Familial Cancer最新文献

Purpose: Management of cancer risks associated with the CHEK2 gene, a moderate penetrance breast cancer gene, is challenging in real-world practice. Family history, traditional breast cancer risk factors, and specific genetic CHEK2 variants are risk modifiers in this setting and add complexity for surveillance and risk-reduction decisions. Here, we present a case series of Brazilian CHEK2 carriers affected by breast cancer.

Methods: Patients evaluated in the Oncogenetics Department of Hospital Sírio-Libanês (Brasília, Brazil) between November 2017 and September 2021, who had a personal history of breast cancer and a germline genetic test with a pathogenic or likely pathogenic CHEK2 variant, were selected for case description. Clinical pearls and knowledge gaps were highlighted for each case.

Results: Twelve women were included in this descriptive analysis. All patients had early-stage breast cancer. Most of them were diagnosed with breast cancer prior to age 50 (9/12) and had a close relative affected by breast cancer (9/12). Seven patients harbored intronic pathogenic variants. Clinical pearls included the following: lack of risk estimates for intronic CHEK2 variants among non-European ancestry CHEK2 carriers, environmental exposures as a risk modifier, notable non-breast cancer diagnosis at young ages, incidental germline finding during tumor profiling, breast cancer diagnosis before the recommended age of breast cancer screening, family history of breast cancer as a risk modifier, and clinical outcomes after breast cancer treatment.

Conclusions: Improvements in cancer risk assessment and cancer prevention for CHEK2 carriers are still needed to overcome current clinical challenges on the management of these patients.

PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal dominant disorder characterized by high penetrance and significant phenotypic variability. In most patients, targeted high-throughput sequencing (HTS) approaches enable the detection of loss-of-function pathogenic variants in PTEN, a tumor suppressor gene acting as a negative regulator of the PI3K-AKT pathway. We describe a patient exhibiting a clinical phenotype strongly indicative of PHTS, yet lacking a molecular diagnosis through PTEN-targeted HTS. After several years of diagnostic uncertainty, trio whole genome sequencing (WGS) ultimately identified a de novo germline deep intronic 98 bp deletion in PTEN intron 5 (c.492 + 1671_492 + 1768del). Targeted RNA sequencing revealed the inclusion of a pseudoexon, resulting in a frameshift and predicted protein truncation at codon 171 (p.Val166Asnfs*6). These data underline the importance of WGS approaches in detecting deep intronic structural variants, that may be overlooked by conventional methods.

Germline pathogenic variants of the RPS20 (ribosomal protein S20) gene are suspected to be involved in the predisposition to familial colorectal cancer (CRC) with no DNA mismatch repair deficiency. RPS20 pathogenic variants are very rare with only five reported cases in the literature. We report in this work the retrospective germline analysis of RPS20 for 1035 consecutive patients with a personal and/or familial history suggestive of hereditary predisposition to CRC. Within this series, a pathogenic variant in known CRC genes was found in 15% of cases and we describe one RPS20 loss-of-function variant (NM_001146227.1:c.115_116del, p.(Leu39Aspfs*33)). This frameshift is the first reported de novo variant in CRC, it was identified in in a female patient diagnosed with rectal cancer at the age of 35, 11 adenomatous polyps in 5 years and breast cancer at the age of 43. RPS20 has an intriguing role in oncogenesis, acting as an oncogene or tumour suppressor depending on the context, and is also involved in Diamond-Blackfan anemia via gain of function or dominant negative variants. This is therefore a complex gene for genetic counselling and, given the rarity of RPS20 pathogenic variants, we emphasise the need to collect data to clarify the phenotypic spectrum of RPS20-associated cancers and thus improve management.

Germline variants in RUNX1 and DDX41 are well-established contributors to hereditary myeloid neoplasms and are increasingly recognized as critical predisposing factors in the developing myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). This case report details a 51-year-old male diagnosed with MDS with excess blasts-1 (MDS-EB1), who harbored a rare combination of pathogenic germline variants in RUNX1 and a novel potentially pathogenic variant in DDX41 variant, alongside a somatic DDX41 mutation. The coexistence of these germline variants highlights the genetic complexity underlying hereditary myeloid neoplasms and reinforces the necessity of comprehensive genomic testing to ensure accurate diagnosis and informed clinical management. The interplay between RUNX1 and DDX41 variants may drive leukemogenesis, with the germline RUNX1 variant potentially fostering a cellular environment that enables the acquisition of somatic DDX41 mutations, leading to hematological malignancies. Conversely, the germline DDX41 variant may disrupt hematopoiesis and, when combined with RUNX1 dysfunction, contribute to disease progression. This case underscores the importance of screening germline variants in patients with myeloid neoplasms. It emphasizes the need to confirm the origin of these variants in non-hematopoietic tissues, such as fibroblasts (gold standard), to avoid misinterpretation caused by clonal hematopoiesis. Further research is warranted to elucidate the molecular mechanisms driving the interaction between RUNX1 and DDX41 variants and their collective impact on disease progression, treatment outcomes, and familial risk.

