The kallikrein-related peptidase family: Dysregulation and functions during cancer progression.

The purpose of the present study was to evaluate the correlation between molecular factors such as BRCA1 DNA repair associated (BRCA1), checkpoint kinase 2 (CHEK2) and nucleotide binding oligomerization domain containing 2 (NOD2) gene mutations and clinicopathological factors in patients with breast cancer (BC). Prognostic factors were analyzed in BC patients with confirmed BRCA1 (n=73), CHEK2 (n=51) and NOD2 (n=31) mutations. The control group was selected from BC patients without mutations (n=392). The BRCA-associated cancer cases were significantly more often triple negative compared with sporadic cancer (62% vs. 14%; P=0.0001). Luminal B HER2-positive and HER2-positive non-luminal subtypes were observed more often in the control group (33 and 17%). The luminal A subtype was detected in 53% of CHEK2 mutation carriers and 45% of NOD2 mutation carriers. A lower histological grade was observed significantly more often in patients with CHEK2 mutations in comparison with the control group (88 vs. 69%; P=0.003). Lymph nodes without metastases were reported more frequently in NOD2 mutation carriers (74 vs. 54%; P=0.038), in BRCA1 mutations (73 vs. 54%; P=0.004) and, although not significantly, in CHEK2 mutation carriers (69 vs. 54%; P=0.071) compared with the control group. In conclusion, BRCA1 mutation was associated with TNBC and the luminal B HER2 (-) subtype. HER2-positive subtypes were characteristic of the control group. CHEK2 and NOD2 mutation carriers had a more favorable profile of prognostic factors.

/pdf/molecular-characteristics-of-breast-cancer-according-to-dzlhc0ksc0.pdf

Molecular characteristics of breast cancer according to clinicopathological factors

Our study was aimed to investigate the diagnostic and prognostic performance of serum human tissue kallikrein 7 (KLK7) in cervical cancer. The study comprised of 78 patients with cervical cancer, 36 patients with benign cervical diseases, and 50 healthy controls. Serum KLK7 levels were determined using ELISA method. Receiver operating characteristic curve was performed to assess the diagnostic performance of serum KLK7. Survival curves by the Kaplan-Meier method were plotted to display overall survival distributions. Univariable and multivariable Cox regression analysis were performed to assess independent prognostic factors for overall survival in cervical cancer. Serum KLK7 levels in cervical cancer patients were 3.13±1.99 μg/ml, significantly higher than the values obtained from patients with benign cervical disease (1.40±1.14 μg/ml; P<0.001) and healthy controls (1.27±0.73 μg/ml; P<0.001), respectively. The sensitivity, specificity, positive and negative predictive values of serum KLK7 for cervical cancer were 75.6, 80.2, 77.6, and 78.4%, respectively. Serum KLK7 levels in patients with cervical cancer were significantly correlated with FIGO stage, lymph node metastasis, and stromal invasion. When analyzed with a survival curve, high serum KLK7 level was correlated with poor prognosis. Our findings suggest that serum KLK7 may be a valuable diagnostic biomarker for cervical cancer, and may help to determine the individual prognosis of these patients.

Serum human kallikrein 7 represents a new marker for cervical cancer

PURPOSE The treatment of ovarian cancer continues to pose a challenge especially through the development of platinum-resistant disease and still has the highest mortality rate among gynecologic cancers. Patients are usually diagnosed with advanced stages where complete cytoreduction and standard platinum-based chemotherapy are the mainstay of treatment. Advances into the molecular underpinnings of DNA damage repair highlighted BRCA 1/2 and other related genes as key regulators of platinum sensitivity. Our study characterizes clinical features and outcomes associated with BRCA mutations in a cohort of ovarian cancer patients. METHODS Patient data from our Institute was retrospectively extracted for all patients that were tested for the presence of BRCA germline or somatic mutations through next generation sequencing between May 2016 and August 2018. RESULTS Eighty-eight patients were included in the present analysis. Advanced FIGO stage IIIC-IV was common at presentation (71.6%), with 58% of patients undergoing primary debulking surgery. BRCA mutant cases represented 44% and were associated with a significantly higher frequency for complete pathologic response, first and second platinum sensitive relapse and a significantly longer overall survival for advanced stage cases treated with neoadjuvant chemotherapy. Mean age at presentation was significantly lower in the BRCA mutated (52 years) compared to BRCA wildtype patients (54.2 years, p=0.045). CONCLUSIONS Upfront knowledge of BRCA status is encouraged, given the recent advent of targeted therapies and for the decision regarding optimal sequence of available therapeutic strategies.

The clinical features associated with mutated BRCA1 and 2 genes in ovarian cancer patients.

