Familial Cancer最新文献

Since panel genetic testing has become widely available, national guidelines recommend that individuals who previously underwent BRCA1/2-only testing should undergo updated testing to include other hereditary breast and ovarian cancer predisposition genes. Our study assessed the yield of additional hereditary cancer predisposition testing in patients who previously underwent negative BRCA1/2 testing. Additionally, our study included a small pilot to evaluate whole exome sequencing in patients with a strong family history. Patients enrolled in a registry study who previously underwent negative BRCA1/2 testing were included and stratified into three categories based on personal and family cancer history-strongly suggestive, moderately suggestive, and possibly suggestive. Updated testing with a 36-gene pan-cancer panel was performed on most participants. A selected set of participants had whole exome sequencing. Patients with a pathogenic variant identified were offered clinical confirmatory testing. Rates of positive test results were compared among the three groups. Clinically relevant pathogenic variants in non-BRCA1/2 genes from the 36-gene panel test were identified in 8.1% of participants, most commonly in PALB2 (1.9%), ATM (1.2%), and MSH6 (1.2%). Positive findings were more common in patients with strongly suggestive history, but the differences were not statistically significant. Exome testing in individuals with a strongly suggestive personal and family history did not yield novel findings. Our findings aligned with previous studies and support the use of expanded gene panel testing in all patients meeting testing criteria who previously underwent negative BRCA1/2 testing. Our small pilot whole exome sequencing did not identify any novel finding.

Efficient use of genetic biobank data in support of clinical care would enhance the adoption of personalized medicine. Identification of carriers of medically actionable variants that predispose to cancer enables intensified screening and follow-up to decrease disease risk. Pathogenic variants of the MLH1 gene cause Lynch syndrome with a significant risk of developing cancer. Here, we introduce a novel approach for the large-scale screening of biobank SNP-array-based genotyping data to analyze copy-number variants (CNVs). With the method developed, we analyzed the Helsinki Biobank cohort of 121 073 samples and identified 29 MLH1 exon 16 deletion (MLH1∆Ex16) carriers, of which five (17%) had not been previously identified in healthcare. Our results demonstrate a high positive predictive value for the identification of MLH1∆Ex16 carriers from genotyping data. The cost-efficient method for detection of CNV carriers from large biobank genotyping cohorts described here facilitates intensified screening and follow-up aiming to cancer prevention.

Germline pathogenic variants (GPVs) in RB1 are associated with the pediatric-onset intra-ocular malignancy retinoblastoma and typically present in infancy as multi-focal or bilateral disease. Survivors of retinoblastoma are at high risk for developing subsequent malignant neoplasms (SMNs); indeed, these are the leading cause of death for individuals cured of their retinoblastoma. With the exception of sarcomas, typically occurring at the site of antecedent radiation therapy for the original retinoblastoma diagnosis, and melanoma, little is known of other SMNs in retinoblastoma survivors. Here, we describe a unique case of pancreatic adenocarcinoma (PDAC) in a patient with a RB1 GPV who was diagnosed with retinoblastoma as an infant. At age 57, he was diagnosed with PDAC. Sequence analysis of the PDAC revealed the acquisition of a somatic second-hit in RB1 in the PDAC. Multispectral immunofluorescence analyses of the PDAC tumor illustrated selective loss of the RB protein in the tumor that was accompanied by the continued expression of p16^ink4a, encoded by the CDKN2A gene. In PDAC, CDKN2A loss is a common early event that contributes to carcinogenesis. This case may suggest that PDAC is a rare late component of RB1-associated tumor predisposition and illustrates that biallelic loss of RB1 is an alternative mechanism by which the RB1-pathway can be disrupted in PDAC independent of CDKN2A inactivation.

