Hereditary colorectal cancer syndromes, such as Lynch syndrome and familial adenomatous polyposis (FAP), present significant clinical challenges due to the heightened cancer risks associated with these genetic conditions. This review explores genetic profiling impact on surgical decisions for hereditary colorectal cancer (HCRC), assessing options, timing, and outcomes. Genotypes of different HCRCs are discussed, revealing a connection between genetic profiles, disease severity, and outcomes. For Lynch syndrome, mutations in the MLH1, MSH2, MSH6, and PMS2 genes guide the choice of surgery. Subtotal colectomy is recommended for patients with mutations in MLH1 and MSH2, while segmental colectomy is preferred for those with MSH6 and PMS2 mutations. In cases of metachronous colon cancer after segmental colectomy, subtotal colectomy with ileorectal anastomosis is advised for all mutations. Surgical strategies for primary rectal cancer include anterior resection or abdominoperineal resection (APR), irrespective of the specific mutation. For rectal cancer occurring after a previous segmental colectomy, proctocolectomy with ileal pouch-anal anastomosis (IPAA) or APR with a permanent ileostomy is recommended. In FAP, surgical decisions are based on genotype-phenotype correlations. The risk of desmoid tumors post-surgery supports a single-stage approach, particularly for certain APC gene variants. Juvenile Polyposis Syndrome (JPS) surgical decisions involve genetic testing, polyp characteristics with attention to vascular lesions in SMAD4 mutation carriers. However, genetic profiling does not directly dictate the specific surgical approach for JPS. In conclusion this review highlights the critical role of personalized surgical plans based on genetic profiles to optimize patient outcomes and reduce cancer risk. Further research is needed to refine these strategies and enhance clinical guidelines.

Lynch syndrome (LS), also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is an autosomal dominant cancer syndrome which causes about 2-3% of cases of colorectal carcinoma. The development of LS is due to the genetic and epigenetic inactivation of genes involved in the DNA mismatch repair (MMR) system, causing an epiphenomenon known as microsatellite instability (MSI). Despite the fact that the genetics of the vast majority of MSI-positive (MSI+) cancers can be explained, the etiology of this specific subset is still poorly understood. As a possible new mechanism, it has been recently demonstrated that the overexpression of certain microRNAs (miRNAs, miRs), such as miR-155, miR-21, miR-137, can induce MSI or modulate the expression of the genes involved in LS pathogenesis. MiRNAs are small RNA molecules that regulate gene expression at the post-transcriptional level by playing a critical role in the modulation of key oncogenic pathways. Increasing evidence of the link between MSI and miRNAs in LS prompted a deeper investigation into the miRNome involved in these diseases. In this regard, in this study, we discuss the emerging role of miRNAs as crucial players in the onset and progression of LS as well as their potential use as disease biomarkers and therapeutic targets in the current view of precision medicine.

Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC) and endometrial cancer (EC). Although colonoscopy reduces CRC in LS, the protection is variable. We assessed the prevalence and incidence of neoplasia in LS during surveillance colonoscopy in the United States and factors associated with advanced neoplasia.
Patients with LS undergoing ≥1 surveillance colonoscopy and with no personal history of invasive CRC or colorectal surgery were included. Prevalent and incident neoplasia was defined as occurring <6 months before and ≥6 months after germline diagnosis of LS, respectively. We assessed advanced adenoma (AA), CRC, and the impact of mismatch repair pathogenic variant (PV) and typical LS cancer history (personal history of EC and/or family history of EC/CRC) on outcome.
A total of 132 patients (inclusive of 112 undergoing prevalent and incident surveillance) were included. The median examination interval and duration of prevalent and incident surveillance was .88 and 1.06 years and 3.1 and 4.6 years, respectively. Prevalent and incident AA were detected in 10.7% and 6.1% and invasive CRC in 0% and 2.3% of patients. All incident CRC occurred in MSH2 and MLH1 PV carriers and only 1 (.7%) while under surveillance in our center. AAs were detected in both LS cancer history cohorts and represented in all PVs.
In a U.S. cohort of LS, advanced neoplasia rarely occurred over annual surveillance. CRC was diagnosed only in MSH2/MLH1 PV carriers. AAs occurred regardless of PV or LS cancer history. Prospective studies are warranted to confirm our findings.

