scholarly journals ATM Serine/Threonine Kinase and its Role in Pancreatic Risk

Genes ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 108 ◽  
Author(s):  
Neha Nanda ◽  
Nicholas J. Roberts
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Susceptibility ◽  
Ductal Adenocarcinoma ◽  
Ataxia Telangiectasia Mutated ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Cancer Susceptibility Genes ◽  
History Of ◽  
Impact Patient Care ◽  
Generation Sequencing

Next-generation sequencing has led to the recent discovery of several novel pancreatic cancer susceptibility genes. These genes include ataxia telangiectasia mutated (ATM), a serine/threonine kinase that is an integral component of DNA repair. Pathogenic germline ATM variants are frequently identified in patients with pancreatic ductal adenocarcinoma (PDAC) with and without a family history of the disease. Loss of ATM is also a frequent somatic event in the development of PDAC. These discoveries have advanced our understanding of the genetic basis of pancreatic cancer risk and will impact patient care through appropriate patient–risk stratification; personalized screening and early detection efforts; and, for some, targeted therapy.

scholarly journals Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma

2017 ◽  
Vol 35 (30) ◽  
pp. 3382-3390 ◽  
Author(s):  
Koji Shindo ◽  
Jun Yu ◽  
Masaya Suenaga ◽  
Shahriar Fesharakizadeh ◽  
Christy Cho ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Family History ◽  
Germline Mutation ◽  
Cancer Susceptibility ◽  
Germline Mutations ◽  
Susceptibility Genes ◽  
Familial Pancreatic Cancer ◽  
Cancer Susceptibility Genes ◽  
Periampullary Neoplasms ◽  
History Of

Purpose Deleterious germline mutations contribute to pancreatic cancer susceptibility and are well documented in families in which multiple members have had pancreatic cancer. Methods To define the prevalence of these germline mutations in patients with apparently sporadic pancreatic cancer, we sequenced 32 genes, including known pancreatic cancer susceptibility genes, in DNA prepared from normal tissue obtained from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with non-neoplastic diseases who underwent pancreatic resection at Johns Hopkins Hospital between 2000 and 2015. Results Thirty-three (3.9%; 95% CI, 3.0% to 5.8%) of 854 patients with pancreatic cancer had a deleterious germline mutation, 31 (3.5%) of which affected known familial pancreatic cancer susceptibility genes: BRCA2 (12 patients), ATM (10 patients), BRCA1 (3 patients), PALB2 (2 patients), MLH1 (2 patients), CDKN2A (1 patient), and TP53 (1 patient). Patients with these germline mutations were younger than those without (mean ± SD, 60.8 ± 10.6 v 65.1 ± 10.5 years; P = .03). Deleterious germline mutations were also found in BUB1B (1) and BUB3 (1). Only three of these 33 patients had reported a family history of pancreatic cancer, and most did not have a cancer family history to suggest an inherited cancer syndrome. Five (1.7%) of 288 patients with other periampullary neoplasms also had a deleterious germline mutation. Conclusion Germline mutations in pancreatic cancer susceptibility genes are commonly identified in patients with pancreatic cancer without a significant family history of cancer. These deleterious pancreatic cancer susceptibility gene mutations, some of which are therapeutically targetable, will be missed if current family history guidelines are the main criteria used to determine the appropriateness of gene testing.

Clinical impact of pathogenic germline variants in pancreatic cancer: Results from a multicenter prospective universal genetic testing study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4118-4118
Author(s):  
Pedro Luiz Serrano Uson Junior ◽  
Douglas Riegert-Johnson ◽  
Lisa A. Boardman ◽  
Mitesh J. Borad ◽  
Daniel H. Ahn ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Outcomes ◽  
Cancer Susceptibility ◽  
Familial Cancer ◽  
Family Counseling ◽  
Disease Stage ◽  
Germline Variants ◽  
Sequencing Platform ◽  
Cancer Susceptibility Genes ◽  
Gene Panel Testing

4118 Background: Germline variations in cancer susceptibility genes have important implications on treatment and family counseling in pancreatic cancer (PC). We report the prevalence and clinical outcomes of unselected PC patients with pathogenic germline variants (PGV) detected using a universal testing approach. Methods: We undertook a prospective multi-site study of germline sequencing using an >80 gene next-generation sequencing platform among 250 PC patients (not selected for age or family cancer history) between April 1, 2018 and March 31, 2020. Demographic, tumor characteristics and clinical outcomes were compared between PGV carriers and non-carriers. Results: Of 250 patients, the mean age was 65 years (SD 8.7), 56% were male, 83.6% were white and 65.6% had advanced disease (Stage III and IV). PGV were found in 15.2% (N=38) of patients, two patients had more than one PGV. Variants of uncertain significance were found in 44.4% (N=111). Family history of cancer (OR 2.36, 95% CI: 1.14-5.19, p=0.025) was associated with a higher risk of PGV. In a median follow up of 16.5 months, median overall survival was 16.8 months in PGV carriers compared with 16.5 months in non-carriers (HR 0.51, 95 %CI, 0.25-1.01, p=0.05). Higher levels of CA 19-9 and advanced stages (III and IV) were associated with worse outcomes in both groups. Overall, 68% of PGV carriers had mutations in homologous recombination repair (HRR) genes, including BRCA1, BRCA2, PALB2, ATM, CHEK2, NBN, RAD51C. In 65% of HRR gene carrier’s systemic therapy with platinum was used. Conclusions: Universal multi-gene panel testing in pancreatic cancer reveals that 1 in 6 patients are carriers of PGV and is associated with improved survival. Multi-gene germline testing should be used to aid in treatment selection, prognostication, and familial cancer counseling. Distribution of the 40 PGV by penetrance status.[Table: see text]

