Hereditary Cancer in Clinical Practice最新文献

Background: In Norway, we have offered testing of PMS2 since 2006, and have a large national cohort of carriers. The aim of this study was to describe all PMS2 variants identified, and to describe frequency, spectrum and penetrance of cancers in carriers of class 4/5 variants.

Methods: All detected PMS2 variants were collected from the diagnostic laboratories and reclassified according to ACMG criteria and gene specific guidelines. Data on variant, gender, cancer diagnosis, age at diagnosis, and age at last known follow-up was collected on all carriers of class 4/5 variants from electronic patient records. The Kaplan-Meier algorithm was used to calculate cumulative risk of any cancer, colorectal cancer and endometrial cancer.

Results: In total, 220 different PMS2 variants were detected. Twenty nine class 4/5 variants were identified in 482 carriers. The most common pathogenic variant was the founder mutation c.989-1G > T, detected in 204 patients from 58 families. Eighty seven out of 482 (18.0%) had been diagnosed with colorectal cancer, 10 of these (11.8%) before 40 years. Cumulative risk at 70 years in our cohort was 34.7% for colorectal cancer and 26.1% for endometrial cancer.

Conclusions: After 15 years of genetic testing, 29 different class 4/5 variants have been detected in Norway. Almost half of Norwegian PMS2 carriers have the founder variant 989-1G > T. Penetrance of colorectal cancer in our cohort was moderate but variable, as 11.5% of those diagnosed were younger than 40 years.

Background: Lynch syndrome represents the most common hereditary cause of both colorectal and endometrial cancer. It is caused by defects in mismatch repair genes, as well as EPCAM. Universal screening of colon tumors for Lynch syndrome via microsatellite instability (MSI) and/or immunohistochemistry (IHC) can identify patients and families at risk to develop further cancers and potentially impact surveillance and treatment options. The approach to implementation of universal screening, taking ethical considerations into account, is critical to its effectiveness, with patient perspectives providing valuable insight.

Methods: Patients whose colon tumors underwent universal screening at Penn State Hershey Medical Center over a period of 2.5 years were mailed a survey on universal screening in 2017. Along with the survey, they received a recruitment letter and a summary explanation of research. The survey included both multiple choice and free-response questions that covered topics including respondent knowledge of Lynch syndrome, attitudes toward universal screening and experiences with the screening protocol as implemented.

Results: Sixty-six of 297 possible patients (22.2%) responded to the survey, including 13 whose screening results raised concern for Lynch syndrome. 75.8% of respondents supported universal tumor screening without informed consent. 92.4% preferred receiving screening results regardless of outcome. Respondents described benefits to screening for themselves and their families.

Conclusions: While broadly supporting universal tumor screening without informed consent, respondents also wanted more information shared about the screening policy, as well as their results. These patient preferences should be one of many factors considered when implementing universal screening and can also inform practices regarding both tumor profiling and universal genetic testing, which is becoming more prevalent.

Background: Adrenal tumours are associated with familial adenomatous polyposis (FAP). In the literature, most studies use the clinical definition of FAP (more than 100 adenomatous polyps found in endoscopic studies). However, not all patients that meet clinical criteria for FAP carry pathogenic mutations in the adenomatous polyposis coli (APC) gene, as there is genetic heterogeneity responsible for FAP with the polyposis sometimes explained by genetic and environmental factors other than pathogenic APC mutations. Reciprocally, not all the patients with pathogenic APC variants will fulfil the classic criteria of FAP.

Objective: This study aims to investigate the characteristics of adrenal tumours in patients with pathogenic or likely pathogenic APC variants and explore the hormonal function of these patients.

Method: This is a retrospective cohort study. Patients with pathogenic or likely pathogenic APC variants were recruited and their radiological assessments were reviewed. Patient demographic data, APC variants, adrenal mass characteristics and hormonal testing results were collected.

Result: The prevalence of adrenal mass was 26.7% (24/90) among patients with pathogenic or likely pathogenic APC variants. Using the classic definition, the prevalence was 32.4% (22/68). Four patients had adrenal hormone testing, two of which had Conn's syndrome and two had nonspecific subclinical results.

Conclusion: In our cohort, the prevalence of adrenal tumours among patients with pathogenic and likely pathogenic APC mutations is at least twice to three times higher than the general population prevalence reported from international population-based studies. The hormonal functions of patients with pathogenic APC variants and adrenal tumours can be investigated with routine testing in further research.

