An exploration of genotype-phenotype link between Peutz-Jeghers syndrome and STK11: a review

Abstract

Peutz-Jeghers Syndrome (PJS) is an autosomal dominant hereditary polyposis syndrome. Clinical features include hamartomatous polyps, mucocutaneous pigmentation and an increased predisposition towards developing malignancy. Variants in STK11, a tumour suppressor gene, located on Chromosome 19, predispose to PJS. Peutz-Jeghers Syndrome is associated with increased rates of malignancy, particularly gastrointestinal. However, PJS is also associated with increased gynaecological, testicular and thyroid papillary malignancy. Truncating variants in STK11 are thought to predispose to a more severe phenotype. Phenotype severity is based on earlier onset of gastrointestinal pathology arising from the polyps, such as intussusception or earlier onset malignancy. Missense variants are generally considered less severe than truncating variants. There remain a large number of variants of undetermined significance. Studies have attempted to correlate the location of variants with impact on protein structure and overall severity of the PJS phenotype. The results from these cohort studies have consistently found a non-random distribution of variants. Nevertheless, a consensus on phenotype severity based on variant location is yet to be established. A centralised database that collates all known variants would facilitate the interpretation of these variants, best under the governance of an international disease-specific organisation (InSiGHT). In particular, it could help explore the significance of variants based on their type or location. Understanding the genotype-phenotype link between STK11 variants and PJS could allow more personalised care for PJS patients and their families via appropriate risk stratification and personalised and targeted cancer screening.

Intratubular Large Cell Hyalinizing Sertoli Cell Tumor of the Testes in Peutz-Jeghers Syndrome: A Case Report

“…Our case report is one of the few exceptions to this belief as he showed both polyps related and cancer related complications. Small intestine comparison with the common population [2][3][4]. In other words, an 11-fold elevated risk of cancer has been reported in PJS [5].…”

“…Polyposis disorders of the bowel in the pediatric population require close medical care to minimize cancer risk in the gastrointestinal tract and in other organ systems [1]. Peutz-Jeghers syndrome (PJS), is a rare autosomal dominant disease manifests as multiple gastrointestinal hamartomatous polyposis, mucocutaneous pigmentation, and increased risk of gastrointestinal (GI) or extraintestinal neoplasia due to a germline mutation in the STK11(LKT1)/LKB1 gene located on the short arm of chromosome 19 [2]. The estimated lifetime cumulative cancer risk in individuals with PJS is over 76% in…”

Birt-Hogg-Dubé syndrome with simultaneous hyperplastic polyposis of the gastrointestinal tract: case report and review of the literature

“…On the other hand, the finding of gastrointestinal hyperplastic polyposis could be related to genetic variant in genes such as STK11, associated with Peutz-Jeghers syndrome [35]; APC, associated with familial adenomatous polyposis [36]; and PTEN, associated to Cowden syndrome [37]; or less often in TSC1/2 genes, associated to Tuberous sclerosis complex, whose gastrointestinal manifestations are uncommon [38]. The search for variants in other genes was not possible in the patient of the present report, due to his death and not autopsy authorization.…”

Familial Pancreatic Cancer

“…The group of tumor syndromes includes the autosomal dominant PJS with mutations in the tumor suppressor gene LKB1/STK1 on chromosome 19, which usually regulates energy coupling, cell division, and growth [17]. The risk of developing PDAC with this mutation is around 35% [25,40,41].…”

“…These precursor lesions are termed pancreatic intraepithelial neoplasia (PanINs), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN) [11,15,16]. Cancer syndromes like Peutz-Jeghers Syndrome (PJS) or familial atypical multiple mole melanoma (FAMMM) syndrome can raise the risk of developing pancreatic cancer [17,18]. …”