Lynch-associated Cancers Research Articles

Pilot study of gene mutations associated with Lynch syndrome in Slovak patients with breast cancer.

Lynch syndrome (LS) is an autosomal dominant inherited disorder which causes an increased risk of cancer, especially colorectal and endometrial carcinomas. Recent studies have shown an association between LS and breast cancer as well. The aim of our study is to highlight the possible presence of mutations in genes associated with LS in patients with breast cancer and the need to include the examination of Lynch-associated genes in patients with a family history of breast cancer as well as in patients with recurrent breast cancer, as well as with the occurrence of other Lynch-associated cancer. We analyzed tumor tissue samples from 78 patients with primary breast cancer. Our samples were tested with a gene panel associated with the risk of developing breast cancer, while in our study we focused primarily on the occurrence of mutations in mismatch-repair genes. DNA isolated from tumor tissue was sequenced using next generation sequencing (NGS) and analyzed using the Ingenuity Variant Analysis tool. To confirm the germline mutation, we examined the patient's blood sample using NGS sequencing. As a result of our analysis, we managed to identify a mutation in the PMS2 gene in one patient's breast tumor tissue. The presence of this mutation indicates that the resulting cancer may be a consequence of LS. As for pathogenicity, this was probably a pathogenic variant, as we detected deletions in the exon region, which led to frameshift mutation. Moreover, we also identified single-nucleotide pathogenic variants in the TP53 and PIK3CA genes. To definitively establish the diagnosis of LS in the patient, we examined a blood sample, where we also identified a mutation of the PMS2 gene. LS is underdiagnosed in many Lynch-associated cancers. However, in the case of a familial occurrence of breast cancer and other Lynch-associated genes, it is important to think about a possible diagnosis of LS and, if the patient meets the diagnostic criteria, to carry out a genetic examination of Lynch-associated genes.

Updates in gynecologic care for individuals with lynch syndrome.

Lynch syndrome is an autosomal dominant hereditary cancer syndrome caused by germline pathogenic variants (PVs) in DNA mismatch repair genes (MLH1, MSH2, PMS2, MSH6) or the EPCAM gene. It is estimated to affect 1 in 300 individuals and confers a lifetime risk of cancer of 10-90%, depending on the specific variant and type of cancer. Lynch syndrome is the most common cause of inherited colorectal cancer, but for women, endometrial cancer is more likely to be the sentinel cancer. There is also evidence that certain PVs causing Lynch syndrome confer an increased risk of ovarian cancer, while the risk of ovarian cancer in others is not well defined. Given this, it is essential for the practicing gynecologist and gynecologic oncologist to remain up to date on the latest techniques in identification and diagnosis of individuals with Lynch syndrome as well as evidence-based screening and risk reduction recommendations for those impacted. Furthermore, as the landscape of gynecologic cancer treatment shifts towards treatment based on molecular classification of tumors, knowledge of targeted therapies well-suited for mismatch repair deficient Lynch tumors will be crucial. The objective of this review is to highlight recent updates in the literature regarding identification and management of individuals with Lynch syndrome as it pertains to endometrial and ovarian cancers to allow gynecologic providers the opportunity to both prevent and identify Lynch-associated cancers earlier, thereby reducing the morbidity and mortality of the syndrome.

Lynch syndrome: further defining the pediatric spectrum

Lynch syndrome (LS) is an autosomal dominant cancer predisposition syndrome defined molecularly by the presence of a pathogenic heterozygous variant in one of the mismatch repair genes: MLH1, MSH2, MSH6, PMS2, or EPCAM. The incidence of LS in the general population is estimated at 1 in 279, with an even higher incidence in those with colorectal cancer and endometrial cancer, the two most common Lynch-associated cancers. Lynch syndrome is currently considered an “adult onset” cancer predisposition syndrome, with the majority of malignancies appearing in adulthood, and recommended screening beginning in adulthood. At present, expert guidelines discourage testing minors for Lynch syndrome.We report seven cases in which children presented with LS and pediatric malignancy, suggesting possible association of childhood onset of cancers with monoallelic mismatch repair deficiency.

Multi-gene hereditary cancer testing, family history and prognosis in men with prostate cancer.

