocutaneous pigmentation, hamartomatous gastrointestinal polyposis, and an increased risk for various malignancies. We here report the results of the first Italian collaborative study on Peutz–Jeghers syndrome.

Aims

To assess cancer risks in a large homogenous cohort of patients with Peutz–Jeghers syndrome, carrying, in large majority, an identified STK11/LKB1 mutation.

Methods

One-hundred and nineteen patients with Peutz–Jeghers syndrome, ascertained in sixteen different Italian centres, were enrolled in a retrospective cohort study. Relative and cumulative cancer risks and genotype–phenotype correlations were evaluated.

Results

36 malignant tumours were found in 31/119 (29 STK11/LKB1 mutation carriers) patients. The mean age at first cancer diagnosis was 41 years. The relative overall cancer risk was 15.1 with a significantly higher risk (p < 0.001) in females (22.0) than in males (8.6). Highly increased relative risks were present for gastrointestinal (126.2) and gynaecological cancers (27.7), in particular for pancreatic (139.7) and cervical cancer (55.6). The Kaplan–Meier estimates for overall cumulative cancer risks were 20%, 43%, 71%, and 89%, at age 40, 50, 60 and 65 years, respectively.

Conclusion

Peutz–Jeghers syndrome entails markedly elevated cancer risks, mainly for pancreatic and cervical cancers. This study provides a helpful reference for improving current surveillance protocols.

Introduction

Peutz–Jeghers syndrome (PJS) is a rare dominantly inherited disease characterized by the association of gastrointestinal hamartomatous polyposis, mucocutaneous hyperpigmentation, and an increased cancer risk at different target organs. The estimated incidence of PJS is between 1/8,300 and 1/200,000 live births and the syndrome is associated with germline mutations in the STK11/LKB1 gene [1], [2], [3]. The gene encodes a ubiquitously expressed multitasking serine–threonine kinase, which plays a critical role in several cell functions, including proliferation, cell cycle arrest, differentiation, energy metabolism, and cell polarity [4].

Pathogenic STK11/LKB1 mutations are usually identified in 80–94% of patients using conventional mutation screening techniques such as direct sequencing of individual exons and multiplex ligation-dependent probe amplification (MLPA). Different types of mutation have been found including small insertions, deletions, splicing defects, nonsense and missense mutations. In approximately 30% of cases partial or whole gene deletions are detected [5].

PJS causes an increased risk of gastrointestinal (GI) and non-gastrointestinal (non-GI) cancers in addition to the frequent occurrence of other rare tumour types such as those of the sex-cord with annular tubules (SCTAT) in the ovary, and sex-cord and Sertoli-cell type testicular tumours. The GI target organs showing increased cancer risk include the stomach, the small intestine, the colon and the pancreas while among non-GI cancers breast, endometrial, ovary and lung tumours are frequent.

Different studies and several meta-analyses on large cohorts of PJS patients have been reported with the aim to precisely assess cancer risk, age of onset and spectrum of malignancies in PJS patients [1], [6], [7], [8]. Based on these systematic reviews of large PJS patients’ series specific surveillance guidelines have been proposed although no consensus has been reached yet, due to the wide variability in cancer risk estimates.

Collaborative studies report invariably, with some exceptions, cancer risks based on surveys of heterogeneous patients’ groups. Here, we report the first collaborative study on a large and homogenous Italian PJS patients’ cohort carrying, in the large majority, an identified STK11/LKB1 mutation, with the aim of assessing relative and cumulative cancer risks in this specific population.

In our PJS patient cohort the cumulative cancer risk of any cancer was nearly 90% by age 65, which is higher than what has been reported recently [1], [4]. The cancer risk was especially elevated in female PJS patients. Compared with the general population and with previous reports of relative risk (RR) for cancer at specific sites, in our cohort the cancer risk was particularly increased for pancreatic cancer (RR: 139) and cervical cancer (RR: 55).

Section snippets

Materials and methods

The study was designed as a retrospective cohort study. A total of 119 PJS patients ascertained through sixteen different specialized centres throughout Italy were enrolled in the study between 1997 and 2009. All patients signed an informed consent to participate to this study and the entire study was approved by the local Ethical Board for Human Experimentation Review of University Hospital of Bari. All 119 patients were included in the analysis if they fulfilled the diagnostic clinical

Results

Data on 119 PJS patients (58 males, 48.7%), of which 99 had an identified STK11/LKB1 mutation, were available for analysis. Among 119 patients a total of 71 patients were classified as familial and derived from 27 families while 48 were sporadic cases. The median age at diagnosis of PJS was 17 years (range 1–50). At the closing date of the study, the median age of the 108 patients still alive was 36 (range 3–65 years) while the median age of the 11 patients deceased was 50 (range 31–62 years).

Discussion

The present study has been conducted by the Italian Association for the study of Familial and Hereditary Gastrointestinal Tumours (AIFEG), which includes the main Italian Centres involved in the PJS ascertainment. Thus, the observed findings are representative of the clinical and biological features of clinically recognized cases of PJS in the whole country. The present study provides additional information regarding the cancer spectrum in a homogeneous cohort of PJS patients, which will help

Conflict of interest statement

The authors disclose no existing conflict of interest.

Funding

The study was supported by the following grants: Fondazione Cassa di Risparmio di Puglia “Caratterizzazione molecolare dei geni responsabili di poliposi amartomatose intestinali finalizzata al controllo tempestivo del rischio di neoplasia” and “Fondi d’ateneo RS 2007–2008–2009” from Università di Bari “Aldo Moro”.

Acknowledgments

We thank all the patients and all AIFEG members for their precious contribution.

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