Role of GALNT12 in the genetic predisposition to attenuated adenomatous polyposis syndrome

Lorca, Víctor; Rueda, Daniel; Martín-Morales, Lorena; Povés, Carmen; Fernández-Aceñero, María Jesús; Ruíz-Ponte, Clara; Llovet, Patricia; Marrupe, David; García-Barberán, Vanesa; García-Paredes, Beatriz; Pérez‐Segura, Pedro; Hoya, Miguel de la; Dı́az-Rubio, Eduardo; Caldés, Trinidad; Garré, Pilar

doi:10.1371/journal.pone.0187312

Cited by 9 publications

(6 citation statements)

References 19 publications

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“…#112;80). This variant has been described several times, and although the role of GALNT12 in familial cancer is controversial, this particular variant most likely confers a moderate risk (Guda et al, 2009;Clarke et al, 2012;Seguí et al, 2014;Lorca et al, 2017;Evans et al, 2018). In EXO1 we identified the c.2212-1G>C variant in two individuals (no.…”

Section: Pathogenic and Likely Pathogenic Moderate And Low Risk Variantsmentioning

confidence: 92%

New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients

et al. 2020

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A genetic diagnosis facilitates personalized cancer treatment and clinical care of relatives at risk, however, although 25% of colorectal cancer cases are familial, around 95% of the families are genetically unresolved. In this study, we performed gene panel analysis on germline DNA of 32 established or candidate colorectal cancer predisposing genes in 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (≤40 years at diagnosis). We identified pathogenic or likely pathogenic genetic variants in 10.1% of the participants in genes such as APC, POLE, MSH2 or PMS2. The MSH2 variant, c.2168C>T, p.(Ser723Phe) was previously described as a variant of unknown significance, but we have now reclassified it to be likely pathogenic. The POLE variant, c.1089C>A, p.(Asn363Lys) was identified in a patient with three metachronous colorectal cancers from age 28 and turned out to be de novo. One pathogenic PMS2 variant was novel. We also identified a number of highly interesting variants of unknown significance in APC, BUB1, TP53 and RPS20. The RPS20 variant is novel and was found in a large Amsterdam I positive family with a multi tumor phenotype including 12 cases of CRC from as early as age 24. This variant was found to segregate with cancer in the family and multiple in silico tools predict it to be pathogenic. Our data further support the shift from phenotypic-based cancer panels to large panels including all established genes involved in hereditary cancer syndromes or (targeted) whole genome sequencing. Additionally, identification of a likely disease-predisposing variant in RPS20 expands the phenotypic spectrum of RPS20-related cancers and emphasize that this gene is relevant to include in colorectal cancer gene panels.

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Section: Pathogenic and Likely Pathogenic Moderate And Low Risk Variantsmentioning

confidence: 92%

New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients

et al. 2020

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“…In fact, 2 patients harboring germline variants of GALNT12 and AXIN2 did not respond clinically, but showed a radiometabolic response. The first is a gene codifying for an enzyme catalyzing the initial reaction in O-linked oligosaccharide biosynthesis; the latter is a gene that is likely to play an important role in the betacatenin-Wnt pathway (37)(38)(39). These genes, when impaired, have been associated to increased risk of colorectal cancer (both) and breast cancer (AXIN2) (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

“…The first is a gene codifying for an enzyme catalyzing the initial reaction in O-linked oligosaccharide biosynthesis; the latter is a gene that is likely to play an important role in the beta-catenin-Wnt pathway ( 37 – 39 ). These genes, when impaired, have been associated to increased risk of colorectal cancer (both) and breast cancer ( AXIN2 ) ( 37 – 39 ). The one patient with germline APC mutation, conversely, experienced a clinical response.…”