Approximately 5% of colorectal cancers arise within an inherited colorectal cancer syndrome, with known underlying genetic etiologies. These syndromes increase the risk of colorectal and extracolonic cancers. Identification of a specific genetic pathogenic variant defines the syndrome, and quantifies the elevated risks compared to the general population. Thus, knowing and understanding the risks associated with each pathogenic variant allows for risk-stratification and a more individualized management strategy. These factors influence both the timing of surgery and the extent of colorectal surgery for patients with these syndromes. Familial Adenomatous Polyposis (FAP) is a dominantly inherited polyposis syndrome caused by pathogenic variant in the APC gene and results in a near 100% chance of developing colorectal cancer if not treated. There is a genotype-phenotype correlation in which the affected gene locus is associated with severity of polyposis and the risk of desmoid disease. Prophylactic surgery ranging from total abdominal colectomy or total proctocolectomy is recommended before cancer develops. Lynch syndrome is a non-polyposis inherited syndrome caused by a pathogenic variant in MLH1, MSH2, MSH6, or PMS2. Although prophylactic colectomy in Lynch syndrome is uncommon, total abdominal colectomy as prophylaxis in the setting of colon cancer is recommended due to the likelihood of metachronous colorectal cancer. This article reviews the role of genetics surgical decision making with respect to the timing and extent of surgery within the hereditary colorectal cancer syndromes.

BACKGROUND: Individuals with Lynch syndrome (LS) and hereditary non-polyposis colorectal cancer (HNPCC) are at increased risk of both colorectal cancer and other cancers. The interplay between immunosuppression, a comorbid inflammatory condition (CID), and HNPCC on cancer risk is unclear.
OBJECTIVE: To evaluate the impact of CIDs, and exposure to monoclonal antibodies and immunomodulators, on cancer risk in individuals with HNPCC.
METHODS: Individuals prospectively followed in a hereditary cancer registry with LS/HNPCC with the diagnosis of inflammatory bowel disease or rheumatic disease were identified. We compared the proportion of patients with cancer in LS/HNPCC group with and without a CID. We also compared the proportion of patients who developed cancer following a CID diagnosis based upon exposure to immunosuppressive medications.
RESULTS: A total of 21 patients with LS/HNPCC and a CID were compared to 43 patients with LS/HNPCC but no CID. Cancer occurred in 84.2% with a CID compared to 76.7% without a CID (P = 0.74) with no difference in age at first cancer diagnosis 45.5 ± 14.6 vs 43.8 ± 7.1 years (P = 0.67). LS specific cancers were diagnosed in 52.4% with a CID vs 44.2% without a CID (P = 0.54). Nine of 21 (42.9%) patients were exposed to biologics or immunomodulators for the treatment of their CID. Cancer after diagnosis of CID was seen in 7 (77.8%) of exposed individuals vs 5 (41.7%) individuals unexposed to biologics/immunomodulators (P = 0.18). All 7 exposed compared to 3/5 unexposed developed a LS specific cancer. The exposed and unexposed groups were followed for a median 10 years and 8.5 years, respectively. The hazard ratio for cancer with medication exposure was 1.59 (P = 0.43, 95%CI: 0.5-5.1).
CONCLUSIONS: In patients with LS/HNPCC, the presence of a concurrent inflammatory condition, or use of immunosuppressive medication to treat the inflammatory condition, might not increase the rate of cancer occurrence in this limited study.

Identifying individuals who have Lynch syndrome involves a complex diagnostic workup that includes taking a detailed family history and a combination of various tests such as immunohistochemistry and/or molecular which may be germline and/or somatic. The National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer have come together to publish this practice resource for the evaluation of Lynch syndrome. The purpose of this practice resource was to provide guidance and a testing algorithm for Lynch syndrome as well as recommendations on when to offer testing. This practice resource does not replace a consultation with a genetics professional. This practice resource includes explanations in support of this and a summary of background data. While this practice resource is not intended to serve as a review of Lynch syndrome, it includes a discussion of background information and cites a number of key publications which should be reviewed for a more in-depth understanding. This practice resource is intended for genetic counselors, geneticists, gastroenterologists, surgeons, medical oncologists, obstetricians and gynecologists, nurses, and other healthcare providers who evaluate patients for Lynch syndrome.