Colorectal cancer can be prevented in most patients with FAP by performing (procto)colectomy and lifelong endoscopic surveillance. Subsequently, the challenge is to prevent duodenal and gastric cancer. Duodenal cancer is one of the most common FAP-related causes of death and, in the last decade, the incidence of gastric cancer has increased. Performing frequent endoscopic surveillance with removal of neoplasia is important to prevent cancer especially since cancers in the upper GI tract generally have a poor prognosis. Moreover, the goal is to prevent upper GI surgery as these procedures are associated with substantial morbidity. In this review, we provide the prevalence of upper GI polyposis and cancer, describe endoscopic and histologic features, and discuss strategies for surveillance and treatment.

Germline (likely-)pathogenic variants (PV) in CDH1 predispose carriers to hereditary diffuse gastric cancer and lobular breast cancer. Previous studies from the United States suggest CDH1 variant carriers have an increased risk for adenomas or sessile serrated lesions (SSL), yet data linking CDH1 PVs and colorectal neoplasia are scarce. We aimed to investigate colonoscopy findings in CDH1 PVs. Adults carrying a PV/LPV in CDH1 with ≥ 1 colonoscopy between 01/01/2004-12/31/2023 were included. Patients were sourced from the David G. Jagelman Inherited Colorectal Cancer Registries at Cleveland Clinic and the German Consortium for Familial Intestinal Cancer. 103 CDH1 PV carriers were included. Most were female (66%) and white (93.1%). The median age at first colonoscopy was 47 years. The adenoma detection rate (ADR) was 29.4% (95% CI:19.9-41.1%) in the German cohort and 48.6% (95% CI: 33.0-64.4%) in the Cleveland cohort (p = 0.055) and significantly correlated with age (< 45 years, 13.6% (95% CI: 6.40-26.7%); 45-49 years, 52.4% (95% CI: 32.4-71.7%); ≥50 years, 52.6% (95% CI: 37.3-67.5%); p < 0.001). The ADR in Cleveland was higher than the U.S. average ADR but the difference was not statistically significant (48.6% vs. 35.6%, p = 0.08), and the ADR in the German cohort (29.4%) was similar to the national German average risk screening cohort (31.3% in men, p = 0.84; 20.1% in women, p = 0.08). In our screening cohort with CDH1 PV carriers, we demonstrated an ADR of 13.5% in individuals under 45 years, similar to the ADR in patients aged 25-40 years with a family history of CRC. Overall, SSL detection rate was 9.7%. Colorectal cancer was diagnosed in 3 patients (3.2%), 2/3 with an early age of onset before the age of 50 years. This first international study provides preliminary evidence of a higher ADR in U.S. CDH1 PV carriers compared to the general population, with a high number of adenomas detected before the age of 50. This may indicate an increased CRC risk that should be explored in larger studies.

Identification of somatic and germline BRCA1/2 pathogenic variants in epithelial ovarian cancer (EOC) patients is essential for determining poly-(ADP-ribose)-polymerase (PARP) inhibitor sensitivity and genetic predisposition. In the Netherlands, BRCA1/2 testing changed to a tumor-first approach to efficiently identify both somatic and germline pathogenic variants in all patients. Here, we performed an in-depth evaluation of the first four years of the tumor-first test-pathway. Data of consecutive series of patients diagnosed with EOC in two regions were obtained from the Netherlands Cancer Registry. Tumor and/or germline test data were retrieved from hospital databases. The primary outcome was the percentage of patients completing the BRCA1/2 test-pathway, defined as having a negative tumor test or a referral for a germline test in case of a positive tumor test or no tumor test. Factors associated with test-pathway completion were identified through multivariable logistic regression analysis. In total, 69.8% (757/1085) completed the test-pathway. This was 74.4% in the most recent year. Younger patients, patients diagnosed in year three or four, patients with high-grade serous/high-grade endometrioid carcinoma, advanced stage disease, middle or high socioeconomic status, and patients who underwent surgery or chemotherapy, were more likely to complete the test-pathway. We report inequalities in genetic testing access in EOC patients, which highlight the need for better guideline adherence, particularly in older patients, those with low socioeconomic status, low-grade histotypes, early-stage disease and those without surgery or chemotherapy. Additionally, timely testing of patients, and testing relatives if patients cannot be tested, are crucial to increase test uptake.