Background: Fear of cancer recurrence (FCR) affects virtually all patients who have been treated for cancer, to varying degrees. Breast cancer survivors who carry a BRCA1 or BRCA2 gene mutation are at high risk of cancer recurrence. No study has yet assessed FCR specifically in this population.

Objectives: This cross-sectional study, conducted in women who were treated for breast cancer and carrying a BRCA1/2 mutation, aimed to: (1) assess the mean level of FCR and estimate the proportion of patients with clinical levels of FCR; (2) examine the relationships between FCR and selected psychological variables (e.g., avoidance, intolerance to uncertainty) and quality of life; (3) explore whether FCR levels vary as a function of the past preventive treatment received; and (4) to assess the associations between FCR and the presence of decisional conflict or regret regarding the various preventive options.

Method: Participants were recruited through an e-mail sent to an oncogenetic network mailing list (Réseau ROSE). Participants were asked to complete a battery of questionnaires online assessing FCR and other psychological and quality of life variables.

Results: A total of 89 women completed the survey. Most participants had undergone a preventive mastectomy (62.9%) and a preventive salpingo-oophorectomy (75.3%) at the time of the study. The mean Fear of Cancer Recurrence Inventory-severity score was 16.8, which exceeds the clinical cut-off score of 13, and 70.8% of the participants showed a clinical level of FCR. FCR was significantly associated with higher levels of anxiety and depression, and higher avoidance and intolerance of uncertainty, but not with quality of life. No significant difference was observed on the total FCR score between women who had received preventive surgery (mastectomy and/or salpingo-oophorectomy) and those considering it, and those not considering it. The association was significant between higher FRC scores and greater decisional conflicts and regrets about choosing to undergo preventive surgery.

Conclusion: These data suggest that FCR is a significant problem for breast cancer survivors carrying a BRCA1/2 genetic mutation, even after undergoing a prophylactic surgery. This highlights the importance of providing these women with specific psychological intervention focusing on FCR.

Background: Hereditary cancer is estimated to account for up to 10% of the worldwide cancer burden; 5% of all thyroid cancers are thought to be genetic. Inheritance of a deleterious mutation in genes associated with a high lifetime risk of developing cancer. Cancer-predisposing genes can promote the initiation and progression of thyroid cancer by enhancing the activation of major signaling pathways through oxidative stress mechanisms.

Aim: Identification of the possible link between familial susceptibility to cancer and the level of oxidative stress in thyroid cancer patients.

Methods: Patients with thyroid cancer (with and without genetic predisposition) were investigated. Study participants were treated in Limited Liability Company (LLC) "Oncology Scientific Research Center" (Tbilisi, Georgia). The study group was collected between 2020 and 2021. In patients' blood, the thyroid hormones content (free Triiodothyronine (fFT3), free Thyroxine (fFT4), bound Triiodothyronine (FT3), bound Thyroxine (FT4), Thyroid-stimulating hormone (TSH)), and oxidative stress intensity (total activity of non-enzymatic antioxidant system (TAA) and the lipid peroxidation product, malondialdehyde (MDA), content) were investigated.

Results: The difference in free and bound forms of T3 and T4 levels in the blood serum between patients with thyroid cancer (Group 2 and Group 3) and the control group (Group 1) was not statistically significant (F_1,2=0.5, p_1,2=0.8, F_1,3=2.31, p_1,3=0.16). In patients with thyroid cancer the TSH level significantly increased compared to the control group (Group 1) (TSH (mean ± Std error): Group 1- 1.21 ± 0.12, Group 2-2.45 ± 0.11 (F_1,2=107, p_1,2<0.001), Group 3-2.47 ± 0.17 (F_1,3=150, p_1,3<0.001)) and the MDA levels increased by 4-5 fold. In patients with thyroid cancer from families with cancer aggregation(Group 2), the level of TAA statistically significantly decreased (F_1 - 2=200; p_1 - 2<0.001), in patients without genetic predisposition to cancer(Group 3), the level of TAA did not change compared to the control (F_1 - 3= 2.13; p_1 - 3=0.15), CONCLUSIONS: Oxidative stress plays a critical role in tumorigenesis, and antioxidant/oxidant imbalance may contribute to the malignant transformation of normal tissue. In patients with familial susceptibility to cancer mutations of several genes, which are involved in the regulation of oxidative metabolism, may contribute to the disruption of the redox balance, increase the level of oxidative stress, and contribute to the development of thyroid cancer.

