Hereditary Nonpolyposis Research Articles

Solitary Loss of PMS2 in a patient with Colon carcinoma

Abstract Introduction/Objective In the United States, there are about 150,000 new cases of Colorectal cancer (CRC) and about 50,000 CRC related deaths each year. Hereditary nonpolyposis colorectal cancer (Lynch Syndrome) accounts for 2% - 4% of CRC. It is characterized by germline mutations in mismatch repair (MMR) genes - MLH1, MSH2, MSH6 and PMS2. Patients with Lynch syndrome have up to an 80% lifetime risk (LTR) of CRC and up to 60% LTR of endometrial cancer. Lynch syndrome patients also have an associated LTR of ovarian cancer (38%), upper urologic tract cancer (18%), gastric cancer (13%), small bowel cancer (6%), hepatobiliary tract cancer (4%), and brain tumors (3% - usually glioblastoma). Methods/Case Report A 76-year-old man with history of moderately differentiated colorectal adenosarcoma involving the transverse colon and a recently diagnosed grade group 5 (Gleason 4 + 5) prostate adenocarcinoma, currently being managed at an outside hospital. The case was sent to UAB for DNA MMR/microsatellite instability (MSI) status evaluation testing. Immunostaining showed loss of PMS2 and intact expression of MLH1, MSH2 and MSH6. These results were confirmed by the IdyIIa MSI assay which detected microsatellite instability in 5 of 7 markers and negative for BRAF V600E variant confirming microsatellite instable tumor. Results (if a Case Study enter NA) NA Conclusion Solitary loss of PMS2 in colonic adenocarcinoma is uncommon and may be caused by an underlying germline mutation of MLH-1 or PMS2, thus could represent Lynch Syndrome. Our patient’s age doesn’t favor Lynch syndrome. Next step would be to perform MLH-1 promoter methylation to confirm sporadic nature of carcinoma. Somatic methylation of the MLH1 promoter occurs in approximately 80% of CRC with defective MMR. Prostate cancer is not currently considered a part of Lynch syndrome.

S511 Direct Genetic Screening Approach in Hereditary Nonpolyposis Colorectal Cancer: A Health Economics Analysis in High-risk Colorectal Cancer Population; Perspective from Middle-Income Country

S511 Direct Genetic Screening Approach in Hereditary Nonpolyposis Colorectal Cancer: A Health Economics Analysis in High-risk Colorectal Cancer Population; Perspective from Middle-Income Country

National Experiences from 30 Years of Provider-Mediated Cascade Testing in Lynch Syndrome Families-The Danish Model.

Cascade genetic testing and surveillance reduce morbidity and mortality in Lynch syndrome. However, barriers to conveying information about genetic disorders within families result in low uptake of genetic testing. Provider-mediated interventions may increase uptake but raise legal and ethical concerns. We describe 30 years of national experience with cascade genetic testing combining family- and provider-mediated contact in Lynch syndrome families in the Danish Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Register. We aimed to estimate the added value of information letters to family members in Lynch syndrome families (provider-mediated contact) compared to family members not receiving such letters and thus relying on family-mediated contact. National clinical practice for cascade genetic testing, encompassing infrastructure, legislation, acceptance, and management of the information letters, is also discussed. Cascade genetic testing resulted in 7.3 additional tests per family. Uptake of genetic testing was 54.4% after family-mediated and 64.9% after provider-mediated contact, corresponding to an odds ratio of 1.8 (p < 0.001). The uptake of genetic testing was highest in the first year after diagnosis of Lynch syndrome in the family, with 72.5% tested after provider-mediated contact. In conclusion, the Danish model combining family- and provider-mediated contact can increase the effect of cascade genetic testing.

Lynch Syndrome Biopathology and Treatment: The Potential Role of microRNAs in Clinical Practice.

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.

