Hereditary Cancer in Clinical Practice最新文献

Background: BRCA2 germline mutations are known to predispose carriers to various cancer types, including breast, ovarian, pancreatic and prostate cancer. An association with melanoma has also been reported. However, the full tumour spectrum associated with BRCA2 mutations, particularly in patients with other concurrent pathogenetic mutations, is unexplored.

Case presentation: We present a 70-year-old female patient with a pathogenic BRCA2 c.5946del variant. Over a period of 15 years, she has developed two independent breast cancers, well-differentiated liposarcoma, clear cell renal cell carcinoma and myeloproliferative neoplasia. This unusual tumour spectrum and the staggered occurrence of these tumours required multiple rounds of genetic testing and led to a delayed diagnosis of the BRCA2-associated tumour predisposition. In addition to the BRCA2 mutation, extended germline testing revealed an APC c.3920T > A variant and variants of unknown significance in the BRIP1 and ATR genes. The molecular analysis of the tumours revealed distinct profiles with differences in HRD status and in copy number variations, indicating no common origin.

Conclusions: Our case study revealed that the pathogenic BRCA2 c.5946del germline variant can be associated with an unusual tumour spectrum, which may lead to a delayed diagnosis of a hereditary tumour predisposition. Thus, upfront genetic testing using large multigene panels or whole-genome sequencing in encouraged, especially in cases with a prominent family history.

Background: A complex inheritance has been suggested in families with colorectal-, gastric- and prostate cancer. Therefore, we conducted a genome-wide association study (GWAS) in colorectal cancer patients, who's relatives had prostate-, and/or gastric cancer.

Methods: The GWAS analysis consisted of 685 cases of colorectal cancer and 4780 healthy controls from Sweden. A sliding window haplotype analysis was conducted using a logistic regression model. Thereafter, we performed sequencing to find candidate variants, finally to be tested in a nested case-control study.

Results: Candidate loci/genes on ten chromosomal regions were suggested with odds ratios between 1.71-3.62 and p-values < 5 × 10-8 in the analysis. The regions suggested were 1q32.2, 3q29, 4q35.1, 4p15.31, 4q26, 8p23.1, 13q33.3, 13q13.3, 16q23.3 and 22q11.21. All regions, except one on 1q32.2, had protein coding genes, many already shown to be involved in cancer, such as ZDHHC19, SYNPO2, PCYT1A, MYO16, TXNRD2, COMT, and CDH13. Sequencing of DNA from 122 colorectal cancer patients with gastric- and/or prostate cancer in their families was performed to search for candidate variants in the haplotype regions. The identified candidate variants were tested in a nested case-control study of similar colorectal cancer cases and controls. There was some support for an increased risk of colorectal-, gastric-, and/or prostate cancer in all the six loci tested.

Conclusions: This study demonstrated a proof of principle strategy to identify risk variants found by GWAS, and identified ten candidate loci that could be associated with colorectal, gastric- and prostate cancer.

Genetic testing for breast cancer predisposing genes has expanded beyond BRCA1 and BRCA2 and now includes panels of 20 or more genes. It is now recommended that all women diagnosed with breast cancer at age 65 or below be offered testing for an extended gene panel. The rationale for testing includes personalizing the management of breast cancer according to the mutation found. For BRCA1 and BRCA2 carriers, the finding of a mutation has clear implications for cancer management, but for other genes, such as ATM, the management implications are less clear. Women with an ATM mutation have a lifetime risk of breast cancer of approximately 25%, the majority of which are ER-positive. The risk of ovarian cancer is approximately 5%. It is not yet clear how the identification of an ATM mutation in a patient newly diagnosed with breast cancer should impact on her treatment and follow-up. At present, these women are treated in the same way as women without a mutation. It is important that large prospective studies be conducted looking at various treatment modalities in women with breast cancer and an ATM mutation in order to optimize outcomes.

Background: Efficient and scalable solutions are needed to identify patients who qualify for germline cancer genetic testing. We evaluated the clinical validity of a brief, patient-administered hereditary cancer risk assessment digital tool programmed to assess if patients meet criteria for germline genetic testing, based on personal and family history, and in line with national guidelines.