Background: The aim of the study was to test a universal screening strategy on endometrial cancer to evaluate its effectiveness to find Lynch Syndrome (LS) cases to two established clinical criteria: Amsterdam II criteria, and the revised Bethesda criteria to select cases for prescreening with immunohistochemistry (IHC). Cases were subsequently screened for germline disease causing variants regarding the DNA mismatch repair (MMR) genes.

Methods: IHC was performed on 221 endometrial cancer (EC) cases, using antibodies against the DNA mismatch repair proteins MLH1, PMS2, MSH2, and MSH6. MMR loss was found in 54 cases, and gene mutation screening was undertaken in 52 of those.

Results: In this set of patients, the use of Amsterdam II criteria detected two (0.9%), the Bethesda criteria two (0.9%), and universal testing five (2.3%) cases of LS. The combination of universal testing and family history criteria resulted in detection of five patients (2.3%) with LS.

Conclusions: Based on our results and other similar studies to date we propose a screening protocol for LS on EC tumors with prescreening using IHC for the four MMR proteins on all new EC cases diagnosed before 70 years of age, followed by mutation screening of all tumors with loss of MSH2 and/or MSH6 or only PMS2, plus consideration for mutation screening of all LS genes in cases fulfilling the clinical Amsterdam II criteria regardless of MMR status on IHC.

Background: Somatic mutations in the EGFR gene occur in about 50% of non-small cell lung cancers, with the T790M mutation significantly contributing to secondary resistance against EGFR-TKI drugs. However, EGFR T790M germline mutations rarely occur.

Case presentation: In this study, we report a case of a lung adenocarcinoma family lineage linked to a germline EGFR T790M mutation. The main subject was diagnosed with stage IV lung adenocarcinoma and experienced a 19-month period without disease progression while treated with Osimertinib. We collected both clinicopathological and familial data from a patient with lung adenocarcinoma. Next-generation sequencing of 40 key genes was performed on the proband's tumor tissue. To detect EGFR germline mutations, Sanger sequencing was conducted on peripheral blood mononuclear cells from the proband and his two daughters. Mutations such as EGFR T790M, EGFR 19-Del, TP53, and PIK3CA were identified in the proband's lung cancer tissue. Additionally, germline EGFR T790M mutations were confirmed in the proband and his daughters through sequencing of their peripheral blood samples. CT scans revealed multiple pulmonary nodules in both daughters.

Conclusions: These observations suggest that germline mutations in EGFR T790M could be strongly linked to a familial predisposition to lung cancer.

Background: Germline mutations in CDKN2A result in Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM) (OMIM #155,601), which is associated with an increased risk of pancreatic ductal adenocarcinoma and melanoma. FAMMM has been reported globally, but it is quite rare in Japan. We report two families with familial pancreatic cancer with suspected pathogenic variants of CDKN2A that were incidentally identified through comprehensive genomic profiling.

Case presentation: The first case is a 74-year-old woman with a diagnosis of pancreatic carcinoma with multiple liver metastases. She had family histories of pancreatic cancer, but no personal or family history of malignant melanoma. Whole exon sequencing detected a germline CDKN2A variant evaluated as likely pathogenic. The results were disclosed to her daughters after she died, and the same CDKN2A variant was detected in one of the daughter. The daughter was referred to a nearby hospital for her clinical management. The second case is a 65-year-old man with pancreatic ductal adenocarcinoma. He had family histories of pancreatic cancer, but no personal or family history of malignant melanoma. He underwent a comprehensive genomic profiling test using pancreatic cancer tissue, and detected a presumed germline pathogenic variant of CDKN2A. Germline testing confirmed the same CDKN2A variant. Genetic analysis of his relatives produced negative results. Other blood relatives are scheduled for genetic analysis in the future. We report two families with familial pancreatic cancer with suspected pathogenic variants of CDKN2A that were incidentally identified through comprehensive genomic profiling.

Conclusions: In current Japanese precision medicine, comprehensive genetic analysis can reveal rare genetic syndromes and offer us the opportunity to provide health management for patients and their relatives. However, gene-specific issues are raised in terms of the evaluation of a variant's pathogenicity and the extent of surveillance of the at-risk organs due to a lack of genetic and clinical data concerning CDKN2A variant carriers in Japan.