Colorectal cancer (CRC) with CpG island methylator phenotype (CIMP) is recognized as a subgroup of CRC that shows association with particular genetic defects and patient outcomes. We analyzed CIMP status of 229 individuals with CRC using an eight-marker panel ( CACNA1G , CDKN2A , CRABP1 , IGF2 , MLH1 , NEUROG1 , RUNX3 and SOCS1 ); CIMP-(+) tumors were defined as having ≥ 5 methylated markers. Patients were divided into individuals who developed a “unique” CRC, which were subclassified into early-onset CRC (EOCRC) and late-onset CRC (LOCRC), and patients with multiple primary CRCs subclassified into synchronous CRC (SCRC) and metachronous CRC (MCRC). We found 9 (15.2%) CIMP-(+) EOCRC patients related with the proximal colon (p = 0.008), and 19 (26.8%) CIMP-(+) LOCRC patients associated with tumor differentiation (p = 0.045), MSI status (p = 0.021) and BRAF mutation (p = 0.001). Thirty-five (64.8%) SCRC patients had at least one CIMP-(+) tumor and 20 (44.4%) MCRC patients presented their first tumor as CIMP-(+). Thirty-nine (72.2%) SCRC patients showed concordant CIMP status in their simultaneous tumors. The differences in CIMP-(+) frequency between groups may reflect the importance of taking into account several criteria for the development of multiple primary neoplasms. Additionally, the concordance between synchronous tumors suggests CIMP status is generally maintained in SCRC patients.

Germline changes in the CDH1 tumor suppressor gene predispose to diffuse gastric cancer and lobular breast cancer. In carriers of deleterious germline CDH1 variants, prophylactic gastrectomy is recommended. In case of germline missense variants, it is mandatory to assess the functional impact on E-cadherin, the protein encoded by CDH1, and to predict their clinical significance. Herein, we have identified a recurrent germline missense variant, c.1679C>G, segregating with gastric cancer in three unrelated Spanish families. Through genetic, transcriptional, in silico and in vitro studies, we demonstrate the deleterious effect of the c.1679C>G variant and its association with hereditary diffuse gastric cancer, providing relevant data to relatives and allowing an accurate genetic counseling.

INTRODUCTION: Not all patients with hereditary diffuse gastric cancer (HDGC) are found to carry germline pathogenic variants in the associated gene CDH1 , which translates into a challenging clinical management and poor cancer prevention. Thus, several studies have searched for other candidate genes, among which stands PALB2 . Our work explores the implication of this known cancer gene in HDGC. METHODS: We searched for germline PALB2 variants by Sanger sequencing in a series of 58 patients with HDGC who tested negative for CDH1 alterations. RESULTS: No clearly pathogenic variants in PALB2 were found in these patients. Only 5 rare genetic variants were identified, 3 of which were classified as variants of uncertain significance. DISCUSSION: Despite the promising association between PALB2 and HDGC suggested by certain works in the literature, our findings do not support PALB2 as a high predisposition gene for HDGC. Larger studies are needed to define its role in this disease and therefore improve cancer prevention.

Background The limited knowledge about the PTEN hamartoma tumor syndrome (PHTS) makes its diagnosis a challenging task. We aimed to define the clinical and genetic characteristics of this syndrome in the Spanish population and to identify new genes potentially associated with the disease. Results We reviewed the clinical data collected through a specific questionnaire in a series of 145 Spanish patients with a phenotypic features compatible with PHTS and performed molecular characterization through several approaches including next generation sequencing and whole exome sequencing (WES). Macrocephaly, mucocutaneous lesions, gastrointestinal polyposis and obesity are prevalent phenotypic features in PHTS and help predict the presence of a PTEN germline variant in our population. We also find that PHTS patients are at risk to develop cancer in childhood or adolescence. Furthermore, we observe a high frequency of variants in exon 1 of PTEN, which are associated with renal cancer and overexpression of KLLN and PTEN. Moreover, WES revealed variants in genes like NEDD4 that merit further research. Conclusions This study expands previously reported findings in other PHTS population studies and makes new contributions regarding clinical and molecular aspects of PHTS, which are useful for translation to the clinic and for new research lines.

Background: The limited knowledge about the PTEN hamartoma tumor syndrome (PHTS) makes its diagnosis a challenging task. We aimed to define the clinical and genetic characteristics of this syndrome in the Spanish population and to identify new genes potentially associated with the disease.Results: We reviewed the clinical data collected through a specific questionnaire in a series of 145 Spanish patients with a phenotypic features compatible with PHTS and performed molecular characterization through several approaches including next generation sequencing and whole exome sequencing (WES).Macrocephaly, mucocutaneous lesions, gastrointestinal polyposis and obesity are prevalent phenotypic features in PHTS and help predict the presence of a PTEN germline variant in our population. We also find that PHTS patients are at risk to develop cancer in childhood or adolescence. Furthermore, we observe a high frequency of variants in exon 1 of PTEN, which are associated with renal cancer and overexpression of KLLN and PTEN. Moreover, WES revealed variants in genes like NEDD4 that merit further research.Conclusions: This study expands previously reported findings in other PHTS population studies and makes new contributions regarding clinical and molecular aspects of PHTS, which are useful for translation to the clinic and for new research lines.