Background: Female patients with Peutz-Jeghers syndrome (PJS) have an increased risk of breast cancer (BrCa), and surveillance is recommended. However, clinicopathological features of their tumors and prognosis are lacking. To facilitate more precise future guideline development, we evaluated these data.

Methods: We conducted an international survey for InSiGHT members to collect retrospective data on PJS patients with diagnosed breast cancer.

Results: We received 23 responses, including three centers with data on BrCa patients. All reported BrCa patients were female. In total, the cohort comprised 27 patients with 34 BrCa (five bilateral synchronous, one bilateral metachronous, and one metachronous unilateral tumours). The median age at first cancer diagnosis was 45 years (range 26-67). Most cancers were ductal carcinoma, either invasive (13) or in situ (DCIS; 19). TNM staging for invasive cancer was available in thirteen cases, of which nine were T1N0M0. Among tumors with histological reports, 14/15 were oestrogen receptor positive, 8/15 were progesterone receptor positive, and 4/15 were HER2 positive. There were no triple negative breast cancers. Twenty-five patients had follow-up data, comprising 229 patient years. Eleven patients had died of any cause during follow-up. Survival at 5 years was 73%.

Conclusion: Overall, breast cancers that occur in this PJS population seem to have favorable characteristics and prognosis. These data will help inform discussions about risk management in patients with PJS. Further research is needed to better understand lifetime risk, the optimal surveillance modality and its outcomes.

In patients with Familial Adenomatous Polyposis (FAP), large desmoid tumors can develop all over the body. However, the most frequent presentation is as large intra-abdominal masses, usually located in the mesentery of the small bowel. From there, they tend to grow and invade both the abdominal wall and/or the retroperitoneal structures. This can cause life-threatening complications such as recurrent abdominal sepsis with fistulation and damage to vital organs. In selected patients, the only option may be radical resection and replacement by intestinal transplantation (ITx). We aimed to review all the current literature on ITx for FAP-related desmoids and provide an update from the largest single-center experience (2007-2024). All patients undergoing ITx for FAP-related desmoid were included. Between 2007 and 2024, 166 ITx was performed in 158 patients at Addenbrooke's Hospital, Cambridge, UK. Of these, 20 (12%) were for desmoid associated with FAP (10 modified multivisceral transplants, 8 isolated ITx and 2 liver-containing grafts). The five-year all-cause patient survival was 92%, median follow-up was 4.3 years. As the patients presented with very advanced disease, many technical challenges were faced such as: extensive ureteric involvement, abdominal wall fistulation, management of previously formed ileo-anal pouches and extra-abdominal recurrences. Graft selection was another evolving issue, as foregut resection- versus sparing techniques require careful preoperative risk stratification due to increased long-term cancer risk in FAP patients. For certain patients with advanced FAP/desmoid disease, ITx can allow for a radical resection with excellent survival and functional outcomes. However, there is a high degree of initial morbidity associated with the operation and patients should be appropriately counselled. Graft selection and degree of native organ resection requires a careful balanced discussion.

Interpreting variants of uncertain significance (VUS) in mismatch repair (MMR) genes remains a major challenge in managing Lynch syndrome and other hereditary cancer syndromes. This review outlines recommended VUS classification procedures, encompassing foundational and specialized methodologies tailored for MMR genes by expert organizations, including InSiGHT and ClinGen's Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP). Key approaches include: (1) functional data, encompassing direct assays measuring MMR proficiency such as in vitro MMR assays, deep mutational scanning, and MMR cell-based assays, as well as techniques like methylation-tolerant assays, proteomic-based approaches, and RNA sequencing, all of which provide critical functional evidence supporting variant pathogenicity; (2) computational data/tools, including in silico meta-predictors and models, which contribute to robust VUS classification when integrated with experimental evidence; and (3) enhanced variant detection to identify the actual causal variant through whole-genome sequencing and long-read sequencing to detect pathogenic variants missed by traditional methods. These strategies improve diagnostic precision, support clinical decision-making for Lynch syndrome, and establish a flexible framework that can be applied to other OMIM-listed genes.