Salivary dysfunction commonly occurs in many older adults and is considered a physiological phenomenon. However, the genetic changes in salivary glands during aging have not been characterized. The present study analyzed the gene expression profile in salivary glands from accelerated aging klotho deficient mice (klotho-/-, 4 weeks old). Microarray analysis showed that 195 genes were differentially expressed (z-score > 2 in two independent arrays) in klotho null mice compared to wild-type mice. Importantly, alpha2-Na+ /K+ -ATPase (Atp1a2), Ca2+ -ATPase (Atp2a1), epidermal growth factor (EGF), and nerve growth factor (NGF), which have been suggested to be regulators of submandibular salivary gland function, were significantly decreased. When a network was constructed from the differentially expressed genes, proliferator-activated receptor-γ (PPAR γ), which regulates energy homeostasis and insulin sensitivity, was located at the core of the network. In addition, the expression of genes proposed to regulate various PPAR γ-related cellular pathways, such as Klk1b26, Egfbp2, Cox8b, Gpx3, Fabp3, EGF, and NGFβ, was altered in the submandibular salivary glands of klotho-/- mice. Our results may provide clues for the identification of novel genes involved in salivary gland dysfunction. Further characterization of these differentially expressed genes will be useful in elucidating the genetic basis of aging-related changes in the submandibular salivary gland.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcp.26172

Global analysis of gene expression profiles in the submandibular salivary gland of klotho knockout mice.

Human tissue kallikrein (KLK1) and is related peptidases (KLK2-KLK15) are a family of 15 homologous serine proteases, participating in numerous processes of normal physiology. Considering the irreversible impact of proteases on substrates, the tissue-dependent regulation of KLKs activity becomes crucial for their beneficial role in normal homeostasis. Moreover, KLKs expression is strongly regulated at the transcriptional and post-transcriptional level by steroid hormones and miRNAs, respectively. Deregulation of KLKs expression, secretion and/or activation has been observed in most human malignancies and there is a trend to identify their role in the multi-complex process of cancer development. The identification of extracellular matrix (ECM) proteins, cell-surface receptors, cell-surface adhesion molecules and growth factors among substrates, clearly support the driving role of KLK abnormal expression and function during tumorigenesis and cancer progression. KLKs have also clinical utility in cancer diagnosis and monitoring like KLK 3 (PSA) in prostate cancer. In this review, we tried to summarize the existing literature about the role of KLKs in gastrointestinal cancers as well as to emphasize their clinical significance for patients' prognosis.

Kallikrein-related peptidases in cancers of gastrointestinal tract: an inside view of their role and clinical significance.

PURPOSE BRCA mutation carriers can benefit from targeted clinical interventions. On the other hand, families with evident aggregation of breast cancer (BC) cases and a BRCA-negative genetic test can still be considered as of elevated risk, since the underlying genetic factor remains unidentified. In the present study, we compared clinical and demographic characteristics between BRCA1 mutation carriers (BRCA1mut) and non-carriers (non-BRCA1) in a Greek group of BC patients (n=321). METHODS Data were collected and analyzed from 321 women with BC, with 131 patients screened for pathogenic mutations in the high-penetrant genes BRCA1 and BRCA2. Collected data included demographics, pedigrees, tumor histopathology and immunohistochemistry findings. RESULTS In BRCA1mut patients, their mothers and grand- mothers were diagnosed at a younger age compared to non-BRCA1-carriers. Additionally, BRCA1mut patients were diagnosed with mainly estrogen receptor (ER) negative (p<0.001), Her-2 negative (p<0.05) and triple negative (p<0.01) tumors. The youngest generation was diagnosed with familial breast cancer (FBC) 9.7 years earlier than their mothers (p<0.001). Age at BC diagnosis negatively correlated with the nuclear grade of breast tumors (r=-0.3, p<0.05). Among parous individuals, the number of full-term pregnancies significantly correlated with the age at BC onset (r=0.19, p<0.05). CONCLUSION Despite their similarities, FBC cases with identified BRCA1 mutations exhibit a clearly distinct profile. We have identified an anticipation effect in FBC patients, with significantly reduced age at diagnosis in younger generations. Increased parity seems to prevent early BC onset. This is the first study comparing clinical and demographic characteristics of FBC BRCA1mut and non-carriers in a Greek cohort.

Epidemiological and clinicopathological characteristics of BRCA-positive and BRCA-negative breast cancer patients in Greece.

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Kallikrein-related peptidases in cancers of gastrointestinal tract: an inside view of their role and clinical significance.

Epidemiological and clinicopathological characteristics of BRCA-positive and BRCA-negative breast cancer patients in Greece.