Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts

Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88 defect

Gastric cancer is caused by both genetic and environmental factors. A woman who suffered from recurrent candidiasis throughout her life developed diffuse-type gastric cancer at the age of 23 years. Using whole-exome sequencing we identified a germline homozygous missense variant in MYD88. Immunological assays on peripheral blood mononuclear cells revealed an impaired immune response upon stimulation with Candida albicans, characterized by a defective production of the cytokine interleukin-17. Our data suggest that a genetic defect in MYD88 results in an impaired immune response and may increase gastric cancer risk

The Temporal Development of Fatty Infiltrates in the Neck Muscles Following Whiplash Injury: An Association with Pain and Posttraumatic Stress

Radiological findings associated with poor recovery following whiplash injury remain elusive. Muscle fatty infiltrates (MFI) in the cervical extensors on magnetic resonance imaging (MRI) in patients with chronic pain have been observed. Their association with specific aspects of pain and psychological factors have yet to be explored longitudinally.44 subjects with whiplash injury were enrolled at 4 weeks post-injury and classified at 6 months using scores on the Neck Disability Index as recovered, mild and moderate/severe. A measure for MFI and patient self-report of pain, loss of cervical range of movement and posttraumatic stress disorder (PTSD) were collected at 4 weeks, 3 months and 6 months post-injury. The effects of time and group and the interaction of time by group on MFI were determined. We assessed the mediating effect of posttraumatic stress and cervical range of movement on the longitudinal relationship between initial pain intensity and MFI. There was no difference in MFI across all groups at enrollment. MFI values increased in the moderate/severe group and were significantly higher in comparison to the recovered and mild groups at 3 and 6 months. No differences in MFI values were found between the mild and recovered groups. Initial severity of PTSD symptoms mediated the relationship between pain intensity and MFI at 6 months. Initial ROM loss did not.MFI in the cervical extensors occur soon following whiplash injury and suggest the possibility for the occurrence of a more severe injury with subsequent PTSD in patients with persistent symptoms

Patients’ views of treatment focused genetic testing (TFGT): some lessons for the mainstreaming of BRCA1 and BRCA2 testing

This paper explores patients' views and experiences of undergoing treatment-focused BRCA1 and BRCA2 genetic testing (TFGT), either offered following triaging to clinical genetics (breast cancer) or as part of a mainstreamed care pathway in oncology (ovarian cancer). Drawing on 26 in-depth interviews with patients with breast or ovarian cancer who had undergone TFGT, this retrospective study examines patients' views of genetic testing at this point in their care pathway, focusing on issues, such as initial response to the offer of testing, motivations for undergoing testing, and views on care pathways. Patients were amenable to the incorporation of TFGT at an early stage in their cancer care irrespective of (any) prior anticipation of having a genetic test or family history. While patients were glad to have been offered TFGT as part of their care, some questioned the logic of the test's timing in relation to their cancer treatment. Crucially, patients appeared unable to disentangle the treatment role of TFGT from its preventative function for self and other family members, suggesting that some may undergo TFGT to obtain information for others rather than for self

Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts

Integrating precision cancer medicine into healthcare—policy, practice, and research challenges

Abstract Precision medicine (PM) can be defined as a predictive, preventive, personalized, and participatory healthcare service delivery model. Recent developments in molecular biology and information technology make PM a reality today through the use of massive amounts of genetic, ‘omics’, clinical, environmental, and lifestyle data. With cancer being one of the most prominent public health threats in developed countries, both the research community and governments have been investing significant time, money, and efforts in precision cancer medicine (PCM). Although PCM research is extremely promising, a number of hurdles still remain on the road to an optimal integration of standardized and evidence-based use of PCM in healthcare systems. Indeed, PCM raises a number of technical, organizational, ethical, legal, social, and economic challenges that have to be taken into account in the development of an appropriate health policy framework. Here, we highlight some of the more salient issues regarding the standards needed for integration of PCM into healthcare systems, and we identify fields where more research is needed before policy can be implemented. Key challenges include, but are not limited to, the creation of new standards for the collection, analysis, and sharing of samples and data from cancer patients, and the creation of new clinical trial designs with renewed endpoints. We believe that these issues need to be addressed as a matter of priority by public health policymakers in the coming years for a better integration of PCM into healthcare

Cancer-related distress in unselected women with newly diagnosed breast or ovarian cancer undergoing BRCA1/2 testing without pretest genetic counseling

BACKGROUND: Genetic testing is increasing in patients newly diagnosed with cancer. This study investigated the levels, course and predictors of cancer-related distress, defined as intrusion and avoidance, in women undergoing BRCA1/2 testing without pretest genetic counseling shortly after a diagnosis of breast or ovarian cancer. MATERIAL AND METHODS: Unselected for family history or age, 259 women with breast cancer and 50 women with ovarian cancer, underwent BRCA1/2 testing shortly after diagnosis. Cancer-related distress was measured with the Impact of Event Scale before and after genetic testing. In order to identify predictors of distress, the subscale scores were regressed on baseline predictor variables including sociodemographic and medical variables, perceived social support, and decisional conflict regarding genetic testing. RESULTS: The mean levels of intrusion and avoidance were in the moderate range both before and after genetic testing with a statistically significant decline during follow-up. Younger age, shorter time since diagnosis, lower levels of social support, and a diagnosis of ovarian cancer predicted higher levels of both intrusion and avoidance. In addition, higher levels of decisional conflict and living with a partner predicted higher levels of intrusion. CONCLUSIONS: Women having genetic testing shortly after a diagnosis of breast or ovarian cancer had a moderate mean level of cancer-related distress, which decreased with time. Health personnel offering genetic testing to newly diagnosed women with breast or ovarian cancer should be aware of the potential predictors for increased cancer-related distress identified in this study: younger age, less perceived social support, higher levels of decisional conflict regarding genetic testing, and living with a partner

BRCA1/2 testing in newly diagnosed breast and ovarian cancer patients without prior genetic counselling: the DNA-BONus study

Germline BRCA1/2 testing of breast and ovarian cancer patients is growing rapidly as the result affects both treatment and cancer prevention in patients and relatives. Through the DNA-BONus study we offered BRCA1/2 testing and familial risk assessment to all new patients with breast (N=893) or ovarian (N=122) cancer diagnosed between September 2012 and April 2015, irrespective of family history or age, and without prior face-to-face genetic counselling. BRCA1/2 testing was accepted by 405 (45.4%) and 83 (68.0%) of the patients with breast or ovarian cancer, respectively. A pathogenic BRCA1/2 variant was found in 7 (1.7%) of the breast cancer patients and 19 (22.3%) of the ovarian cancer patients. In retrospect, all BRCA1/2 mutation carriers appeared to fulfill current criteria for BRCA1/2 testing. Hospital Anxiety and Depression Scale (HADS) scores showed that the mean levels of anxiety and depression were comparable to those reported for breast and gynecological cancer patients in general, with a significant drop in anxiety symptoms during a 6-month follow-up period, during which the test result was forwarded to the patients. These results show that BRCA1/2 testing is well accepted in newly diagnosed breast and ovarian cancer patients. Current test criteria based on age and family history are sufficient to identify most BRCA1/2 mutation carriers among breast cancer patients. We recommend germline BRCA1/2 testing in all patients with epithelial ovarian cancer because of the high prevalence of pathogenic BRCA1/2 variants