Section: Discussionmentioning

confidence: 99%

Clinical, Radiometabolic and Immunologic Effects of Olaparib in Locally Advanced Triple Negative Breast Cancer: The OLTRE Window of Opportunity Trial

et al. 2021

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IntroductionOlaparib is effective in metastatic triple negative breast cancer (TNBC) carrying germline mutations in DNA damage repair (DDR) genes BRCA1/2 (gBRCA-mut). The OLTRE window-of-opportunity trial preliminarily investigated potential pathologic, radiometabolic and immune biomarkers of early-response to olaparib in gBRCA-wild-type (wt) TNBC and, as proof-of-concept in gBRCA-mut HER2-negative BC.MethodsPatients received olaparib for 3 weeks (3w) before standard neoadjuvant chemotherapy and underwent multiple FDG18-PET/CT scan (basal, after olaparib), clinical assessments (basal, every 3w), tumor biopsies and blood samplings (baseline, after olaparib). Clinical and radiometabolic responses were evaluated according to RECIST1.1 and PERCIST criteria.Results27 patients with gBRCA-wt TNBC and 8 with gBRCA-mut BC (6 TNBC, 2 HR+/HER2-negative) were enrolled. Three (11.1%) patients showed mutations in non-BRCA1/2 DDR genes and 4 (14.8%) in other genes. 3w olaparib induced 16/35 and 15/27 partial clinical and radiometabolic responses, including in 40.7% and 50.0% gBRCA-wt patients. gBRCA-mut tumors presented numerically higher tumor-infiltrating lymphocytes (TILs) levels and PD-L1 positive tumors. Clinical responders experienced a reduction in T-regs/T-eff ratio (p=0.05), B and NK lymphocytes (p=0.003 both), with an average increase in T-helpers rate (p<0.001) and CD4/CD8 ratio (p=0.02). Ki67% and TILs did not vary significantly (p=0.67 and p=0.77). A numerical increase in PD-L1 positive cases after olaparib was observed, though non-significant (p=0.134). No differences were observed according to gBRCA status and type of response.ConclusionsEarly-stage TNBC might be a target population for olaparib, irrespective of gBRCA mutations. Future trials should combine TILs, PD-L1 and gBRCA status to better identify candidates for escalated/de-escalated treatment strategies including olaparib.

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“…GALNT12 (MIM#610290) controlled the initiation of mucin-type O-linked glycosylation, which plays an important role in adhesion, migration, and immune surveillance. Recent studies have demonstrated the relationship between GALNT12 as a moderate penetrance gene for CRC susceptibility [ 48 , 49 , 50 , 51 ].…”

Section: Predisposing Genes For Hereditary Crc Syndromesmentioning

confidence: 99%

Hereditary Colorectal Cancer Syndromes: Molecular Genetics and Precision Medicine

Chen

2022

Biomedicines

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Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Hereditary CRC syndromes account for approximately 5–10% of all CRC, with a lifetime risk of CRC that approaches 50–80% in the absence of endoscopic or surgical treatment. Hereditary CRC syndromes can be phenotypically divided into polyposis and non-polyposis syndrome, mainly according to the conditions of polyps. The typical representatives are familial adenomatous polyposis (FAP) and Lynch syndromes (LS), respectively. Over the past few decades, molecular genetics enhanced the discovery of cancer-predisposing genes and revolutionized the field of clinical oncology. Hereditary CRC syndromes have been a key part of this effort, with data showing that pathogenic variants are present in up to 10% of cases. Molecular phenotypes of tumors can not only help identify individuals with genetic susceptibility to CRC but also guide the precision prevention and treatment for the development of CRC. This review emphasizes the molecular basis and prevention strategies for hereditary CRC syndromes.

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Role of GALNT12 in the genetic predisposition to attenuated adenomatous polyposis syndrome

Cited by 9 publications

References 19 publications

New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients

New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients

Clinical, Radiometabolic and Immunologic Effects of Olaparib in Locally Advanced Triple Negative Breast Cancer: The OLTRE Window of Opportunity Trial

Hereditary Colorectal Cancer Syndromes: Molecular Genetics and Precision Medicine

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