Evaluation of the psychological state of patients suspected of Lynch syndrome after the germline genetic testing result.

e24201 Background: Lynch syndrome (LS) also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome, is caused by a deficiency of Mismatch Repair Complex (MMR) enzymes. It is an autosomal dominant syndrome associated with an increased risk of developing colorectal cancer and other neoplasms, which can be confirmed using a germline molecular test. Psychological distress can be triggered regardless of the genetic test result. How the individual reacts emotionally and psychologically to the development can influence the processing of information and guidelines and adherence to preventive strategies. In this context, tracking anxiety symptoms provides opportunities for psychosocial follow-up planning. Objective: to evaluate levels of anxiety and depression in cancer patients suspected of having LS submitted to genetic testing. Methods: 84 patients with clinical criteria for LS were submitted to the germline genetic panel by NGS and immediately after the genetic test result, answered the Hospital Anxiety and Depression Scales (HADS). Data were expressed as mean±SD and compared using the Mann-Whitney, Kruskal-Wallis/Dunn, and Spearman correlation tests (SPSS v20.0, p &lt; 0.05). Results: The mean levels of anxiety (5.59±3.31) were significantly higher than that of depression (4.63±3.58) ( p= 0.007), both domains were positively correlated ( p&lt; 0.001, r= 0.447). Eighteen patients (21.4%) had pathogenic mutations in genes of the MMR complex. A positive diagnosis did not affect levels of anxiety or depression (pathogenic variant p= 0.617 and p= 0.478; Significance Uncertain-VUS p= 0.415 and p= 0.561, respectively). Females had higher levels of depression than males ( p= 0.047, with a relative risk of 1.65 times; CI95% = 1.05-13.19); however, other clinical and therapeutic characteristics did not significantly influence anxiety levels or depression. Conclusions: Colorectal cancer women are most sensitive to depression after germline genetic testing, despite the results. These findings reinforce the need for psychological screening of individuals undergoing genetic testing for LS and continuing psychological follow-up after receiving the genetic test.

Brain Tumor in Pediatrics: Pediactric Glioblastoma: Review Article

Background: Glioblastoma (GBM) is a malignant brain tumor that can occur in children and is very aggressive which means it can grow and spread quickly. Approximately 16% of all primary brain and central nervous system neoplasms are glioblastomas. This makes GBM a major public health problem. The incidence of glioblastoma in children varies.glioblastoma Low-grade has a higher incidence in children aged 0 to 14 years, which is 1.8/100,000 while high-grade glioblastoma is 0.5/100,000 lower than low-grade glioblastoma. where the incidence rate of glial and neuroepithelial tumors is higher in children aged 0-14 years.&#x0D; Content: Various factors such as genetic and environmental factors have been studied in terms of the etiology of glioblastoma. GBM develops more frequently in children with specific genetic syndromes, such as neurofibromatosis 1 (NF1), Li-Fraumeni syndrome, hereditary nonpolyposis colon cancer, and tuberous sclerosis. However, most cases of GBM have no known cause. Symptoms of glioblastoma are non-specific. The duration of symptoms is usually short and lasts for several months&#x0D; Summary: In children, central nervous system tumors are the most common, with 3-15% being glioblastomas. Glioblastoma usually presents with non-specific symptoms and lasts a short duration of several months. In addition, the prognosis is also poor with high morbidity and mortality so that to improve the patient's quality of life, effective therapy is needed. Therapy can be in the form of surgery, radiotherapy, or chemotherapy.

Descriptive Statistics for Patients with Glioblastoma Associated with Germline Mismatch Repair Gene Mutation

<h3>Purpose/Objective(s)</h3> Hereditary Nonpolyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, is a genetic mismatch repair mutation associated with increased risk for development of glioblastoma (GBM). There is a paucity of data describing the clinical outcomes of GBM patients with HNPCC. We aim to describe tumor characteristics, treatment patterns, and outcomes. <h3>Materials/Methods</h3> IRB approved retrospective review of consecutive patients with a diagnosis of both HNPCC and GBM at a single institution. <h3>Results</h3> Nine patients with a diagnosis of HNPCC and GBM were treated at a single institution from 2001-2022. Six patients were male. Median age at GBM diagnosis was 61 (range 21-84). Median follow up from the time of GBM diagnosis was 7.83 months. Eight patients had prior malignancies: n=7 with colon adenocarcinoma, n=1 with Burkitt lymphoma. Two patients had active synchronous cancers with GBM. The most common presenting symptoms were facial droop (n=3) and cognitive changes (n=2). Others include headache, gait change, visual field defect, and seizures with n=1 each. All patients underwent surgery: n=2 gross total resection, n=4 subtotal resection, and n=3 biopsy alone. There were 3 temporal lobe, 3 parietal lobe, 2 frontal lobe, and 1 frontoparietal lobe tumors. Two patients had multifocal disease at diagnosis. One patient had a giant cell variant GBM. Seven patients had MSH6 mutations and 2 had MSH2 mutations. Two patients progressed rapidly after surgery and were unable to receive RT. Seven patients received adjuvant radiation therapy (RT): n=5 received concurrent TMZ- 1 with concurrent bevacizumab, 5-fluorouracil, and leucovorin due to synchronous metastatic colon cancer, 1 received no chemotherapy. The most common dose and fractionation schedules were 60 Gy in 30 fractions (fx) (n=3), 40.05 Gy in 15 fx (n=3), and n=1 received 30 Gy in 10 fx due to poor performance status and large tumor volume. One patient received proton therapy for active MS, n=8 received IMRT. Two patients initiated tumor treating fields following RT completion. The median time to progression after RT was 3.35 months, and all progressed within the radiation field. Median survival from diagnosis was 6.5 months (range 1.2-15.5). No patients received immune checkpoint inhibitors. One patient was alive at the time of data collection. Seven died due to GBM progression, and n=1 died from progression of a synchronous malignancy. <h3>Conclusion</h3> In this small series, patients with mismatch repair mutation associated glioblastoma had especially poor outcomes and a rapidly progressive disease course.

