Pancreatic Cancer with Mutation in BRCA1/2, MLH1, and APC Genes: Phenotype Correlation and Detection of a Novel Germline BRCA2 Mutation

Vietri, Maria Teresa; Goletti, Delia; Caliendo, Gemma; Albanese, Luisa; Signoriello, Giuseppe; Napoli, Claudio; Molinari, Anna Maria

doi:10.3390/genes13020321

Cited by 19 publications

(19 citation statements)

References 65 publications

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“…Biallelic MUTYH mutations have been linked to MUTYH -associated polyposis syndrome (MAP). In the past few years, monoallelic MUTYH PVs have been found in patients with gastric, liver, endometrial, breast, ovarian and pancreatic cancer [ 36 , 37 ], and this has led to several studies investigating the impact of germline monoallelic MUTYH PVs in tumorigenesis. We found that 0.56% of families showed a monoallelic frameshift MUTYH PV, while a previous study reported MUTYH PVs in 2.37% of patients with a family history of prostate cancer [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Increased Risk of Hereditary Prostate Cancer in Italian Families with Hereditary Breast and Ovarian Cancer Syndrome Harboring Mutations in BRCA and in Other Susceptibility Genes

Goletti

Caliendo

Tzioni

et al. 2022

Genes

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Hereditary prostate cancer (HPCa) has the highest heritability of any cancer in men. Interestingly, it occurs in several hereditary syndromes, including breast and ovarian cancer (HBOC) and Lynch syndrome (LS). Several gene mutations related to these syndromes have been identified as biomarkers in HPCa. The goal of this study was to screen for germline mutations in susceptibility genes by using a multigene panel, and to subsequently correlate the results with clinical and laboratory parameters. This was undertaken in 180 HBOC families, which included 217 males with prostate cancer (PCa). Mutational analysis was further extended to 104 family members of mutated patients. Screening of HBOC families revealed that 30.5% harbored germline mutations in susceptibility genes, with 21.6% harboring pathogenic variants (PVs) and 8.9% having variants of uncertain significance (VUS). We found PVs at similar frequency in BRCA1 and BRCA2 genes (8.8% and 9.4%, respectively), while 0.56% of PVs were present in well-established susceptibility genes PALB2, TP53 and RAD51C. Moreover, 0.56% of monoallelic PVs were present in MUTYH, a gene whose function in tumorigenesis in the context of PCa is still unclear. Finally, we reported double heterozygosity (DH) in BRCA1/2 genes in a single family, and found double mutation (DM) present in BRCA2 in a separate family. There was no significant difference between the mean age of onset of PCa in HBOC families with or without germline mutations in susceptibility genes, while the mean survival was highest in mutated patients compared to wild type. Furthermore, PCa is the second most recurrent cancer in our cohort, resulting in 18% of cases in both mutated and non-mutated families. Our investigation shows that PVs were located mostly in the 3′ of BRCA1 and BRCA2 genes, and in BRCA2, most PVs fell in exon 11, suggesting a mutation cluster region relating to risk of HPCa. A total of 65 family members inherited the proband’s mutation; of these, 24 developed cancer, with 41 remaining unaffected.

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Section: Discussionmentioning

confidence: 99%

Increased Risk of Hereditary Prostate Cancer in Italian Families with Hereditary Breast and Ovarian Cancer Syndrome Harboring Mutations in BRCA and in Other Susceptibility Genes

Goletti

Caliendo

Tzioni

et al. 2022

Genes

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“…Given the direct implication of BRCA1/2 signaling in the pathophysiology of hereditary pancreatic adenocarcinoma (PDAC) [285], as well as the recently reported prognostic impact of HER2 expression or amplification in the survival of PDAC patients [286], we examined possible alterations in the expression profiles of BRCA1/2 and HER2 mRNAs In contrast, colon cancer mesenchymal cells do not express iNOS and instead overexpress eNOS that impairs the CSC phenotype and induces tumor cell proliferation [282]. The above findings indicate that the type and expression levels of each NOS isoform in CSCs might be specific to cancer type and tumor aggressive potential, as well as the impact of inflammation-induced iNOS and NO in tumorigenesis.…”

Section: Implication Of Inos Her2 and Brca1/2 In Csc Pathophysiologymentioning

confidence: 99%

“…Given the direct implication of BRCA1/2 signaling in the pathophysiology of hereditary pancreatic adenocarcinoma (PDAC) [285], as well as the recently reported prognostic impact of HER2 expression or amplification in the survival of PDAC patients [286], we examined possible alterations in the expression profiles of BRCA1/2 and HER2 mRNAs in our PDAC CSC models. Both MiaPaca2 and PANC1 cell lines are proficient in BRACA1/2 wildtype expression [287], while HER2 levels are more profound in MiaPaca2 than PANC1 [288].…”

