Frequently asked questions about Molecular Cancer

Molecular Cancer is as a forum for cutting edge cancer-related papers. This editorial will answer frequently asked question about this open-access and on-line journal as well as its publisher BioMed Central

TGFβ(1 )signaling via α(V)β(6 )integrin

BACKGROUND: Transforming growth factor β(1 )(TGFβ(1)) is a potent inhibitor of epithelial cell growth, thus playing an important role in tissue homeostasis. Most carcinoma cells exhibit a reduced sensitivity for TGFβ(1 )mediated growth inhibition, suggesting TGFβ(1 )participation in the development of these cancers. The tumor suppresor gene DPC4/SMAD4, which is frequently inactivated in carcinoma cells, has been described as a key player in TGFβ(1 )mediated growth inhibition. However, some carcinoma cells lacking functional SMAD4 are sensitive to TGFβ(1 )induced growth inhibition, thus requiring a SMAD4 independent TGFβ(1 )pathway. RESULTS: Here we report that mature TGFβ(1 )is a ligand for the integrin α(V)β(6), independent of the common integrin binding sequence motif RGD. After TGFβ(1 )binds to α(V)β(6 )integrin, different signaling proteins are activated in TGFβ(1)-sensitive carcinoma cells, but not in cells that are insensitive to TGFβ(1). Among others, interaction of TGFβ(1 )with the α(V)β(6 )integrin resulted in an upregulation of the cell cycle inhibitors p21/WAF1 and p27 leading to growth inhibition in SMAD4 deleted as well as in SMAD4 wildtype carcinoma cells. CONCLUSIONS: Our data provide support for the existence of an alternate TGFβ(1 )signaling pathway that is independent of the known SMAD pathway. This alternate pathway involves α(V)β(6 )integrin and the Ras/MAP kinase pathway and does not employ an RGD motif in TGFβ(1)-sensitive tumor cells. The combined action of these two pathways seems to be necessary to elicit a complete TGFβ(1 )signal

Integrated genomic study of quadruple-WT GIST (KIT/PDGFRA/SDH/RAS pathway wild-type GIST)

BACKGROUND: About 10-15% of adult gastrointestinal stromal tumors (GIST) and the vast majority of pediatric GIST do not harbour KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations (J Clin Oncol 22:3813-3825, 2004; Hematol Oncol Clin North Am 23:15-34, 2009). The molecular biology of these GIST, originally defined as KIT/PDGFRA wild-type (WT), is complex due to the existence of different subgroups with distinct molecular hallmarks, including defects in the succinate dehydrogenase (SDH) complex and mutations of neurofibromatosis type 1 (NF1), BRAF, or KRAS genes (RAS-pathway or RAS-P).In this extremely heterogeneous landscape, the clinical profile and molecular abnormalities of the small subgroup of WT GIST suitably referred to as quadruple wild-type GIST (quadrupleWT or KITWT/PDGFRAWT/SDHWT/RAS-PWT) remains undefined. The aim of this study is to investigate the genomic profile of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, by using a massively parallel sequencing and microarray approach, and compare it with the genomic profile of other GIST subtypes. METHODS: We performed a whole genome analysis using a massively parallel sequencing approach on a total of 16 GIST cases (2 KITWT/PDGFRAWT/SDHWT and SDHBIHC+/SDHAIHC+, 2 KITWT/PDGFRAWT/SDHAmut and SDHBIHC-/SDHAIHC- and 12 cases of KITmut or PDGFRAmut GIST). To confirm and extend the results, whole-genome gene expression analysis by microarray was performed on 9 out 16 patients analyzed by RNAseq and an additional 20 GIST patients (1 KITWT/PDGFRAWTSDHAmut GIST and 19 KITmut or PDGFRAmut GIST). The most impressive data were validated by quantitave PCR and Western Blot analysis. RESULTS: We found that both cases of quadrupleWT GIST had a genomic profile profoundly different from both either KIT/PDGFRA mutated or SDHA-mutated GIST. In particular, the quadrupleWT GIST tumors are characterized by the overexpression of molecular markers (CALCRL and COL22A1) and of specific oncogenes including tyrosine and cyclin- dependent kinases (NTRK2 and CDK6) and one member of the ETS-transcription factor family (ERG). CONCLUSION: We report for the first time an integrated genomic picture of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, using massively parallel sequencing and gene expression analyses, and found that quadrupleWT GIST have an expression signature that is distinct from SDH-mutant GIST as well as GIST harbouring mutations in KIT or PDGFRA. Our findings suggest that quadrupleWT GIST represent another unique group within the family of gastrointestintal stromal tumors

Population-based epidemiology, risk factors and screening of intraductal papillary mucinous neoplasm patients

Intraductal papillary mucinous neoplasm (IPMN) was first recognized in the 1980s with increasing publications over the last decade as the incidence increased sharply, especially at tertiary-care referral centers. Population-based studies have estimated the age and sex-adjusted cumulative incidence of IPMN to be 2.04 per 100 000 person-years (95% confidence interval: 1.28-2.80). It is now understood that IPMN can be classified anywhere along the spectrum of the adenoma to carcinoma sequence and often harbors mutations in genes such as KRAS early in the disease process. Many patients are diagnosed incidentally after imaging of the abdomen for other diagnostic purposes. Patients that present with a history of symptoms such as pancreatitis and abdominal pain are at high risk of harboring a malignancy. Clinicopathologic features such as involvement of the main pancreatic duct, presence of mural nodules, and side branch disease > 3.0 cm in size may indicate that there is an underlying invasive component to the IPMN. In addition, the incidence of extra-pancreatic neoplasms is higher in patients with IPMN, with reported rates of 25% to 50%. There are no current screening recommendations to detect and diagnose IPMN but once the diagnosis is made, screening for extrapancreatic neoplasms such as colon polyps and colorectal cancer should be considered. Surgical resection is the recommend treatment for patients with high-risk features while close observation can be offered to patients without worrisome signs and symptoms of carcinoma