Familial Cancer最新文献

While universal tumor testing for Lynch Syndrome (LS) is recommended in all new diagnoses of colorectal cancer (CC) and endometrial cancer (EC), the cost and availability of this test in low-resource settings poses challenges. The PREdiction Model for gene Mutations (PREMM₅) is a clinical algorithm designed to assess the risk of an individual carrying estimates one's risk of carrying a LS mutation. This study aims to assess the feasibility of using PREMM₅ to screen for LS risk in Guatemala. This cross-sectional pilot study enrolled 50 patients with colorectal or endometrial cancer receiving treatment at LIGA-INCAN, a cancer hospital in Guatemala City, between June 2022-July 2022. Patients were contacted by phone and administered the PREMM₅ survey, followed by an additional feasibility questionnaire. Of the 50 participants, 62% of patients had a PREMM₅ predicted probability of ≥ 2.5%, the threshold above which genetic testing is recommended. Almost all patients found the survey easy to complete (98%), were able to easily recall personal (90%) and family (88%) medical history, understood its purpose (94%), and reported an interest in (96%) and ability to (98%) act on the results if applicable. Our study shows the role of the PREMM₅ as a feasible tool for identifying individuals at risk of carrying mutations associated with LS in this low-resource setting. By implementing the PREMM₅ model, high risk individuals can be identified early, enabling timely interventions and improving outcomes in this at-risk population.

Germline genomic sequencing is increasingly integrated into pediatric cancer care, with pathogenic cancer-predisposing variants identified among 5-18% of affected children and variants of uncertain significance (VUS) in up to 70%. Given the potential medical implications for children and their families, parents' psychosocial responses to learning results are important to understand. Parents of children with cancer who learned their children's germline pathogenic or VUS results following paired tumor and germline genomic sequencing described their cognitive and affective responses to results in an open-ended write-in question after disclosure (M = 10 months post-disclosure; range = 1-28). Responses were coded and categorized using content analysis, then compared across results using chi-square and Fisher's exact test. Parents of children with pathogenic (n = 9), VUS (n = 52), and pathogenic plus VUS results (n = 9) described negative emotions, positive reactions, mixed emotions (i.e., positive and negative emotions), and neutral reactions. Negative emotions were described significantly more frequently with pathogenic results than VUS only (χ² = 5.19; p = .02), with peace of mind and empowerment only described for those with VUS. Parents also described approach(es) to coping (e.g., faith, plan of action) and reactions specific to the uncertainty of VUS (e.g., disappointment at no explanation for cancer etiology). A subset with VUS described decreasing worry/distress with increased understanding of results, whereas others displayed misconceptions regarding VUS. Screening for emotional adjustment is warranted for parents of children with cancer receiving pathogenic germline results, and screening for understanding is warranted with VUS. Findings highlight the importance of pre-and posttest genetic counseling.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline pathogenic/likely pathogenic variants in TP53. Genotype-phenotype correlations are progressively being characterized in LFS with certain TP53 variants associated with attenuated penetrance and phenotypes. We report on a family harboring a TP53 p.R181H variant presenting with a restricted cancer phenotype in adulthood. The proband was a female with breast cancer at the age of 71 years who had three first degree relatives also diagnosed with breast cancer after the age of 40 years (mother, two sisters). Of the nine individuals harboring the variant (6 genetically confirmed, 3 obligate heterozygous), six have not developed malignancies at this time (age range: 36–42). No childhood-onset cancers were reported in this family. A concomitant literature review identified 51 additional individuals harboring the p.R181H variant in TP53, presenting a tumor phenotype dominated by breast cancer. Rare occurrences of other adult-onset cancers (prostate, colorectal and thyroid) and only few childhood onset cancer were documented. These observations are consistent with functional analysis showing that p.R181H retains partial p53 function and suggesting possible reduced cancer penetrance, particularly in the pediatric setting.

To determine the preoperative detection of signet ring cancer cells (SRC) on upper endoscopy (EGD) in patients with CDH1 pathogenic variant (PV) undergoing gastrectomy. To evaluate the development of advanced diffuse gastric cancer (DGC) in patients choosing surveillance. Guidelines recommend prophylactic total gastrectomy (pTG) in CDH1 PV carriers with family history of DGC between 18 and 40 years. Annual EGD with biopsies according to established protocols is recommended in carriers with no SRC and no family history of DGC, with consideration of pTG. Retrospective analysis of asymptomatic patients with CDH1 PVs with ≥ 1 surveillance EGD. Outcomes included pre-operative EGD detection of SRC, surgical stage, and progression to advanced DGC in those electing surveillance with EGD. 48 patients with CDH1 PVs who had ≥ 1 EGD were included. 24/ 48 (50%) underwent gastrectomy, including pTG in 7 patients. SRCC were detected on gastrectomy specimen in 21/24 (87.5%). SRCs were identified by EGD in 17/21 patients who had SRCC on gastrectomy specimens (sensitivity 81%, 17/21). All cancers were stage pT1a. The remaining 17 patients (50% with a family history of gastric cancer) continue in annual EGD surveillance with a median follow-up of 34.6 months. No SRCC or advanced DGC have been diagnosed. No CDH1 PV carriers without SRCC on random biopsies followed in an endoscopic program developed advanced DGC over a median follow up of 3 years. In the short term, EGD surveillance might be a safe alternative to immediate pTG in experienced hands in referral centers.