Methods: We applied the tool to cases seen in a nationwide telehealth genetic counseling practice. Validity of the tool was evaluated by comparing the tool's assessment to that of the genetic counselor who saw the patient. Patients' histories were extracted from genetic counselor-collected pedigrees and input into the tool by the research team to model how a patient would complete the tool. We also validated the tool's assessment of which specific aspects of the personal and family history met criteria for genetic testing. Descriptive statistics were used.

Results: Of the 152 cases (80% female, mean age 52.3), 56% had a personal history of cancer and 66% met genetic testing criteria. The tool and genetic counselor agreed in 96% of cases. Most disagreements (4/6; 67%) occurred because the genetic counselor's assessment relied on details the tool was not programmed to collect since patients typically don't have access to the relevant information (pathology details, risk models). We also found complete agreement between the tool and research team on which specific aspects of the patient's history met criteria for genetic testing.

Conclusion: We observed a high level of agreement with genetic counselor assessments, affirming the tool's clinical validity in identifying individuals for hereditary cancer predisposition testing and its potential for increasing access to hereditary cancer risk assessment.

Background: To study BRCA1/2 gene variants in La Rioja in the northcentral area of Spain.

Methods: We performed a molecular analysis of BRCA1 and BRCA2 in 642 individuals from 427 different families from June 2008 to December 2019.

Results: We identified 71 families with pathogenic variants in these genes, 32 families with BRCA1 variants and 39 families with BRCA2 variants. The pathogenic variants c.959delG in BRCA1 and c.1363_1369delTCAGAGA, c.1397dupA, c.4234_4236delACTinsC and c.8387delC in BRCA2 have not been previously described. The c.81-2 A > T variant in BRCA1, detected in two unrelated families, has not been reported previously in the Spanish population. Two large genomic deletions were found in the BRCA1 gene in exons (Ex) 23-24 and Ex1A-1B-2, and one deletion was found in the BRCA2 gene in Ex2. The pathogenic variant c.5123 C > A in BRCA1 was detected in 8 unrelated families and was the most frequent pathogenic variant in our population. The c.6024dupG mutation in BRCA2 was detected in 6 unrelated families; the c.2808_2011delACAA mutation in BRCA2 was found in 5 different families; the c.211 A > G mutation in BRCA1 was found in three different families; and the c.68_69delAG, c81-2 A > T, c.4038_4039delAA, and c.5266dupC variants in BRCA1 and the c.2457delA, c.2701delC, c.5116_5119delAATA, c.6275delTT, c.7558 C > T and c.7617 + 1G > A variants in BRCA2 were found in two different families.

Conclusions: The spectrum of pathogenic variants in the BRCA1/2 genes in La Rioja is similar to that in other Spanish regions, with some unique characteristics. The pathogenic c.6024dupG variant in the BRCA2 gene was detected in a large number of families and could have a founding effect in the Ebro riverside areas in the regions of La Rioja and Navarra.

Trial registration: Not applicable.

More than 25 years ago, CDH1 pathogenic variants (PVs) were identified as the primary cause of hereditary diffuse gastric cancer (HDGC), an inherited cancer syndrome that increases the lifetime risk of developing diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Since DGC is associated with a poor prognosis, a prophylactic total gastrectomy (PTG) is currently the gold standard for reducing the risk of DGC in CDH1 PV carriers. However, as germline genetic testing becomes more widespread, many CDH1 PV carriers have been identified, including in families with lower penetrance levels or without a history of gastric cancer (GC). When including these families, recent findings suggest that the cumulative lifetime risk of developing advanced DGC is much lower than previously thought and is now estimated to be 13-19%. This lower risk, combined with the fact that around one third of the CDH1 PV carriers decline PTG due to potential lifelong physical and psychological consequences, raises critical questions about the current uniformity in recommending PTG to all CDH1 PV carriers. As a result, there is a growing need to consider alternative strategies, such as endoscopic surveillance. However, despite the currently lower estimated risk of infiltrative (advanced) DGC, almost every PTG specimen shows the presence of small low-stage (pT1a) signet ring cell (SRC) lesions of which the behaviour is unpredictable but often are considered indolent or premalignant stages of DGC. Therefore, the primary goal of surveillance should be to identify atypical, deeper infiltrating lesions rather than every SRC lesion. Understanding the progression from indolent to more infiltrative lesions, and recognizing their endoscopic and histological features, is crucial in deciding the most suitable management option for each individual.

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.