5073 Background: Multi-gene hereditary cancer testing is common in prostate cancer (PC). We assessed the frequency of pathogenic mutations (mt) and examined associations with family history (FH), cancer recurrence, and overall survival (OS). Methods: Men with clinically localized or metastatic PC consented to germline DNA testing using a validated panel of 30 genes associated with elevated risk for common cancers (Color Genomics). Chi-square test and Fisher’s exact test were used to compare pathogenic mt and clinical characteristics. The Kaplan-Meier method was used to evaluate the associations of mt status with PSA recurrence and OS. Results: 315 men (median age 69, range 38-89) were included; 140 (44.4%) with localized and 175 (55.6%) with metastatic PC. 215 (68.3%) reported a FH of any cancer in one and 101 (32.1%) in ≥ 2 first-degree relatives. Genomic testing detected 12.1% of pts possessed a pathogenic mt (39 mt in 38 pts): BRCA2 (n = 12, 3.8%), CHEK2 (n = 10, 3.2%), APC (n = 7, 2.2%), MUTYH (n = 3, 0.9%), ATM (n = 2, 0.6%), and 1 each (0.3%) with NBN, PALB2, RAD51D, MSH2, and PMS2. Variants of uncertain significance were detected in 52 (16.5%). Men with FH of prostate, breast, ovarian, pancreatic cancer or/and melanoma (182/315, 58%), were more likely to have BRCA2 pathogenic mt (P = 0.049). Median age of diagnosis was 55 with BRCA2 versus 62 in non-carriers (P = 0.01). No association was found between FH of Lynch-associated cancers (colon, endometrial, gastric) and mismatch repair gene variants. The prevalence of pathogenic mt was significantly higher with visceral metastases (P = 0.001) but did not differ between localized and advanced PC pts (P = 0.602). In men with clinically localized PC at diagnosis (n = 226, 71.7%), pathogenic mt were associated with a shorter time to recurrence (30 vs 53 months, P = 0.004). Men with advanced PC (n = 175) and germline APC or MUTYH mt had worse median OS (44 vs 318 months, P = 0.004). Conclusions: Our findings confirm the incidence of men with non-PC FH associated with DNA repair gene mt and support testing in early stage pts. Further, our data support the prognostic significance of germline genetic alterations which deserves study in a larger cohort of pts.

Lynch Syndrome: From Screening to Diagnosis to Treatment in the Era of Modern Molecular Oncology.

Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline alterations in the mismatch repair genes and is the most common etiology of hereditary colorectal cancer. While Lynch syndrome was initially defined by the clinical Amsterdam criteria, these criteria lack the sensitivity needed for clinical utility. This review covers the evolution of screening for Lynch syndrome from the use of tumor microsatellite instability and/or somatic alterations in mismatch repair protein expression by immunohistochemistry to the newest methods using next-generation sequencing. Additionally, it discusses the clinical implications of the diagnosis of Lynch syndrome as it affects cancer therapeutics and the role of screening in noncolorectal Lynch-associated cancers. As molecular oncology continues to evolve, it is crucial to remain current on the increasing complexity of Lynch syndrome diagnostics and treatment options.

Recent advances in Lynch syndrome.

Lynch syndrome is one of the most common hereditary cancer predisposition syndromes and is associated with increased risks of colorectal and endometrial cancer, as well as multiple other cancer types. While the mechanism of mismatch repair deficiency and microsatellite instability and its role in Lynch-associated carcinogenesis has been known for some time, there have been significant advances recently in diagnostic testing and the understanding of the molecular pathogenesis of Lynch tumors. There is also an increased awareness that the clinical phenotype and cancer risk varies by specific mismatch repair mutation, which in turn has implications on surveillance strategies for patients. Even the treatment of Lynch-associated cancers has changed with the addition of immunotherapy for advanced disease. This progress report aims to review some of the many advances in epidemiology, molecular pathogenesis, diagnosis, clinical phenotype, cancer surveillance, treatment, and chemo- and immune-prevention strategies in the Lynch syndrome field over the past 5years.

Systematic Review: An Update on the Spectrum of Urological Malignancies in Lynch Syndrome.

Background:Lynch syndrome is an autosomal dominant disorder that predisposes individuals affected to certain malignancies. Colon and endometrial cancers are the malignancies most highly associated with Lynch syndrome. However, growing body of evidence links Lynch syndrome to urological cancers.Objective:This review aims to clarify the type of urological malignancies that fall under the Lynch-associated cancer spectrum.Methods:Using PRISMA guidelines, a systematic search between January 1990 to February 2018, was conducted using the MEDLINE database with the application of the following MESH terms: colorectal neoplasms, hereditary nonpolyposis; DNA mismatch repair; urologic neoplasms; kidney pelvis; ureteral neoplasms; urinary bladder; carcinoma, transitional cell; prostatic neoplasms; testicular neoplasms.Results:Upper tract urothelial cancers are well established under the Lynch spectrum. Increasing evidence supports its association with prostate cancer. However, there is, inconclusive and limited evidence for an association with bladder and testicular cancer.Conclusions:The evidence underpinning certain urological malignancies associated with Lynch syndrome has expanded in recent years. Our review may assist in providing a summary of the current standing in literature. However, we recommend further investigations to better clarify associations, particularly with prostate, bladder and testicular cancer.