Anti-cancerous medications and PTEN treatment modalities for the control of endometrial malignancy

Endometrial most tumors still up in the air to emerge at Post menopause but at this point its miles been apparent pre-menopause. Unsettling influence in estrogen and progesterone degrees alters the monthly cycle in a regenerative framework. Growing out of and the crazy blast of uterus linage reasons the development of thick covering onto the parts of the uterus which reasons unbalanced draining and distinctive hormonal aggravation incurring most malignancies and diverse digestion unsettling influences. In connection with most diseases, a Lynch disorder, moreover known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) expands the danger to survivability. Utilization of immunosuppressive specialists, Anti-dangerous Drugs, and inhibitors are stifling utilizing chemotherapy, imaging systems, and radiotherapy which comparatively reasons harm to the cells gift with inside the spot of the attacked cells. Endometrial most malignancies can't be relieved anyway intrusion might be suppressed with the utilization of against carcinogenic pills that have demonstrated unreasonable limit and adequacy with the sickness.

Merged testing for colorectal cancer syndromes and re-evaluation of genetic variants improve diagnostic yield: Results from a nationwide prospective cohort.

Approximately 5% of patients with colorectal cancer (CRC) have a Mendelian predisposition for the disease. Identification of the disease‐causing genetic variant enables carrier testing and tailored cancer prevention within affected families. To determine the panorama and genetic variation of Mendelian CRC syndromes among referrals at the cancer genetics clinics in Sweden, 850 patients clinically selected for CRC genetic investigation were included in a prospective study that tested for all major hereditary polyposis and nonpolyposis CRC conditions. Genetically defined syndromes were diagnosed in 11% of the patients. Lynch syndrome was predominant (n = 73) followed by familial adenomatous polyposis (n = 12) and MUTYH‐associated polyposis (n = 8); the latter of which two patients presented with CRC before polyposis was evident. One patient with a history of adolescent‐onset CRC and polyposis had biallelic disease‐causing variants diagnostic for constitutional mismatch repair deficiency syndrome. Post‐study review of detected variants of unknown clinical significance (n = 129) resulted in the reclassification of variants as likely benign (n = 59) or as diagnostic for Lynch syndrome (n = 2). Our results reveal the panorama of Mendelian CRC syndromes at the cancer genetics clinics in Sweden and show that unified testing for polyposis and nonpolyposis CRC conditions as well as regular reexamination of sequence data improve the diagnostic yield.

