Hereditary Cancer in Clinical Practice最新文献

Background: Hereditary breast and ovarian cancer (HBOC) confers a markedly increased lifetime risk of breast and ovarian cancers. As no effective surveillance method for early detection of ovarian cancer has been established, risk-reducing salpingo-oophorectomy (RRSO) is recommended for patients with HBOC to prevent disease onset. We evaluated the clinical characteristics of patients with HBOC and the surgical outcomes of RRSO performed at our institution.

Methods: We retrospectively reviewed women diagnosed with HBOC at our institution between 2018 and 2024. For analyses of surgical outcomes, male patients, patients with prior bilateral adnexectomy, and patients diagnosed with HBOC who did not undergo RRSO were excluded. Clinical data including patient characteristics, surgical procedures, genetic testing, and pathological findings were assessed.

Results: A total of 283 women were diagnosed with HBOC, and 43 (15.1%) underwent testing based on the results of affected relatives. After excluding 39 patients with prior bilateral adnexectomy, and 105 who did not undergo RRSO, 139 patients were included in the surgical analysis. The uptake rate of RRSO among female patients with HBOC was 57%. The median age at surgery was 50 years (range, 35-75). Pathogenic BRCA1 variants were identified in 48 patients (34.5%), BRCA2 variants in 90 (64.7%), and both BRCA1 and BRCA2 variants in 1 (0.7%). A history of malignancy was observed in 121 patients (breast cancer, n = 121; pancreatic cancer, n = 1; ovarian cancer, n = 1; others, n = 3). Laparoscopic RRSO was performed in 138 cases, with one additional hysterectomy performed laparoscopically and one via laparotomy. No perioperative complications were observed. All 6 cases before April 2020 were performed outside insurance coverage; after insurance coverage was initiated in April 2020, 16 were non-covered and 117 were covered by insurance. Pathological examination revealed occult high-grade serous carcinoma in 4 patients (2.9%) and serous tubal intraepithelial carcinoma in 5 patients (3.6%). To date, no cases of primary peritoneal carcinoma following RRSO have been identified.

Conclusions: RRSO was performed safely at our institution, with the detection rate of intraepithelial and invasive carcinoma comparable to previous reports. Although no cases of primary peritoneal carcinoma have been observed postoperatively to date, the residual risk remains, indicating the need for continued long-term surveillance.

Background: Cancer family syndromes can predispose to malignancies of different sites, including brain and spinal tumours. Germline mutations associated with a high risk of cancer can also be found in patients with metastatic tumours of the brain. We present a few such cases, underscoring the importance of DNA germline testing in all primary and metastatic brain tumours.

Case presentations: We report four cases illustrating the role of DNA testing in intervention decisions in families of patients with both primary and secondary brain tumours. In this article, we included a case of Li-Fraumeni, Lynch, and von Hippel-Lindau syndromes, as well as a metastatic widespread example of BRCA1-related ovarian cancer.

Conclusions: In all primary and metastatic brain tumours, genetic testing for germline mutations of high-risk cancers should be considered.

Objective: To identify predictors of decisional conflict among women with a BRCA pathogenic variant (PV) who were eligible for risk reducing salpingo-oophorectomy (RRSO) who had not made a decision to have surgery at least one year after receiving genetic test results.

Methods: Women with a BRCA1 or BRCA2 PV between the ages of 35 and 70 years old, who had not elected for RRSO at least 12 months after receipt of genetic test results, were administered self-report questionnaires investigating demographic variables, decisional conflict (Decisional Conflict Scale), cancer-related distress (Impact of Event Scale) and cancer risk perception. Decisional conflict scores were generated and a multivariable linear regression was conducted to identify variables associated with decisional conflict.

Results: A sample of 107 women completed questionnaires. Overall, 44 participants (41%) had a high decisional conflict score (greater than 37.5) related to the RRSO decision. Higher education (β = 11.40, 95% C.I: 0.59, 22.20; p = 0.039), non-white race (β = 11.12, 95% C.I: 0.66, 21.57; p = 0.037), and having children (β = 22.89, 95% C.I: 10.07, 35.71; p < 0.001) were significantly associated with higher decisional conflict. Lower decisional conflict was significantly associated with genetic testing more than 3 years prior (β = -13.14, 95% C.I: -23.27, -2.99; p = 0.012).

Conclusions: Many women with a BRCA PV who have not elected for RRSO are experiencing high levels of decisional conflict related to the decision regarding RRSO. Interventions that target decisional conflict are needed to increase the uptake of RRSO which will result in a reduction of the risk of ovarian cancer in women with BRCA1 or BRCA2 PV.