How to Screen for Hereditary Cancers in General Pathology Practice.

-As a pathologist, an awareness of the particular diagnoses that can serve as "sentinels" for an underlying genetic syndrome can be incredibly beneficial to patients and their families. This is a complex and ever-changing field of medicine, where remaining up to date with diagnostic and treatment options is challenging. Simply raising the possibility of an underlying syndrome may not, in itself, be diagnostic; however, this may present an opportunity for genetic assessment, and possibly early intervention or primary prevention of disease in the kindred. In the last decade, immunohistochemistry has emerged as a useful tool in hereditary cancer screening. This is best exemplified by the use of mismatch repair immunohistochemistry as a screening tool in colorectal and endometrioid carcinomas. Reflex testing of all tumors for deficiencies in these proteins is now resulting in superior identification and treatment of Lynch-associated cancers, and families harboring these syndromes. Despite the success and potential value of immunohistochemistry as a genetic screening tool, hematoxylin-eosin morphology remains a valuable tool for hereditary cancer screening and is the focus of this article. -To highlight the utility of hematoxylin-eosin morphology as a valuable tool for hereditary cancer screening. -Primary literature review with PubMed. -Recognition of tumors associated with cancer predisposition may identify individuals and families at high risk for cancer and may also have peridiagnostic utility with regard to implications for targeted therapy.

Tu1019 A Prospective Evaluation of the Feasibility of Process Engineering Intervention on the Screening and Testing of Lynch Syndrome in Individuals With a Personal and/or Family History of Lynch-Associated Cancers

Tu1019 A Prospective Evaluation of the Feasibility of Process Engineering Intervention on the Screening and Testing of Lynch Syndrome in Individuals With a Personal and/or Family History of Lynch-Associated Cancers

Evaluation of the colorectal cancer risk conferred by rareUNC5Calleles

To evaluate the risk associated with variants of the UNC5C gene recently suspected to predispose to familial colorectal cancer (CRC). We screened patients with familial CRC forms as well as patients with sporadic CRCs. In a first time, we analyzed exon 11 of the UNC5C gene in 120 unrelated patients with suspected hereditary CRC, 58 patients with suspected Lynch-associated cancer or polyposis, and 132 index cases of Lynch syndrome families with a characterized mutation in a DNA mismatch repair (MMR). Next, 1023 patients with sporadic CRC and 1121 healthy individuals were screened for the variants identified in patients with familial cancer. Of 120 patients with familial CRC of unknown etiology, one carried the previously reported mis-sense mutation p.Arg603Cys (R603C) and another exhibited the unreported variant of unknown significance p.Thr617Ile (T617I). The p.Ala628Lys (A628K) mutation previously described as the main UNC5C risk variant for familial CRC was not detected in any cases of familial CRC of unknown etiology, but was present in a patient with familial gastric cancer and in two Lynch syndrome patients in co-occurrence with MMR mutations. A statistically non-significant increase in cancer risk was identified in familial CRC and/or other Lynch-associated cancers (1/178 patients vs 2/1121 healthy controls, OR = 3.2, 95%CI: 0.29-35.05, P = 0.348) and in sporadic CRCs (4/1023 patients vs 2/1121 healthy controls, OR = 2.2, 95%CI: 0.40-12.02, P = 0.364). We confirm that UNC5C mutations are very rare in familial and sporadic CRCs, but further investigations are needed to justify routine UNC5C testing for diagnostic purposes.

Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines

J. Balmana1, F. Balaguer2, A. Cervantes3 & D. Arnold4, on behalf of the ESMO Guidelines Working Group* Department of Medical Oncology, Hospital Vall d’Hebron, Vall d’Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona; Department of Gastroenterology, Hospital Clinic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona; Department of Hematology and Medical Oncology, INCLIVA, University of Valencia, Valencia, Spain; Department of Medical Oncology, Tumor Biology Clinic, Albert Ludwigs University, Freiburg, Germany;

‘PREMM 1,2,6 MODEL’ as a new gene specific prediction model for Lynch Syndrome: retrospective review of mutation positive cases

Lynch Syndrome, also called Hereditary NonPolyposis Colorectal Cancer (HNPCC), occurs as a consequence of germline mutations in the mismatch repair (MMR) system (Stoffel et al., 2009), mainly in MLH1 and MSH2 (>90% of cases), but also in MSH6 and PMS2 [1]. Kastrinos et al., (2011) developed a new web-based multivariable polytomous logistic regression model for Providing gene specific Risk Estimates (Model) (PREMM 1,2,6) that uses genotype-phenotype data from MLH1, MSH2, and MSH6 mutation carriers to generate individualized predictions for each gene based on personal and family history characteristics [1] recommends that a gene prediction of >5% should be a threshold for a referral for further genetic risk assessment. A search was performed to obtain a list of patients seen at the Prince of Wales Hereditary Cancer Clinic who were sequenced for mutations in MLH1, MSH2 or MSH6 from 1994 to 2011 with 78% occurring after 2005. A total of 40 patient pedigrees were obtained and used for the PREMM 1,2,6 model, 29 were mutation positive and 11 were tested inconclusive. 17% of probands were selected for testing based on tumour testing and the remainder were selected based on family history alone. The model included proband and first and second degree relative’s age and diagnosis of colorectal cancer and endometrial cancer. This model also used an inclusion for extra colonic Lynch-associated cancers. Each proband was also assessed by the Amsterdam II criteria and given a risk category according to the Australian Cancer Network Guidelines of average, 1, 2 or 3. A gene-specific mutation prediction cut off of 5% was instigative of a mutation for 21 probands (8/12 for MLH1, missing 33%, 11/13 for MSH2, missing 2% and 2/4 for MSH6). Based on this limited data, endometrial cancer was highly predictive for MSH6. The prevalence of extracolonic, nonendometrial HNPCC-associated cancers was higher among MSH2 carriers than MLH1 and MSH6 carriers, being weakly predictive. The specific gene estimates were not useful for when tumour analysis was unavailable, with 59% (17) mutation positive probands having a low Premm1,2,6 score, which would not have support a decision to pursue single gene testing. Amsterdam II criteria and Australian Network Guidelines have been previously found to be an ineffective strategy for triage for gene testing for Lynch Syndrome. Further study on a larger cohort is needed to determine if the PREMM 1,2,6 model is an effective triage tool for gene testing for Lynch Syndrome.

Endometrial cancer patients and compliance with genetic counseling: Room for improvement

Introduction Immunohistochemistry (IHC) for the presence or absence of DNA mismatch repair (MMR) proteins in tumor samples is a quick and relatively inexpensive method to screen for Lynch syndrome (LS). At our institution we have found that > 20% of patients lack expression of MMR proteins and > 10% would be expected to benefit from genetic counseling (GC). However, compliance with referral to GC is poor. Therefore, we set out to analyze the reasons for noncompliance, hypothesizing that it could be due to a perception of a low risk for developing other cancers. Methods All patients with endometrial cancer between 2007 and 2009 were identified. Patients with absence of MMR protein expression who would be expected to benefit from GC were identified. These patients were sent a questionnaire assessing the utilization of GC services as well as their perception of LS and Lynch-associated cancers. Results Forty-seven patients out of 384 were identified who would have been expected to benefit from GC. Of the responders, 20 patients (77%) reported that they were referred by their physician for GC, of which 9 saw a genetic counselor, 8 had genetic testing, and 3 mutations were detected. The primary reason for not seeing a genetic counselor was no insurance coverage/cost of the visit followed by anxiety for the results. Nine patients stated that the patient/family did not want to know information regarding cancer risk. As compared to the general population 35% thought their risk of having LS was higher, 12% thought it was the same, 15% lower, and 38% was unsure. Forty-six percent of patients thought the risk of colon cancer was higher than background risk, and 26% thought it was the same. Conclusion Most patients underestimate their risk of LS associated heritable cancer. Physicians should pay more attention to family history and IHC in order to refer patients appropriately. In addition, more verbal and written information may enable patients to accurately assess their cancer risk. This could further improve compliance with genetic counseling and detection of Lynch syndrome.

The role of expanded testing for Lynch syndrome in women with endometrial cancer.

The role of expanded testing for Lynch syndrome in women with endometrial cancer.

Testing women with endometrial cancer to detect Lynch syndrome.