359 Lynch syndrome and breast cancer: Our experience

Introduction and aims: of the study: Lynch Syndrome (LS), also known as Hereditary Non-Polyposis Colorectal cancer (HNPCC), is a hereditary cancer predisposition syndrome caused by autosomal dominant mutation in tumor suppressor genes, the DNA mismatch repair proteins (MMR). Alterations in four DNA MMR genes are related to LS: MLH1, MSH2, MSH6 and PMS2. LS is associated with a variety of cancers, mostly with colorectal and endometrial cancer. We present three cases of breast cancer associated with LS. Methods: Three different patients presented to our clinic with abnormal mammographic findings and were diagnosed with breast cancer and LS. The first patient who was 68 years old and had a personal history of thyroid, endometrial and breast cancer, presented with a newly diagnosed DCIS in the contralateral breast. The second one, a 60 year old woman had a personal history of endometrial cancer, while our third patient was 45 years old and had a family history of breast cancer (sister, 36 years old). Genetic testing revealed mutations in MSH6 gene in the first two patients and in PMS2 gene in the third one. Discussion: Approximately 5% of endometrial and 1% of ovarian cancer occur because of LS. LS patients have a life time risk of 5-14% for breast cancer, 4-12% for ovarian cancer, 30-70% for colon cancer and 30-60% for endometrial cancer. According to the literature breast cancer in LS patients seems to be related more often with MSH6 mutations. Risk management guidelines for these patients are available, recommending earlier and more frequent gastrointestinal and gynecologic screening. Breast cancer screening is based upon the individual risk resulting from personal and family history. In some cases apart from hysterectomy with bilateral salpingo-oophorectomy, bilateral mastectomy appears to be necessary. Conclusions: It is significant to offer genetic consultation and testing in patients with breast cancer and personal or family history of colorectal, ovarian, endometrial and breast cancer.

Rectal Cancer in Patients with Hereditary Nonpolyposis Colorectal Cancer Compared with Sporadic Cases: Response to Neoadjuvant Chemoradiation and Local Recurrence.

This study aimed to assess the effect of neoadjuvant chemoradiation (nCXRT) on tumor regression and oncologic outcome of middle and low rectal cancer in patients of hereditary nonpolyposis colorectal cancer (HNPCC) compared to sporadic cases. This was a retrospective cohort study that compared the outcomes of patients with HNPCC presenting with middle or low rectal cancer indicated for nCXRT vs patients with sporadic rectal cancer. All patients received long-course nCXRT followed by total mesorectal excision. Primary outcome was pathologic tumor regression grade (TRG) assessed after resection. Secondary outcomes included disease-free survival and overall survival. Fifty-eight patients with HNPCC (24 female) were included in the study matched with 58 patients with sporadic rectal cancer (out of 166 using propensity score matching). Patients with HNPCC and sporadic rectal cancer were matched regarding tumor pathology TNM stage and lymphovascular invasion. In the HNPCC group, 36 patients (62%) had tumor regression (TRG3 = 6 (10.3%); TRG2 = 12 (20.6%); TRG1 = 18 (31%)) compared to 52 patients (92%) who had tumor regression in the control group (TRG4 = 9; TRG3 = 15; TRG2 = 18; TRG1 = 10) (p < 0.0007). After a median follow-up of 48 months, survival analysis revealed higher local recurrence and lower overall survival in patients with HNPCC compared to patients with sporadic rectal cancer. Rectal cancer in patients with HNPCC showed poorer response to nCXRT and was followed by higher local recurrence and lower overall survival than patients with sporadic rectal cancer. Tumor regression was detected in <65% of patients with HNPCC compared to >90% of patients with sporadic rectal cancer, and none of patients with HNPCC had a complete response.

Identification of SNPs in hMSH3/MSH6 interaction domain affecting the structure and function of MSH2 protein.

MutS homolog 2 (MSH2) is a mismatch repair gene that plays a critical role in DNA repair pathways, and its mutations are associated with different cancers. The present study aimed to find out the single nucleotide polymorphisms (SNPs) of MSH2 protein associated with causing structural and functional changes leading to the development of cancer with the help of computational tools. Four different tools for predicting deleterious SNPs (SIFT, PROVEAN, PANTHER, and PolyPhen), two tools each for identifying disease association (PhD-SNP and SNP&GO) and estimating stability (I-mutant and MUPro) were employed. Homology modeling, energy minimization, and root mean square deviation calculation were used to estimate structural variations. Twenty-seven SNPs and five SNPs (double amino acid change) were identified based on a consensus approach that might be associated with the structural and functional change in MSH2 protein. Molecular docking reveals that six SNPs affect the interaction of MSH2 and MSH6. Twelve identified SNPs were reported to be linked with hereditary nonpolyposis, colorectal cancer, and Lynch syndrome. Further, selected SNPs need to be validated in an in vitro system for their precise association with cancer predisposition.