Familial non-medullary thyroid cancer (FNMTC) is a form of endocrine malignancy exhibiting an autosomal dominant mode of inheritance with largely unknown germline molecular mechanism. Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is another hereditary autosomal dominant cancer syndrome which, if proven to be caused by germline mutations in mismatch repair genes (MMR)-MLHL, MSH2, MSH6, PMS2, and EPCAM-is called Lynch syndrome (LS). LS results in hereditary predisposition to a number of cancers, especially colorectal and endometrial cancers. Tumors in LS are characterized by microsatellite instability (MSI) and/or loss of MMR protein expression in immunohistochemistry (IHC). MSI is a rare event in thyroid cancer (TC), although it is known to occur in up to 2.5% of sporadic follicular TC cases. There are limited data on the role of germline MMR variants FNMTC. The goal of this study was to analyze the potential clinical and molecular association between HNPCC and FNMTC. We performed a cohort study analyzing the demographic, clinical, and pathologic data of 43 kindreds encompassing 383 participants (104 affected, 279 unaffected), aged 43.5 [7-99] years with FNMTC, and performed high-throughput whole-exome sequencing (WES) of peripheral blood DNA samples of selected 168 participants (54 affected by FNMTC and 114 unaffected). Total affected by thyroid cancer members per family ranged between 2 and 9 patients. FNMTC was more prevalent in women (68.3%) and characterized by a median tumor size of 1.0 [0.2-5.0] cm, multifocal growth in 44%, and gross extrathyroidal extension in 11.3%. Central neck lymph node metastases were found in 40.3% of patients at presentation, 12.9% presented with lateral neck lymph node metastases, and none had distant metastases. Family history screening revealed one Caucasian family meeting the clinical criteria for FNMTC and HNPCC, with five members affected by FNMTC and at least eight individuals reportedly unaffected by HNPCC-associated tumors. In addition, two family members were affected by melanoma. Genome Analysis Tool Kit (GATK) pipeline was used in variant analysis. Among 168 sequenced participants, a heterozygous missense variant in the MSH2 gene (rs373226409; c.2120G>A; p.Cys707Tyr) was detected exclusively in FNMTC- HNPCC- kindred. In this family, the sequencing was performed in one member affected by FNMTC, HPNCC-associated tumors and melanoma, one member affected solely by HNPCC-associated tumor, and one member with FNMTC only, as well as seven unaffected family members. The variant was present in all three affected adults, and in two unaffected children of the affected member, under the age of 18 years, and was absent in non-affected adults. This variant is predicted to be damaging/pathogenic in 17/20 in-silico models. However, immunostaining performed on the thyroid tumor tissue of two affected by FNMTC family members revealed intact nuclear expression of MSH2, and microsatellite stable status in both tumors that were tested. Although the MSH2 p.Cys707Tyr variant is rare with a minor allele frequency (MAF) of 0.00006 in Caucasians; it is more common in the South Asian population at 0.003 MAF. Therefore, the MSH2 variant observed in this family is unlikely to be an etiologic factor of thyroid cancer and a common genetic association between FNMTC and HNPCC has not yet been identified. This is the first report known to us on the co-occurrence of FNMTC and HNPCC. The co-occurrence of FNMTC and HNPCC-associated tumors is a rare event and although presented in a single family in our large FNMTC cohort, a common genetic background between the two comorbidities could not be established.

暂无摘要。

UNASSIGNED: Familial cancers comprise a considerable distribution of colorectal cancers (CRCs), of which only about 5% occurs through well-established hereditary syndromes. It has been demonstrated that deleterious variants at the newly identified cancer-predisposing genes could describe the etiology of undefined familial cancers.
UNASSIGNED: The present study aimed to identify the genetic etiology in a 32-year-old man with early onset familial CRC employing several molecular diagnostic techniques. DNA was extracted from tumoral and normal formalin-fixed-paraffin-embedded (FFPE) blocks, and microsatellite instability (MSI) was evaluated. Immunohistochemistry staining of MMR proteins was performed on tumoral FFPE blocks. Next-generation sequencing (NGS), multiplex ligation-dependent amplification (MLPA) assay, and Sanger sequencing were applied on the genomic DNA extracted from peripheral blood. Data analysis was performed using bioinformatics tools. Genetic variants interpretation was based on ACMG.
UNASSIGNED: MSI analysis indicated MSI-H phenotype, and IHC staining proved no expressions of MSH2 and MSH6 proteins. MLPA and NGS data showed no pathogenic variants in MMR genes. Further analysis of NGS data revealed a candidate WRN frameshift variant (p.R389Efs*3), which was validated with Sanger sequencing. The variant was interpreted as pathogenic since it met the criteria based on the ACMG guideline including very strong (PVS1), strong (PS3), and moderate (PM2).
UNASSIGNED: WRN is a DNA helicase participating in DNA repair pathways to sustain genomic stability. WRN deficient function may contribute to CRC development that is valuable for further investigation as a candidate gene in hereditary cancer syndrome diagnosis.

Lynch syndrome (LS) increases cancer risk. There is considerable individual variation in LS cancer occurrence, which may be moderated by lifestyle factors, such as body weight and physical activity (PA). The potential associations of lifestyle and cancer risk in LS are understudied. We conducted a retrospective study with cancer register data to investigate associations between body weight, PA, and cancer risk among Finnish LS carriers. The participants (n = 465, 54% women) self-reported their adulthood body weight and PA at 10-year intervals. Overall cancer risk and colorectal cancer (CRC) risk was analyzed separately for men and women with respect to longitudinal and near-term changes in body weight and PA using extended Cox regression models. The longitudinal weight change was associated with an increased risk of all cancers (HR 1.02, 95% CI 1.00-1.04) and CRC (HR 1.03, 1.01-1.05) in men. The near-term weight change was associated with a lower CRC risk in women (HR 0.96, 0.92-0.99). Furthermore, 77.6% of the participants retained their PA category over time. Men in the high-activity group had a reduced longitudinal cancer risk of 63% (HR 0.37, 0.15-0.98) compared to men in the low-activity group. PA in adulthood was not associated with cancer risk among women. These results emphasize the role of weight maintenance and high-intensity PA throughout the lifespan in cancer prevention, particularly in men with LS.