Women with endometrial cancer as a result of Lynch syndrome may not be identified as such by Amsterdam II criteria. We estimated the costs and benefits of different testing criteria to identify Lynch syndrome in women with endometrial cancer. We developed a Markov Monte Carlo simulation model to compare six criteria for Lynch syndrome testing for women with endometrial cancer: Amsterdam II criteria; age younger than 50 years with at least one first-degree relative having a Lynch-associated cancer at any age (FDR); immunohistochemistry (IHC) triage if age younger than 50 years; IHC triage if age younger than 60 years; IHC triage at any age if 1 FDR; and IHC triage of all endometrial cancers. Net health benefit was life expectancy, and primary outcome was the incremental cost-effectiveness ratio (ICER). The model estimated the number of new colorectal cancers associated with each strategy. IHC triage of women with endometrial cancer having at least 1 FDR yielded a favorable ICER of $9,126 per year of life gained. This strategy would subject fewer cases to IHC but identify more mutation carriers than age thresholds of 50 or 60 years. IHC triage of all endometrial cancers could identify the most mutation carriers and prevent the most colorectal cancers but at considerable cost ($648,494 per year of life gained). IHC triage of women with endometrial cancer at any age having at least 1 FDR with a Lynch-associated cancer is a cost-effective strategy for detecting Lynch syndrome.

Familial Risk of Cancer and Knowledge and Use of Genetic Testing

Identification of genetic risk factors for common diseases, including cancer, highlights the importance of familial risk assessment. Little is known about patterns of familial cancer risk in the general population, or whether this risk is associated with knowledge and use of genetic testing. To examine the distribution of familial cancer risk and its associations with genetic testing in the United States. Cross-sectional analysis of the 2005 National Health Interview Survey (NHIS). 31,428 adults who completed the NHIS Cancer Control Supplement. Familial cancer risk was estimated based on the number of first-degree relatives with a breast and ovarian cancer syndrome (BRCA)- or a Lynch-associated cancer, age of onset (<50 or > or = 50 years), and personal history of any cancer. Outcomes included having heard of genetic testing, discussed genetic testing with a physician, been advised by a physician to have testing, and received genetic testing. Most adults (84.5%) had no family history of BRCA- or Lynch syndrome-associated cancer; 12.9% had a single first-degree relative (5.3% with early onset); and 2.7% had > or = 2 first-degree relatives. Although 40.2% of adults had heard of genetic testing for cancer risk, only 5.6% of these individuals had discussed testing with a physician, and of these 36.9% were advised to be tested. Overall, only 1.4% of adults who had heard of genetic testing received a test. Familial risk was associated with higher rates of testing; 49.5% of participants in the highest risk group had heard of testing, of those 14.8% had discussed it with their physician, and 4.5% had received genetic testing. These nationally representative data provide estimates of the prevalence of familial cancer risk in the US and suggest that information about genetic testing is not reaching many at higher risk of inherited cancer.

Microsatellite instability and survival in rectal cancer

High levels of microsatellite instability (MSI-H) have been associated in many studies with improved prognosis in colon cancer. Very few studies have evaluated the effect of MSI-H on rectal cancer survival. We assessed MSI-H and other genetic and epigenetic changes on survival of 990 individuals diagnosed with first primary rectal cancer. MSI was assessed primarily by instability in the mononucleotide repeat BAT-26. The BRAF V600E mutation was assessed by TaqMan assay. The CpG island methylator phenotype (CIMP) was determined by methylation-specific PCR of CpG islands in MLH1, methylated in tumors (MINT)1, (MINT)2, (MINT)31 and CDKN2A. KRAS2 codons 12 and 13 mutations, and TP53 mutations in exons 5-8 were determined by sequencing. Multivariate analysis revealed that MSI-H (HRR 2.47, 95% CI 1.13-5.40) and KRAS2 mutations (HRR 1.37, 95% CI 1.04-1.81) were associated with a significantly higher risk of dying of rectal cancer. Only one of 22 MSI-H tumors showed a BRAF V600E mutation. Of 15 MSI-H rectal cancers evaluated for methylation, two exhibited MLH1 methylation and four exhibited CIMP. The genetic and epigenetic characteristics of MSI-H rectal cancers suggest that they are enriched for Lynch-associated tumors; adverse prognosis associated with MSI-H in these tumors may reflect the relatively high frequency of Lynch-associated cancers and/or the effect of radiation or chemotherapy on Lynch-associated rectal cancers or MSI tumors in general.