Lynch syndrome-associated epithelial ovarian cancer and its immunological profile

IntroductionLynch syndrome is a multi-tumor syndrome characterized by mismatch repair deficiency (MMR-d), microsatellite instability (MSI), and increased tumor-infiltrating lymphocytes (TILs) making these tumors candidates for treatment with immune checkpoint inhibitors. However, response may depend on tumor-induced immune evasion mechanisms, e.g. loss of Beta-2-Microglobulin (B2M) or upregulation of programmed death protein ligand 1 (PD-L1). We investigated the immune response and B2M and PD-L1 expression in Lynch syndrome-associated ovarian cancers. MethodsWe successfully analyzed 30 Lynch syndrome-associated epithelial ovarian cancers collected through the Danish Hereditary Non-Polyposis Colorectal Cancer (HNPCC) register. MMR-d, MSI, immune response (CD3, CD8, and CD68), and immune evasion mechanisms (B2M and PD-L1) were investigated. Statistical associations between these markers were evaluated in addition to survival in relation to B2M/PD-L1. ResultsOf the 29 evaluable tumors, 27 were MMR-d (93.1%). Likewise of 26 evaluable tumors, 14 were MSI (53.8%). MMR-d/MMR-proficiency associated with MSI/MSS in 60.0%. Half of the ovarian tumors presented with high levels of TILs. Loss of B2M expression was observed in 46.7% of the tumors, while expression of PD-L1 was seen in 28.0% of the cases. There was no association between B2M/PD-L1 and MSI/TILs/survival. Loss of B2M was often seen in tumors with low TILs (p = 0.056 or p = 0.059 for CD3 and CD8 positive cells, respectively). ConclusionMMR-d, MSI, and TILs are also seen in Lynch syndrome-associated ovarian cancers making these potential candidates for checkpoint-based immunotherapy. The clinical impact from immune evasion through loss of B2M needs to be investigated further in larger cohorts.

Co-Occurrence of Familial Non-Medullary Thyroid Cancer (FNMTC) and Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Associated Tumors-A Cohort Study.

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.

Isolation and Characterization of Chemo-Resistant Stem Cells from a Mouse Model of Hereditary Non-Polyposis Colon Cancer.

RationaleLoss of function mutations in DNA mismatch repair genes is the primary genetic defects in high-risk hereditary non-polyposis colon cancer (HNPCC). Cytotoxic chemotherapy and anti-inflammatory drugs are potential treatment options. These treatment options lead to systemic toxicity, acquired tumor resistance and the emergence of drug-resistant stem cells. A colonic epithelial cell culture model expressing the relevant genetic defects in chemo-resistant stem cells provides a relevant experimental system for HNPCC.ObjectiveTo develop a colonic epithelial cell culture system from a mouse model for HNPCC and to isolate and characterize drug-resistant stem cells.Experimental Models and BiomarkersThe Mlh1 [-/-]/Apc [-/-] Mlh1/1638N COL-Cl1 cells is a mouse model for HNPCC, and the 5-fluoro-uracil resistant (5-FU-R) phenotype represents a model for the drug-resistant stem cells. Tumor spheroid formation, and the expression of CD44, CD133 and c-Myc represent stem cell markers.ResultsThe HNPCC model exhibits aneuploidy, hyper-proliferation, accelerated cell cycle progression and downregulated cellular apoptosis. Long-term exposure to 5-FU selects for the drug-resistant phenotype. These resistant cells exhibit increased formation of tumor spheroids and upregulated expression of cancer stem cell markers CD44, CD133 and c-Myc.ConclusionIn the present study, a stem cell model for HNPCC was validated and offered a novel experimental approach to test stem cell-targeted alternatives to drug-resistant therapy.

The Quality of Life of Patients with Hereditary Nonpolyposis Colorectal Cancer Undergoing Preoperative Chemoradiation

Of all the neoplastic sites, colorectal cancer (CRC) is one of the most common cancers in the family. Studies estimate that approximately 30% of all the CRC cases are a hereditary form of the disease with a potentially high impact on the quality of life (QoL), with a high risk of recurrence, and with bio–psycho–social functioning. The aim of the study was to assess the QoL of colorectal cancer patients with genetic risk by using the European Organisation for Research and Treatment of Cancer (EORTC) questionnaire version QLQ-CR29. Materials and methods: The cross-sectional, single-center study was performed on a group of 32 patients with genetic risk of colorectal cancer, who underwent preoperative chemoradiation and surgery. Results: The series of values for the scores on the symptom scale varied between 15 and 30, and the average level of symptom scores did not differ significantly between gender (22.0 vs. 22.75; p = 0.636), highlighting a moderate impairment of QoL. Scores for the emotional functioning scale were significantly lower in men (10.33 vs. 13.25; p = 0.049), as were the scores for the physical functions (15.67 vs. 19.15; p = 0.039), showing a decrease in QoL. Conclusions: The overall score showed an average QoL in patients with colorectal cancer with genetic risk, highlighting significant differences in psycho-emotional functioning between women and men.

Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes.

In the past two decades, multiple studies have been undertaken to elucidate the genetic cause of the predisposition to mismatch repair (MMR)-proficient nonpolyposis colorectal cancer (CRC). Here, we present the proposed candidate genes according to their involvement in specific pathways considered relevant in hereditary CRC and/or colorectal carcinogenesis. To date, only pathogenic variants in RPS20 may be convincedly linked to hereditary CRC. Nevertheless, accumulated evidence supports the involvement in the CRC predisposition of other genes, including MRE11, BARD1, POT1, BUB1B, POLE2, BRF1, IL12RB1, PTPN12, or the epigenetic alteration of PTPRJ. The contribution of the identified candidate genes to familial/early onset MMR-proficient nonpolyposis CRC, if any, is extremely small, suggesting that other factors, such as the accumulation of low risk CRC alleles, shared environmental exposures, and/or gene–environmental interactions, may explain the missing heritability in CRC.

A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection

BackgroundIn the context of our Regional Program of Hereditary Cancer, individuals fulfilling the criteria are tested for germline mutations to subsequently establish the clinical management. Our standard diagnostic approach focuses on sequencing a few classic high-risk genes, a method that frequently renders uninformative genetic results. This study aims to examine the improved yield offered by an On-Demand panel.MethodsWe designed an On-Demand panel for the analysis of 35-genes associated with inherited cancer susceptibility in a total of 128 cases of Hereditary Breast and Ovarian Cancer (HBOC) and Hereditary Nonpolyposis Colorectal Cancer (HNPCC).ResultsEighteen deleterious mutations were detected, in both routinely (BRCA2, MLH1, MSH2, PMS2) and non-routinely (ATM, BLM, BRIP1, CHEK2, MUTYH) tested genes. The screening extended to 35 genes rendered by patients carrying several- up to 6-Variants of Unknown Significance (VUS). Moreover, we confirmed the splicing disruption at RNA level for a not previously reported BRIP1 splicing mutation. Using an On-Demand panel, we identified 18 pathogenic mutation carriers, seven of which would have gone unnoticed with traditional analysis.ConclusionsOur results reinforce the utility of NGS gene panels in the diagnostic routine to increase the performance of genetic testing, especially in individuals from families with overlapping cancer phenotypes.

Refining Risk Estimates in Hereditary Nonpolyposis Colorectal Cancer: Are We There Yet?

Refining Risk Estimates in Hereditary Nonpolyposis Colorectal Cancer: Are We There Yet?

Benefit from extended surveillance interval on colorectal cancer risk in Lynch syndrome.

Although patients with Lynch syndrome have an increased risk of developing colorectal cancer, surveillance can reduce morbidity and mortality. Whether or not affected individuals benefit from lifetime surveillance depends on individual factors and patient adherence, and these may vary, complicating risk modelling. The aim of this study was to identify individual factors which influence patient adherence to surveillance programmes and whether extended surveillance interval influenced their risk of developing colorectal cancer. Demographics and survival data were obtained from patients (n=1223) with Lynch syndrome, identified by interrogating the Danish Hereditary Non-Polyposis Colorectal Cancer Register. These data were linked to patient surveillance interval data which had been divided into three subsets (<27months, adherent to the recommended biennial programme; >27months, extended surveillance interval; and no surveillance) to estimate the cumulative risks and hazard ratios (HRs) for colorectal cancer. In all, 147 colorectal cancers (99 first; 48 metachronous) were identified in 1223 patients. Factors associated with adherence to surveillance were female sex, a previous history of cancer and age <75years. The cumulative incidence for colorectal cancer was 38% (95% CI 27%-50%) for surveillance intervals <27months, 48% (95% CI 29%-67%) for intervals >27months and 72% (95% CI 61%-83%) with no surveillance. Adjusted HRs were 0.22 for surveillance intervals <27months and 0.32 for surveillance intervals >27months. Extended surveillance intervals >27months had a non-significant benefit with an HR of 1.51 (95% CI 0.83-2.75) compared to surveillance intervals <27months. This study demonstrates that adherence to colonoscopic surveillance in Lynch syndrome varies with age, sex and cancer historyand demonstrates a consistent benefit from colorectal cancer surveillance, though it might be lower for individuals with extended intervals.