Bloom syndrome (BS) is a rare genetic disorder caused by biallelic inactivation of the BLM gene, which usually manifests in childhood by significant growth retardation, immune deficiency, characteristic skin lesions, cancer predisposition and other distinguishable disease features. To our knowledge, all prior instances of BS have been identified via intentional analysis of patients with clinical suspicion for this disease or DNA testing of members of affected pedigrees. We describe an incidental finding of BS, which occurred upon routine germline DNA analysis of consecutive breast cancer patients. The person with the biallelic pathogenic BLM c.1642C>T (p.Gln548Ter) variant remained clinically healthy for 38 years until she developed breast cancer. Detailed examination of this woman, which was carried out after the genetic diagnosis, revealed mild features of BS. A sister chromatid exchange (SCE) test confirmed the presence of this syndrome. The tumor exhibited triple-negative receptor status, a high proliferation rate, a low tumor mutation burden (TMB), and a moderate level of chromosomal instability (homologous recombination deficiency (HRD) score = 29). The patient showed normal tolerability to radiotherapy and several regimens of cytotoxic therapy. Thus, some BS patients may remain undiagnosed due to the mild phenotype of their disease. BLM should be incorporated in gene panels utilized for germline DNA testing of cancer patients.

Non-small cell lung cancer is the most common cause of cancer death globally. When apparent incidental pathogenic germline variants (PGVs) are uncovered with routine next generation sequencing (NGS) of NSCLCs, germline testing (GT) is recommended to confirm that PGV. Because it is far more common that an uncovered tumor TP53 variant is related to a somatic event than an incidental PGV, however, GT for Li Fraumeni syndrome (LFS) is not recommended based solely on uncovering a NSCLC TP53 variant. Because nearly all tumor EGFR variants are also somatic in origin, GT is not recommended based solely on uncovering a tumor EGFR variant.However, there is evidence that patients with coexisting NSCLC variants in both EGFR and TP53 have significant likelihoods of having LFS. For patients with LFS, there are recommended measures for prevention and early detection of LFS-associated cancers and cascade GT of relatives for LFS. Although co-existing genetic variants in NSCLC are not currently used as a biomarker for GT to identify patients with PGVs, given the evidence reviewed here, select patients with NSCLCs that harbor this dual biomarker (i.e., co-existing TP53/EGFR variants) might reasonably be considered for GT for LFS.

Background and study aims: Lynch syndrome (LS) is a hereditary autosomal dominant condition, with an increased lifetime risk of developing malignancies including colorectal cancer (CRC). Current guidelines differ in recommended colonoscopy-surveillance intervals from 1 to 2 years. Although colonoscopy is considered a safe procedure, there are risks of severe adverse events (SAEs), such as perforation and bleeding, as well as adverse events (AEs), such as abdominal discomfort and post-colonoscopy gastrointestinal infections. Colonoscopy-related bleeding and perforation rates have been reported 0.17% and 0.11%, respectively. However, there are insufficient data regarding complications of colonoscopy-surveillance for LS patients. This study aims to investigate the risk of AEs among LS patients during colonoscopy in the Stockholm region.

Patients and methods: This retrospective cohort study includes 351 LS patients undergoing endoscopic surveillance at the Karolinska University Hospital, August 1989 - April 2021. Data from endoscopic surveillance colonoscopies were extracted from patients' medical records.

Results: Of 1873 endoscopies in 351 LS patients, 12 complications (AEs) were documented within 30 days (0.64%) and with a total of 3 bleedings (SAEs, 0.16%). No perforations were identified.

Conclusion: Colonoscopy surveillance for LS patients shows a comparatively low risk of AEs per-examination. Colonoscopy complications per-patient, including both SAEs and AEs, show a significantly higher risk. Colonoscopy complications only including SAEs, show a comparatively low risk. Understanding the lifetime risk of surveillance-related colonoscopy complications is important when designing targeted surveillance programmes.

A 73-year-old Japanese man with a history of distal biliary cancer treated by pancreatoduodenectomy developed pancreatic acinar cell carcinoma (PACC) treated by remnant pancreatectomy and adjuvant chemotherapy. Thirteen months after surgery, multiple liver metastases developed and FOLFOX chemotherapy was initiated. Based on the PACC diagnosis and a positive family history for breast and ovarian cancer genetic testing was performed which revealed a pathogenic germline BRCA2 variant (c.8629G > T, p.Glu2877Ter). Olaparib therapy was initiated and the metastases responded well (partial response). PACC is a BRCA2-associated cancer which may respond well to PARP inhibitors.

In the early years of my GI fellowship, a healthy 40-year-old man came to my clinic and announced that he was going to die of pancreatic cancer. His brothers, father and uncles had all died of the disease; he felt his fate was inescapable. I asked whether his family members had seen doctors or had any tests. His answer was yes to both. Even so, doctors could not diagnose the pancreatic cancer at early stages. CT scans were always negative. I thought to myself, in order to help this patient-CT scans may not be reliable for early detection. Perhaps other methods of imaging the pancreas might be of more benefit. This patient opened a door that led to a 30-year journey of trying to detect pancreatic cancer at earlier stages when it is curable.

Screening programs for early detection and treatment of pancreatic cancer (PC) and its precursor lesions are increasingly implemented worldwide to reduce disease-specific lethality. Given the relatively low prevalence of the disease, the ideal target of such approaches is an enriched cohort of individuals harboring a lifetime risk of developing PC significantly higher compared to the general population, given either a substantial aggregation of PC cases in their family (i.e. familial pancreatic cancer) or a genomic landscape enriched with pathogenic variants associated with pancreatic carcinogenesis (i.e. mutation carriers). In Italy, a national registry for the census and surveillance of high-risk individuals for PC was launched in 2015, enrolling some 1200 subjects as of today. In this perspective, the scientific background, multi-level structure, and evolution of IRFARPC are outlined, as well as its long-term results, future developments, and areas for improvement.