Hereditary Cancer in Clinical Practice最新文献

Background: Germline genetic susceptibilities of rare cancers of the esophagus, stomach, small intestine, testis, (nonmedullary) thyroid gland and bone with high familial risks are not well known. Here, we use familial risk data from the Swedish Family-Cancer Database which contains records of cancers in Swedish families obtained over a century. We compare familial risks for offspring diagnosed with any of these cancers when their parent had or had not that cancer. We review the global literature of the reported constitutional variants that may explain part of the familial risk.

Main body: Familial risks for esophageal and stomach cancers are about 2.0 and apart from early-onset stomach cancer few high-risk variants are known. Genetic studies may be hampered by dominant environmental risk factors for these cancers. Small intestinal carcinoids have a very high familial risk (28 between siblings) but no high-risk genes have been identified to explain this. Low-risk polygenic variants have been identified. Small intestinal adenocarcinoma is a manifestation in Lynch syndrome. Testicular and thyroid cancers are characterized by high familial risk (about 5) which may be explained largely by a polygenic background, although thyroid cancer is a component in a number of rare cancer syndromes. Several predisposing genes have been identified for bone cancer (familial risk 7).

Conclusions: The discussed cancers are rare and they present with a relatively high familial risk, in spite of lacking identified high-penetrant constitutional variants. It is possible that the polygenic component, already recognized for testis cancer, is stronger than previously expected. Thus polygenic models with rare high/moderate- and low-risk variants could fit the familial risk and shape the germline genetic landscape of these cancers. Polygenic background may have clinical implications.

Background: The widespread application of colonoscopy screening and genetic testing in colorectal cancer (CRC) treatment has led to the identification of a subset of familial adenomatous polyposis (FAP) patients who lack a family history of the disease but harbor germline gene mutations. Moreover, distinct genotypes may be associated with varied clinical presentations and therapeutic options. This case report describes a male patient with de novo FAP who harbored germline double heterozygosity (GDH) for APC and BRCA2 mutations. The patient underwent total colectomy, and genetic testing enabled personalized surveillance and management strategies for his family members.

Case presentation: A 43-year-old male with no family history of cancer presented to the outpatient clinic of the Colorectal Surgery Department with complaints of constipation and hematochezia. Colonoscopy revealed hundreds of polyps throughout the colon and a rectal adenocarcinoma located 5 cm from the anal verge. Gastroduodenal endoscopy did not detect any upper gastrointestinal adenomas. The patient underwent laparoscopic total colectomy with abdominoperineal resection of the rectum and end ileostomy. With the consent of the patient and his family, genetic testing was performed. The index patient was found to carry an APC splicing site mutation (exon 15: c.1744-1G > A) and a BRCA2 missense mutation (exon 17: c.7976G > A: p.R2659K). His daughter was found to have inherited the same germline BRCA2 variant. Additionally, the rectal cancer exhibited proficient DNA mismatch repair (pMMR) status, ERBB2 copy number amplification, and a missense mutation, while the KRAS, NRAS, and BRAF genes were wild-type. Based on the genetic testing results and clinical manifestations, the index patient was diagnosed with familial adenomatous polyposis (FAP) and rectal cancer. Personalized surveillance and management strategies were implemented for the patient and his family, focusing on the risks of extra-colonic diseases and potential malignancies in the prostate, pancreas, breast, and ovaries.

Conclusion: De novo FAP with double germline mutations in APC and BRCA2, along with somatic ERBB2 mutations, is exceptionally rare among hereditary cancer cases. With the rapid advancements in genomics, the detection of multiple gene variants in individuals or families has become increasingly common. Additionally, the application of artificial intelligence (AI) in medical research may provide powerful tools for genetic analysis and clinical decision-making. Consequently, a comprehensive evaluation of family history, a deep understanding of hereditary cancer syndromes, and precise interpretation of genetic mutations are essential for personalized clinical management in the era of precision medicine. However, these tasks pose significant challenges for clinicians and genetic counselors alike.

Background: The Swedish Family-Cancer Database (FCD) is the largest source of data on familial cancer in the world, including practically complete family structures and individual cancer diagnoses from the high-quality cancer registry. We present a novel application of FCD by analyzing age-specific familial risks and interpreting them through likely causes, such as germline pathogenic variants and/or environmental exposures.

