Very high risk of cancer in familial Peutz–Jeghers syndrome

Giardiello, Francis M.; Brensinger, Jill D.; Tersmette, A. C.; Goodman, Steven N.; Petersen, Gloria M.; Booker, Susan V.; Cruz‐Correa, Marcia; Offerhaus, Johan

doi:10.1053/gast.2000.20228

Cited by 1,225 publications

(792 citation statements)

References 57 publications

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“…Moreover, GC risk is elevated in several other hereditary cancer syndromes, namely Lynch syndrome caused by germline mutations in one of the DNA mismatch repair genes [11][12][13], Li-Fraumeni syndrome caused by TP53 germline mutations [14][15][16], familial adenomatous polyposis caused by APC germline mutations [17,18], Peutz-Jeghers syndrome caused by STK11 germline mutations [19][20][21], juvenile polyposis syndrome caused by SMAD4 or BMPR1A germline mutations [22,23], and hereditary breast or ovarian cancer syndrome caused by BRCA1 or BRCA2 germline mutations [10,24,25].…”

Section: Introductionmentioning

confidence: 99%

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Post

Gullo

Oliveira

et al. 2016

Advances in Experimental Medicine and Biology

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Familial clustering is seen in 10% of gastric cancer cases and approximately 1-3% of gastric cancer arises in the setting of hereditary diffuse gastric cancer (HDGC). In families with HDGC, gastric cancer presents at young age. HDGC is predominantly caused by germline mutations in CDH1 and in a minority by mutations in other genes, including CTNNA1. Early stage HDGC is characterized by a few, up to dozens of intramucosal foci of signet ring cell carcinoma and its precursor lesions. These include in situ signet ring cell carcinoma and pagetoid spread of signet ring cells. Advanced HDGC presents as poorly cohesive/diffuse type carcinoma, normally with very few typical signet ring cells, and has a poor prognosis.Currently, it is unknown which factors drive the progression towards aggressive disease, but it is clear that most intramucosal lesions will not have such progression.Immunohistochemical profile of early and advanced HDGC is often characterised by abnormal E-cadherin immunoexpression, including absent or reduced membranous expression, as well as "dotted" or cytoplasmic expression. However, membranous expression of E-cadherin does not exclude HDGC. Intramucosal HDGC (pT1a) presents with an "indolent" phenotype, characterized by typical signet ring cells without immunoexpression of Ki-67 and p53, while advanced carcinomas (pT>1) display an "aggressive" phenotype with pleomorphic cells, that are immunoreactive for Ki-67 and p53. These features show that the IHC profile is different between intramucosal and more advanced HDGC, providing evidence of phenotypic heterogeneity, and may help to define predictive biomarkers of progression from indolent to aggressive, widely invasive carcinomas.6

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Section: Introductionmentioning

confidence: 99%

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Post

Gullo

Oliveira

et al. 2016

Advances in Experimental Medicine and Biology

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“…Hereditary pancreatitis (SPINK1 mutations), hereditary breast ovarian syndrome (BRCA1 and BRCA2 mutations), Peutz‐Jeghers syndrome (STK11/LKB1 mutations), familial atypical multiple mole syndrome (CDKN2A mutations), Lynch syndrome (defects in MLH1, MSH2, MSH6, or PMS2), and familial adenomatous polyposis (APC mutations) have been associated with an increased risk of PC 32, 35, 36, 37, 38, 39. Identification of these cases should allow for focused screening in high‐risk populations.…”

Section: Risk Factors and Early Diagnosismentioning

confidence: 99%

Early diagnosis of pancreatic cancer: Current trends and concerns

Hanada

Amano

Abe

2017

Annals of Gastroent Surgery

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Early detection of pancreatic cancer (PC) is essential for a better prognosis. Some recent studies have demonstrated that a slight dilatation of the main pancreatic duct (MPD) and small cystic lesions were detected initially in most cases diagnosed at an early stage. Detecting these abnormal findings in cases with high risk factors through an effective screening system including image diagnosis, some biological markers, or familial cancer registrations should contribute to early diagnosis of PC. It has been reported that endoscopic ultrasonography (EUS) is essential for detecting tumors <10 mm with a favorable prognosis. Additionally, EUS‐guided fine‐needle aspiration biopsy is useful for confirming final histological diagnosis. For the diagnosis of stage 0 PC, local irregular stenosis of MPD should be an important initial abnormal sign detected by EUS or magnetic resonance cholangiopancreatography. Cytodiagnosis multiple times using pancreatic juice obtained by endoscopic nasopancreatic drainage should be essential for the final diagnosis. Recently, activities of regional networks between specialist doctors in medical centers and general practitioners for early diagnosis of PC have been reported in Japan. In the future, these activities may play an important role in the early diagnosis of PC.

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“…Although there is a possibility that these could transform to become carcinomas, there are several lines of evidence suggesting otherwise and that this aspect of PJS might be functionally separate from the role of LKB1 in suppressing malignant transformation (see below; 'Benign and malignant tumorigenesis'). A markedly increased incidence of carcinomas of the gastrointestinal tract including stomach, small bowel, colon and pancreatic cancer, as well as breast, ovary, uterus, cervix, lung and testis cancer has been observed through longitudinal studies of affected kindreds (Giardiello et al, 1987(Giardiello et al, , 2000Spigelman et al, 1989;Gruber et al, 1998;Lim et al, 2004;Hearle et al, 2006). In addition, rare tumors have been associated with PJS including those of a reproductive origin-including testicular and ovarian sex cord tumors, Sertoli cell tumors and adenoma malignum of the cervix-as well as non-adenocarcinoma pancreatic tumors, including pancreatic intraductal papillary mucinous neoplasia and serous cystadenomas (Podczaski et al, 1991;Young et al, 1995;Tomlinson and Houlston, 1997;Su et al, 1999;Sato et al, 2001;Yee et al, 2003).…”

Section: Peutz-jeghers Syndrome and Human Cancer Geneticsmentioning

confidence: 99%

LKB1; linking cell structure and tumor suppression

2008

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Germ line mutations in the LKB1 tumor suppressor gene are associated with the Peutz-Jeghers polyposis and cancer syndrome. Somatic mutations in Lkb1 are observed in sporadic pulmonary, pancreatic and biliary cancers and melanomas. The LKB1 serine-threonine kinase functionally and biochemically links control of cellular structure and energy utilization through activation of the AMPK family of kinases. Lkb1 regulates cell polarity through downstream kinases including AMPKs, MARKs and BRSKs, and nutrient utilization and cellular metabolism through the AMPK-mTOR pathway. LKB1 has been shown to affect normal chromosomal segregation, TGF-b signaling in the mesenchyme and WNT and p53 activity. Although each of the LKB1-dependent processes and downstream pathways have been individually delineated through work across a range of experimental systems, how they relate to Lkb1's role as a tumor suppressor remains to be fully explored and elucidated. The recent development of mouse cancer models harboring engineered mutations in Lkb1 have offered insights into how LKB1 may be functioning to restrain tumorigenesis and how its role as a master regulator of polarity and metabolism could contribute to its tumor suppressor function.

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Very high risk of cancer in familial Peutz–Jeghers syndrome

Cited by 1,225 publications

References 57 publications

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Early diagnosis of pancreatic cancer: Current trends and concerns

LKB1; linking cell structure and tumor suppression

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