Familial Cancer最新文献

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.

Adenomatous polyposis syndromes are hereditary conditions characterised by the development of multiple adenomas in the gastrointestinal tract, particularly in the colon and rectum, significantly increasing the risk of colorectal cancer and, in some cases, extra-colonic malignancies. These syndromes are caused by germline pathogenic variants (PVs) in genes involved in Wnt signalling and DNA repair. The main autosomal dominant adenomatous polyposis syndromes include familial adenomatous polyposis (FAP) and polymerase proofreading-associated polyposis (PPAP), caused by germline PVs in APC and the POLE and POLD1 genes, respectively. Autosomal recessive syndromes include those caused by biallelic PVs in the DNA mismatch repair genes MLH1, MSH2, MSH6, PMS2, MSH3 and probably MLH3, and in the base excision repair genes MUTYH, NTHL1 and MBD4. This review provides an in-depth discussion of the genetic and molecular mechanisms underlying hereditary adenomatous polyposis syndromes, their clinical presentations, tumour mutational signatures, and emerging approaches for the treatment of the associated cancers. Considerations for genetic testing are described, including post-zygotic mosaicism, non-coding PVs, the interpretation of variants of unknown significance and cancer risks associated with monoallelic variants in the recessive genes. Despite advances in genetic testing and the recent identification of new adenomatous polyposis genes, many cases of multiple adenomas remain genetically unexplained. Non-genetic factors, including environmental risk factors, prior oncologic treatments, and bacterial genotoxins colonising the intestine - particularly colibactin-producing Escherichia coli - have emerged as alternative pathogenic mechanisms.

In the majority of patients with a classical Familial Adenomatous Polyposis (FAP) a pathogenic APC germline variant is identified; usually these are truncating variants in the coding region of APC. However, there are some special circumstances in which FAP is not the result of a pathogenic heterozygous germline variant in APC (mosaicism) and tspecific APC variants which do not cause FAP (I1307K and promotor variants). This paper will discuss these three conditions. APC somatic (postzygotic) mosaicism can be identified in up to 50% of unexplained adenomatous polyposis cases. The ability to identify APC postzygotic mosaicism depends on the the detection method (today usually next-generation sequencing) and also the tissue being analysed (investigation of multiple colorectal adenomas is more sensitive than leukocyte DNA). Identifying mosaicism has important implications in terms of an individual's management and managing risk in family members. The I1307K variant in APC is prevalent among Ashkenazi Jews (AJ) but can also be found in Sephardi Jews and individuals of non-Jewish descent. While this variant does not cause polyposis, it increases the risk of colorectal cancer (CRC) by 1.68-fold in AJ individuals. However, the link between the I1307K variant and CRC risk in non-AJ populations, is less well-established. Furthermore, its potential impact on other types of cancer remains unclear. Consequently, the classification of this variant, along with appropriate screening and surveillance recommendations, remains a subject of ongoing debate among leading medical and genetic organizations. Variants in the APC promotor 1B region cause the relatively newly described condition of gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). It is said to have an isolated gastric phenotype, with neither duodenal, large bowel nor extra-intestinal manifestations. There are many uncertainties regarding this condition, it's penetrance and management. Lack of clinical data and poor understanding of the natural history of the condition remain significant barriers to developing guidelines to manage this condition.

The St Mark's Hospital Polyposis Registry was founded in 1924, the first such unit in the world. This paper documents the development of the unit over the subsequent 100 years, which was inextricably linked to scientific and clinical advance in the field of polyposis syndromes.

Approximately 30% of sebaceous skin lesions (or sebaceous neoplasia) demonstrate DNA mismatch repair (MMR)-deficiency. MMR-deficiency can be caused by Lynch syndrome, resulting from germline pathogenic variants in the DNA MMR genes MLH1, MSH2, MSH6 and PMS2, but other causes include somatic MLH1 gene promoter hypermethylation, constitutional MLH1 gene promoter hypermethylation (MLH1 epimutation), or biallelic somatic MMR gene mutations. In colorectal (CRCs) and endometrial cancers (ECs), tumour MMR-deficiency showing loss of MLH1 and PMS2 protein expression (MLH1/PMS2-deficiency) is predominantly caused by somatic MLH1 hypermethylation, however, it is not clear if somatic MLH1 hypermethylation is a cause of MLH1/PMS2-deficiency in sebaceous neoplasia. This study investigated the causes of MLH1/PMS2-deficiency in 28 cases with sebaceous neoplasia. Germline pathogenic variants in MLH1 were identified in 11 of 28 cases. Of the remaining 17 non-Lynch syndrome cases, two (11.8%) were positive for MLH1 hypermethylation in blood-derived DNA (constitutional MLH1 epimutations). The corresponding sebaceous tissue of these two cases also showed MLH1 hypermethylation. None of the other eight cases with sufficient sebaceous tissue-derived DNA for testing showed somatic MLH1 hypermethylation. Multi-gene panel testing of sebaceous tissue and matched blood-derived DNA identified four cases with biallelic somatic MLH1 mutations as the cause of MLH1/PMS2-deficiency. No cause of MLH1/PMS2-deficiency could be identified in one case. This study demonstrates that biallelic somatic MLH1 mutations and constitutional MLH1 epimutations underlie MLH1/PMS2-deficiency in sebaceous neoplasms after excluding Lynch syndrome. Unlike CRCs and ECs, somatic MLH1 hypermethylation was not identified suggesting it is not a common cause of MLH1/PMS2-deficiency in sebaceous neoplasia.