Section: Implication Of Inos Her2 and Brca1/2 In Csc Pathophysiologymentioning

confidence: 99%

The Breast Cancer Protooncogenes HER2, BRCA1 and BRCA2 and Their Regulation by the iNOS/NOS2 Axis

et al. 2022

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The expression of inducible nitric oxide synthase (iNOS; NOS2) and derived NO in various cancers was reported to exert pro- and anti-tumorigenic effects depending on the levels of expression and the tumor types. In humans, the breast cancer level of iNOS was reported to be overexpressed, to exhibit pro-tumorigenic activities, and to be of prognostic significance. Likewise, the expression of the oncogenes HER2, BRCA1, and BRCA2 has been associated with malignancy. The interrelationship between the expression of these protooncogenes and oncogenes and the expression of iNOS is not clear. We have hypothesized that there exist cross-talk signaling pathways between the breast cancer protooncogenes, the iNOS axis, and iNOS-mediated NO mutations of these protooncogenes into oncogenes. We review the molecular regulation of the expression of the protooncogenes in breast cancer and their interrelationships with iNOS expression and activities. In addition, we discuss the roles of iNOS, HER2, BRCA1/2, and NO metabolism in the pathophysiology of cancer stem cells. Bioinformatic analyses have been performed and have found suggested molecular alterations responsible for breast cancer aggressiveness. These include the association of BRCA1/2 mutations and HER2 amplifications with the dysregulation of the NOS pathway. We propose that future studies should be undertaken to investigate the regulatory mechanisms underlying the expression of iNOS and various breast cancer oncogenes, with the aim of identifying new therapeutic targets for the treatment of breast cancers that are refractory to current treatments.

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“…Most patients with pancreatic cancer are sporadic ( Vietri et al ., 2022 ) and the incidence of pancreatic cancer is estimated to increase further. The risk factors for pancreatic cancer include sex, smoking, alcohol consumption, diabetes and family history.…”

Section: Introductionmentioning

confidence: 99%

Rare germline variants in pancreatic cancer and multiple primary cancers: an autopsy study

Fujitani

Eguchi

Kochi

et al. 2023

European Journal of Cancer Prevention

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BackgroundThere is a lack of information on rare germline variants of pancreatic cancer-predisposing genes. Risk genes for multiple primary cancers may overlap with those for pancreatic cancer.Methods A retrospective study of autopsy cases with a negative family history in the Japanese single nucleotide polymorphism for geriatric research database examined rare germline variants in the protein-coding regions of 61 genes. Targeted sequencing of these genes was performed and classified for pathogenicity using the American College of Medical Genetics and Genomics guidelines. Polyphen-2, SIFT and LoFtool algorithms were used to predict damage to protein function. ResultsOf the 189 subjects used (90 cancer and 99 non-cancer controls), 72 patients had pancreatic cancer (23 had multiple primary cancers) and 18 had no pancreatic cancer in multiple primary cancers. APC, BRCA2, BUB1B, ENG and MSH6 were associated with cancer predisposition, and pathogenic/likely pathogenic (P/LP) variants occurred in 6% [pancreatic cancer (4/72); all-cancer (5/90)] and 54% (49/90) carried only variants of uncertain significance (VUS) among cancer patients. Of these VUS, in pancreatic cancer patients, four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2), and POLQ in men were significantly associated (odds ratio = 3.83; P = 0.025; P = 0.027, respectively). The most abundant predictor of functionally damaging variants was POLQ. ConclusionsThe frequency of P/LP variants in patients with sporadic pancreatic cancer suggests the need for genetic evaluation of individuals with no family history. VUS of MMR genes (MLH1, MSH2, MSH6 and PMS2) and POLQ may be useful in predicting genetic trends in the potential risk of pancreatic cancer, especially in individuals lacking P/LP.

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Pancreatic Cancer with Mutation in BRCA1/2, MLH1, and APC Genes: Phenotype Correlation and Detection of a Novel Germline BRCA2 Mutation

Cited by 19 publications

References 65 publications

Increased Risk of Hereditary Prostate Cancer in Italian Families with Hereditary Breast and Ovarian Cancer Syndrome Harboring Mutations in BRCA and in Other Susceptibility Genes

Increased Risk of Hereditary Prostate Cancer in Italian Families with Hereditary Breast and Ovarian Cancer Syndrome Harboring Mutations in BRCA and in Other Susceptibility Genes

The Breast Cancer Protooncogenes HER2, BRCA1 and BRCA2 and Their Regulation by the iNOS/NOS2 Axis

Rare germline variants in pancreatic cancer and multiple primary cancers: an autopsy study

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