Main body: The basic assumption for this approach is that a discrete familial clustering in a narrow age-interval is not random but may provide causal clues. For this analysis we selected reasonably common cancers to meaningfully scrutinize familial risk through adulthood in which cancers are diagnosed, that included colorectal (CRC) and endometrial cancers, prostate and kidney cancers and breast and lung cancers. The interpretation is based on the literature. The highest familial relative risks for CRC and endometrial cancers were found at ages 40-44 years, matching the peak impact of mismatch repair gene mutations. However endometrial cancer showed also a small early onset component which could not be explained. Age-related familial risks for breast, prostate and kidney cancers also matched data from large-scale sequencing; these included the early onset component in kidney cancer which was likely due to VHL mutations. Age distribution of familial lung cancer was unique in showing a wide peak extending from middle to old ages, which would be consistent with a combination of direct genetic effects and indirect influence on inheritance of smoking dependence.

Conclusions: The present review of age-specific familial risks and age-of-onset data from the literature may allow an interpretation that the familial and germline landscapes are reasonably harmonious for relatively early onset cancers but at higher ages no discrete peaks can be found which may implicate attenuated impact of high-risk genes and polygenic influence.

Background: The Department of Clinical Cancer Genetics at the Institute of Oncology Ljubljana offers genetic counselling and testing to cancer patients and their relatives. Before undergoing genetic testing, patients sign the informed consent form. In addition to giving consent for collection of biological material and genetic testing, patients decide about storage of biological material and participation in international databases. Furthermore, patients decide whether the information regarding their test results may be revealed to their blood relatives and whether they want to be informed about secondary findings.

Methods: Using the signed consent forms, we investigated the effect of selected factors on patients' decisions. Using different statistical methods, we tried to determine the proportion of patients who opted for different items and the effect of gender, age and cancer diagnoses on their decisions.

Results: Nearly all (99.6%) patients, regardless of gender, age, and presence of oncological diagnosis, consented to the storage of their biological material, 98.4% of patients, regardless of gender, age, and presence of oncological diagnosis, wanted to be included in international databases in a pseudo-anonymised form, 98.8% of patients, irrespective of gender, age, and presence of oncological diagnosis, allowed blood relatives to see their results, and 98.4% of patients, irrespective of gender, age and presence of oncological diagnosis, wanted to know whether secondary findings were detected when genetic analysis of their biological material was performed. Men are, on average, more likely to consent but the difference between genders is not statistically significant. Patients without oncological disease were more likely to agree to be included in international databases than patients with a confirmed oncological diagnosis.

Conclusions: Our results show that the vast majority of patients were in favour of the options they were offered. Most importantly, the majority of them allow their genetic test results be revealed to their blood relatives when needed and would participate in international databases. Research in rare diseases, including rare cancer genetic predisposition syndromes, is crucial for optimal diagnostic, prevention and treatment options for patients with rare genetic disorders. The results are also important for refining the approach to pre-and post-test cancer genetic counselling.

Background: Germline TP53 gene variants are intricately linked to Li-Fraumeni syndrome, a rare and aggressive hereditary cancer syndrome. This study investigated the frequency and spectrum of TP53 pathogenic variants associated with Li-Fraumeni syndrome in a large cohort of mainly breast cancer patients from Russia.

Methods: The study analyzed 3,455 genomic DNA samples from cancer patients using next-generation sequencing panels and whole-genome sequencing. Clinically significant TP53 variants were identified and validated using Sanger sequencing. The clinical and family history characteristics of patients with TP53 variants were analyzed.

Results: The analysis identified 13 (0.4%) individuals with clinically significant germline TP53 variants, all of whom were females with either unilateral breast cancer or breast cancer as part of multiple primary malignant neoplasms. The average age of breast cancer manifestation was 39.9 years, with a median of 36 years. Only 38.5% of the TP53 mutation carriers met the modified Chompret criteria for TP53 testing.

Conclusions: The findings underscore the necessity of thorough phenotype and family history analysis in genetic counseling to effectively diagnose LFS, and emphasize the importance of identifying TP53 variant carriers for developing treatment strategies, prognosis, and monitoring, as well as for identifying high-risk family members. The study also highlights that the current guidelines fail to identify over half of the TP53 mutation carriers, suggesting the need for a more comprehensive approach to genetic testing in suspected hereditary cancer cases.