Familial adenomatous polyposis is an inherited genetic disorder responsible for multiple anomalies. Lifelong surveillance protocols are essential to detect and prevent adverse developments. However, limited data exist regarding the long-term feasibility of such programs. This study aims to evaluate the compliance with a surveillance program for patients with familial adenomatous polyposis. The study collated data from all patients who underwent surgery between January 1981 and December 1993, excluding non-French residents. Recorded characteristics included medical history, follow-up results, the indications for operations or other procedures, outcomes of these interventions, and patient status at the end of the follow-up period. One hundred and sixty-four patients were enrolled, comprising 86 females (52.4%). The median age at the time of colorectal resection was 29.6 years [10-67]. Thirty-six (22.0%) were diagnosed with cancer at the time of their surgery. Fifty-eight patients (35.3%) passed away at a median age of 52 years [18-95]. During the follow-up period, 47 patients developed duodenal or reservoir adenomas requiring invasive procedures, or desmoid tumors necessitating treatment. After a possible 30 years of follow-up, 49 survivors (46.2%) are still under observation, while 57 (53.8%) have been lost to follow-up. After 30 years of follow-up, the survival rate was 74.2% for patients who remained under observation, but only 58.2% for those lost to follow-up. Long-term follow-up of patients with familial adenomatous polyposis is associated with a high rate of loss to follow-up. However, those who remain under observation maintain an excellent prognosis. Understanding the reasons for loss to follow-up is challenging but may help in reducing this high attrition rate.

Perivascular epithelioid cell tumors (PEComas) belong to a family of rare mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. Li-Fraumeni syndrome (LFS), an autosomal dominant cancer predisposition syndrome, is caused by a germline variant of the tumor suppressor gene TP53. Here, we report the case of a 20-year-old woman with LFS who developed a PEComa of the liver. She was suspected to have LFS because she had developed osteosarcoma (OS) of the femur along with a concurrent transitional liver cell tumor in the right liver lobe at the age of 8 years. She also tested positive for the germline TP53 missense variant c.722 C > T (p.Ser241Phe). She concurrently experienced recurrence of OS and a new-onset liver tumor at the age of 20 years. Thereafter, microwave ablation was performed for the liver tumor because the Magnetic resonance imaging features suggested that the tumor was a hepatocellular carcinoma. Post-ablation biopsy showed that the tumor cells were spindle-shaped and possessed eosinophilic cytoplasm. Immunohistochemistry revealed that the tumor cells expressed HMB45 and focal alpha-smooth muscle actin. Labeling for S100 protein and cytokeratin-AE1/AE3 yielded negative results. Therefore, a diagnosis of PEComa of the liver was made. Among the ten PEComas reported in patients with Li-Fraumeni syndrome so far, all PEComas except the current case were surgically resected, and no cases of recurrence were documented in the follow-up period. Six of the ten PEComas were located in the liver. We think that the possibility of PEComa should be considered when a liver tumor develops in patients with LFS.

Multiple endocrine neoplasia type 1 (MEN1) syndrome is an autosomal dominant disorder caused by a germline pathogenic variant in the MEN1 tumor suppressor gene. Patients with MEN1 have a high risk for primary hyperparathyroidism (PHPT) with a penetrance of nearly 100%, pituitary adenomas (PitAd) in 40% of patients, and neuroendocrine neoplasms (NEN) of the pancreas (40% of patients), duodenum, lung, and thymus. Increased MEN1-related mortality is mainly related to duodenal-pancreatic and thymic NEN. Management of PHPT differs from that of patients with sporadic disease, as the surgical approach in MEN1-related PHPT includes near-total or total parathyroidectomy because of multigland hyperplasia in most patients and the consequent high risk of recurrence. NEN management also differs from patients with sporadic disease due to multiple synchronous and metasynchronous neoplasms. In addition, the lifelong risk of developing NEN requires special considerations to avoid excessive surgeries and to minimize damage to the patient's function and well-being. This progress report will outline current insights into surveillance and management of the major clinical manifestation of MEN1 syndrome in children and adults with MEN1 diagnosis. In addition, we will discuss MEN1-like clinical presentation with negative MEN1-genetic workup and future clinical and research directions.

Several extra-colonic manifestations, including duodenal polyposis and desmoid tumors, are well-described manifestations in familial adenomatous polyposis (FAP). More recently, an increase in gastric cancer diagnoses has been observed in FAP. This case series presents nine patients with FAP who were diagnosed with gastric cancer at our FAP expertise center, of whom eight were diagnosed between 2017 and 2023, while before 2017 the only diagnosis of gastric cancer was in 2001. Among the nine cases of gastric cancer, seven were located in the proximal stomach amidst carpeting fundic gland polyposis and two were located in the distal stomach. Despite ongoing advances in endoscopic technology, all patients were diagnosed during regular endoscopic surveillance, and six of the nine patients died within two years. We aim to raise awareness on gastric cancer risk in FAP patients and stress the urgent need of improved gastric surveillance strategies with timely detection of gastric cancer precursors.