Hereditary cancer syndromes are genetic conditions that increase an individual's risk for multiple cancer types, often due to mutations that affect critical cellular processes such as DNA repair and cell cycle regulation. Skin cancers, including malignant melanoma (MM), basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and related precancerous lesions may be underrecognized in some hereditary cancer syndromes, as suggested by underlying biological mechanisms and their underreporting in studies. In this narrative review, we examine the skin cancer risks associated with the most prevalent hereditary cancer syndromes, including Li-Fraumeni syndrome (LFS), Lynch syndrome (LS), hereditary breast and ovarian cancer syndrome (HBOC), ATM-associated hereditary cancer syndrome, CHEK2-associated hereditary cancer syndrome, BRIP1-associated cancer predisposition, and hereditary leiomyomatosis and renal cell carcinoma (HLRCC). This review consolidates existing evidence and suggests that mixed cancer syndromes, especially LFS, LS, and HBOC but also pathogenic ATM and CHEK2 variants may predispose individuals to skin cancers, warranting tailored screening and preventive measures. On the basis of emerging evidence, we recommend dermatologic evaluation and individualized UV protection strategies for patients with reviewed hereditary cancer syndromes to reduce skin cancer risk and enhance early detection.

Background: Neurofibromatosis type 1 (NF1; 613113) is a hereditary neurocutaneous disorder that causes tumors in the nervous system, significantly impacting the quality of life (QoL). It is characterized by diverse clinical manifestations, including café-au-lait macules (CALMs), axillary or inguinal freckling, Lisch nodules, skeletal abnormalities, and various types of neurofibromas. Plexiform neurofibromas (PN), a common complication of NF1, are often inoperable and prone to recurrence. The study aimed to describe the clinical characteristics and healthcare burden of NF1, including those with PN and those receiving Selumetinib therapy, in Saudi Arabia.

Methods: This retrospective observational study was conducted at the National Guard Health Affairs King Abdulaziz Medical City in Saudi Arabia. Patient medical records were retrospectively reviewed from January 2016 to January 2024. We included all patients diagnosed with NF1 who fulfilled the National Institutes of Health (NIH) diagnostic criteria in 2021 or had a confirmed pathogenic NF1 variant on genetic testing.

Results: A total of 60 patients with NF1 were included; 55.2% of them were females. CALMs were the most common cardinal criteria, affecting 80% of the patients. Among NF1 patients, 12 had PN (20%). Only four patients received Selumetinib therapy. Genetic testing was performed in 39 patients, revealing pathogenic NF1 variants in 29 (74.4%). Pain medications were used by eight patients (13.3%). NF-1-related pain negatively impacted patients' attention (24%), outdoor activities (24%), and social interactions with friends (20%). Among NF1 patients, 28 (46.7%) required hospitalization, twelve ER visits were conducted by seven (11.7%) NF1 patients, and outpatient services were utilized by nearly all NF1 patients (96.7%), with 1076 outpatient visits. The overall financial burden was high, with NF1 patients incurring $64.5 million, PN patients $13.5 million, and PN patients treated with Selumetinib $3.7 million.

Conclusion: This study highlights the clinical and healthcare challenges of NF1 and PN in Saudi Arabia, emphasizing the need for a multidisciplinary approach that combines medical, psychological, and financial support. The limited access to Selumetinib represents a gap. Increasing treatment accessibility and financial support are key to improving the outcomes and QoL.

Background: Colorectal cancer (CRC) is the fourth most common cancer in Pakistan and poses significant public health challenges. While the majority of CRC cases are sporadic, ~ 5-10% are hereditary, linked to germline pathogenic variants (PVs) in mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and other susceptibility genes (APC, EPCAM). In Pakistan, small-range PVs in MLH1 and MSH2 account for 34.5% of hereditary nonpolyposis colorectal cancer (HNPCC)/suspected-HNPCC and 1.1% of non-HNPCC cases. However, the contribution of large genomic rearrangements (LGRs) in MLH1, MSH2, MSH6, and the 3' end of EPCAM remains uncharacterized.

Methods: We comprehensively screened 199 Pakistani CRC patients (HNPCC/suspected-HNPCC:18 and non-HNPCC:181), previously tested negative for small-range PVs in MMR genes. LGRs in MLH1, MSH2, MSH6, and the 3' end of EPCAM were analyzed using multiplex ligation-dependent probe amplification (MLPA). Deletion breakpoints were characterized using long-range polymerase chain reaction (PCR) and Sanger sequencing.

Results: Five distinct MSH2 deletions (5' upstream, exons 1-3, exons 1-6, exon 7, and exon 11) were identified in 11.1% (2/18) of HNPCC/suspected-HNPCC and 3.3% (6/181) of non-HNPCC cases. A recurrent 5' upstream deletion was identified in four unrelated patients, including one suspected-HNPCC and three non-HNPCC cases. Other deletions were identified in patients with variable family histories of cancer. No LGRs were detected in MLH1, MSH6, or the 3' end of EPCAM. Notably, 87.5% of patients with MSH2 LGRs belonged to Punjabi ethnicity.

Conclusions: Our findings demonstrate that MSH2 LGRs occur at a notable frequency among Pakistani CRC patients, with a recurrent 5' upstream deletion representing a potential Punjabi founder variant. Inclusion of this deletion into targeted genetic testing panels may enhance diagnostic yield and improve risk stratification for CRC in Pakistan.