Comparison of risk-reducing surgery in women with BRCA and non-BRCA ovarian cancer susceptibility genes.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1547-1547
Author(s):  
Zachary Phillip Schwartz ◽  
Mae Zakhour ◽  
Andrew John Li ◽  
Christine S. Walsh ◽  
Bj Rimel ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Susceptibility ◽  
Brca Mutation ◽  
Susceptibility Genes ◽  
Brca Mutations ◽  
Cancer Susceptibility Genes ◽  
Mutation Carriers ◽  
Brca Mutation Carriers ◽  
History Of ◽  
Risk Reducing

1547 Background: Risk reducing gynecologic surgery (RRSO) is standard of care for women with BRCA mutations. The optimal management for women with non-BRCA ovarian cancer susceptibility mutations remains unclear. We sought to characterize the practice patterns for these women at our two institutions. Methods: Women with germline ovarian cancer susceptibility genes who had a RRSO were identified from 1/2000-1/2019 in an IRB approved study. All patients were asymptomatic with no suspicion for malignancy at time of RRSO. Clinico-pathologic characteristics were extracted from the medical records. Continuous variables were analyzed with Kruskal-Wallis and categorical variables analyzed with chi square and t-tests. Results: 152 BRCA1, 95 BRCA2, and 63 Non-BRCA mutation carriers were identified—50 Lynch (22 MLH1, 13 MSH2, 13 MSH6, 2 PMS2) and 13 Other (6 BRIP1, 2 RAD51C, 5 RAD51D). There was no difference between age at testing, age at RRSO, and interval between testing and RRSO between groups. Genetic counseling was higher in Non-BRCA patients. Family history of ovarian cancer was more common in women with BRCA1 and Other germline mutations compared to BRCA2 and Lynch. Family and personal history of breast cancer was high in all groups except Lynch carriers. Prophylactic mastectomy was seen mostly in BRCA mutation carriers. Concomitant hysterectomy was performed in the majority of women (BRCA1 59%, BRCA2 57%, and Other 62%), with the highest frequency in Lynch carriers (86%, p<.01). Occult cancer was only seen in BRCA mutation carriers: BRCA1 (7%), BRCA2 (2%), Lynch (0%), Other (0%). Conclusions: In this cohort, women with Non-BRCA mutations are managed similarly to women with BRCA mutations. We observed no occult cancers in Non-BRCA patients. The optimal role of surgery as a risk reducing strategy in this group requires further study. [Table: see text]

Identification of pancreatic cancer susceptibility genes in the Czech Republic

2016 ◽  
Vol 61 ◽  
pp. S26
Author(s):  
M. Borecka ◽  
M. Janatova ◽  
P. Zemánková ◽  
L. Stolarova ◽  
K. Zdarilova ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Czech Republic ◽  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
The Czech Republic ◽  
Cancer Susceptibility Genes

scholarly journals Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma

2021 ◽  
Vol 22 (19) ◽  
pp. 10219
Author(s):  
Shirin Hafezi ◽  
Maha Saber-Ayad ◽  
Wael M. Abdel-Rahman
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Human Cancer ◽  
Ductal Adenocarcinoma ◽  
Ras Gene ◽  
Kras Mutations ◽  
Oncogenic Mutations ◽  
History Of ◽  
Novel Therapeutic Strategies ◽  
The Impact

The most frequent mutated oncogene family in the history of human cancer is the RAS gene family, including NRAS, HRAS, and, most importantly, KRAS. A hallmark of pancreatic cancer, recalcitrant cancer with a very low survival rate, is the prevalence of oncogenic mutations in the KRAS gene. Due to this fact, studying the function of KRAS and the impact of its mutations on the tumor microenvironment (TME) is a priority for understanding pancreatic cancer progression and designing novel therapeutic strategies for the treatment of the dismal disease. Despite some recent enlightening studies, there is still a wide gap in our knowledge regarding the impact of KRAS mutations on different components of the pancreatic TME. In this review, we will present an updated summary of mutant KRAS role in the initiation, progression, and modulation of the TME of pancreatic ductal adenocarcinoma (PDAC). This review will highlight the intriguing link between diabetes mellitus and PDAC, as well as vitamin D as an adjuvant effective therapy via TME modulation of PDAC. We will also discuss different ongoing clinical trials that use KRAS oncogene signaling network as therapeutic targets.

scholarly journals Histomorphology of pancreatic cancer in patients with inherited ATM serine/threonine kinase pathogenic variants

2019 ◽  
Vol 32 (12) ◽  
pp. 1806-1813 ◽  
Author(s):  
Danielle Hutchings ◽  
Zhengdong Jiang ◽  
Michael Skaro ◽  
Matthew J. Weiss ◽  
Christopher L. Wolfgang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Pathogenic Variants
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