Carcinogenesis encompasses processes that lead to increased mutation rates, enhanced cellular division (tumour growth), and invasive growth. Colorectal cancer (CRC) carcinogenesis in carriers of pathogenic APC (path_APC) and pathogenic mismatch repair gene (path_MMR) variants is initiated by a second hit affecting the corresponding wild-type allele. In path_APC carriers, second hits result in the development of multiple adenomas, with CRC typically emerging after an additional 20 years. In path_MLH1 and path_MSH2 carriers, second hits lead to the formation of microscopically detectable, microsatellite unstable (MSI) crypts, from which CRC develops in about half of carriers over their lifetime, often without progressing through a diagnosable adenoma stage. These divergent outcomes reflect the distinct functions of. the APC and MMR genes. In path_MLH1 and path_MSH2 carriers, a direct consequence of stochastic mutations may be the occurrence of invasive growth before tumour expansion, challenging the paradigm that an invasive cancer must always have an non-invasive precursor. In contrast to other path_ MMR carriers, path_PMS2 carriers who receive colonoscopic surveillance exhibit minimal increase in CRC incidence. This is consistent with a hybrid model: the initial mutation may cause an adenoma, and the second hit in the wild-type PMS2 allele may drive the adenoma towards become cancerous with MSI. Since all mutational events are stochastic, interventions aimed at preventing or curing cancer should ideally target the initial mutational events. Interventions focused on downstream events are external factors that influence which tumour clones survive Darwinian selection. In Lynch Syndrome, surveillance colonoscopy to remove adenomas may select for carcinogenetic pathways that bypass the adenoma stage.

Early identification of hereditary cancer predisposition in adolescents and young adults represents a unique opportunity to target cancer prevention and improve survival in a population at risk for adverse health outcomes. However, adolescents and young adults face challenges unique to their stage of life that can undermine their transition from pediatric to adult healthcare and lead to interruptions in preventative care. The purpose of this study was to understand expert perspectives on factors relevant to designing and implementing a transition clinic for adolescents and young adults with hereditary cancer predisposition. We used qualitative methods informed by human-centered design and implementation science to identify implementation considerations rooted in clinician experience. To understand clinic design and clinician experience at Geisinger transition clinics, we conducted a contextual inquiry using clinic observations and follow-up interviews of clinicians. To learn about designing and implementing a transition program, we also conducted in-depth interviews with national transition experts actively involved in developing, implementing, or participating in transition clinics around the United States. The contextual inquiry resulted in three diagrams depicting the following common elements of transition clinics at our institution: relationship building with patients, care coordination, stepwise transition education, communication between providers, and a sustainable clinic home. Interviews were analyzed deductively using thematic analysis to learn clinician perspectives about program implementation specific to each domain of the RE-AIM theoretical framework: reach, effectiveness, adoption, implementation, and maintenance.

Background: Familial adenomatous polyposis (FAP) is an autosomal dominant colorectal tumour syndrome characterised by the formation of multiple adenomatous polyps throughout the colon. It is important to understand the extracolonic phenotype that characterizes FAP. Most previous case reports of patients with both FAP and intellectual disability (ID) have described deletions in all or part of chromosome 5q, including the APC locus. However, it remains unclear whether the ID phenotype in patients with FAP is due to APC disruption or another genetic defect in the deleted 5q region.

Case presentation: Patient of family 1 is a 32-year-old woman presented with > 500 colorectal adenomatous polyps, gastric fundic gland polyposis, several duodenal adenomas, and mild intellectual disability (ID). She had no known family history of the FAP phenotype or ID. By copy number trio analysis, a 15.4 Mb interstitial heterozygous de novo deletion including APC region was observed in 5q21.2. q22.3. The patient in family 2 was a 29-year-old man with approximately 50 colorectal adenomatous polyps, fundic gland polyposis in the stomach, non-ampullary adenomas in the duodenum, and mild ID. He had no family history of the FAP phenotype or ID. Using copy number trio analysis, a de novo 9.8 Mb heterozygous deletion was identified on 5q22.1. q23.1 which includes the APC region.

Conclusions: Based on previous reports and the present study, we narrowed down the 5p deletion region associated with ID in FAP. Further investigation is required to understand ID due to 5q stromal deletion.

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.