Recent updated management guidelines for Familial Adenomatous Polyposis (FAP) have been published by professional bodies internationally. These recommendations reflect the diverse needs and capabilities of varying health systems worldwide, including thresholds for intervention and population health priorities. Whilst guidelines are closely aligned in many regards, there are areas of disparity. However, alongside discrepancies in guideline recommendations, common challenges also face professional bodies across the globe. Generation of a robust evidence-base in the environment of limited data is difficult in rare diseases such as FAP, underscored by the fact that expert consensus opinion underpins virtually all guidelines. The presence of a wide phenotypic spectrum in FAP and the other hereditary gastrointestinal polyposis syndromes, whilst now well recognised, further complicates the creation of universal recommendations. In this review we draw comparison between the various international guidelines for the management of FAP, using examples to focus on thematic areas of agreement and divergence. However, beyond this, we also wish to highlight the persisting evidence gaps in clinical management, and any areas of ongoing debate among clinicians, where we are yet to establish the optimal approach.

The European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) established in 2017 and connecting more than 50 European expert centres improves access to diagnosis, treatment, and the provision of high-quality healthcare for patients with rare genetic tumour risk syndromes (hereditary cancer), no matter where they live in Europe.

Women with inherited BRCA1/2 mutations are at increased risk of breast and ovarian cancer. The reports on the prevalence and spectrum of these mutations have been primarily focused on individuals with European ancestry. A previous study on Iranian breast cancer patients reported no BRCA1/2 mutation in early-onset breast cancer with no other criteria, which is contrary to other populations. The purpose of this study was to characterize the patterns of these mutations in Iranian breast and ovarian cancer patients and evaluate the predictive efficacy of the Manchester scoring system in patients and their unaffected family members. We retrospectively reviewed the genetic testing performed for breast and ovarian cancer patients and unaffected individuals with a positive family history. The study participants were selected based on the NCCN (National Comprehensive Cancer Network) criteria (version 2.2024). A total of 376 female breast cancer patients, 49 ovarian cancer patients, and 74 unaffected individuals were enrolled in this study. In breast cancer patients, 24 (6.4%) BRCA1 and 23 (6.1%) BRCA2 mutations were detected. In ovarian cancer patients, 9 (18.5%) BRCA1 and 1 (2%) BRCA2 mutations were identified. Three (4.1%) BRCA2 mutations were identified in unaffected individuals. Seven breast cancer patients with age of cancer diagnosis ≤ 40 and no other criteria (including family history) had an underlying mutation: Four BRCA2, and three BRCA1 mutations. The Manchester score performed well, with a sensitivity of 81% and a specificity of 70%. More research is needed to clarify the hereditary component of breast and ovarian cancer in Iranian patients.

It has been suggested that women with a pathogenic variant (mutation) in BRCA1 or BRCA2 are at a higher risk of developing high-grade endometrial cancer. Furthermore, significantly higher follicular (but lower luteal) endometrial thickness, a surrogate marker for endometroid adenocarcinoma risk, has been reported for this high-risk population. Given that medications known to affect endometrial thickness (i.e., tamoxifen, oral contraceptives) are often indicated for BRCA mutation carriers, it is important to elucidate substantial differences exist in carriers. Thus, we conducted a retrospective chart review of endometrial thickness among women with a BRCA1 or BRCA2 who had an intact uterus and were referred to a specialized ovarian cancer clinic between 2007 and 2016. Clinical data was collected from chart review, while endometrial thickness (millimeters; mm) was abstracted from transvaginal ultrasound reports with endometrial dating and compared to published levels in the general population. In total, 114 women were identified, 73 of whom were premenopausal and 41 who were postmenopausal. Among premenopausal women, the median follicular endometrial thickness found was 7.00 mm (n = 40, range 3-13) compared to 6.8 mm (range 2.4-14) in non-carriers and the median luteal endometrial thickness was 10.85 mm (n = 30, range 5-18), compared to 9.6 mm (range 3.3-18.2) in non-carriers. Among postmenopausal women, the median menopausal endometrial thickness was 4.0 mm (n = 41, range 1-18) compared to 4.0 mm (range 1-25) in non-carrier controls. Although based on small numbers, we found no significant difference in the endometrial thickness of BRCA mutation carriers versus non-carriers.