From Genetics to Histomolecular Characterization: An Insight into Colorectal Carcinogenesis in Lynch Syndrome.

Lynch syndrome is a hereditary cancer-predisposing syndrome caused by germline defects in DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2. Carriers of pathogenic mutations in these genes have an increased lifetime risk of developing colorectal cancer (CRC) and other malignancies. Despite intensive surveillance, Lynch patients typically develop CRC after 10 years of follow-up, regardless of the screening interval. Recently, three different molecular models of colorectal carcinogenesis were identified in Lynch patients based on when MMR deficiency is acquired. In the first pathway, adenoma formation occurs in an MMR-proficient background, and carcinogenesis is characterized by APC and/or KRAS mutation and IGF2, NEUROG1, CDK2A, and/or CRABP1 hypermethylation. In the second pathway, deficiency in the MMR pathway is an early event arising in macroscopically normal gut surface before adenoma formation. In the third pathway, which is associated with mutations in CTNNB1 and/or TP53, the adenoma step is skipped, with fast and invasive tumor growth occurring in an MMR-deficient context. Here, we describe the association between molecular and histological features in these three routes of colorectal carcinogenesis in Lynch patients. The findings summarized in this review may guide the use of individualized surveillance guidelines based on a patient's carcinogenesis subtype.

Lynch Syndrome in Thai Endometrial Cancer Patients.

BACKGROUND: Lynch syndrome increases lifetime risk of endometrial cancer to 40-60%. Screening with molecular tumor testing for mismatch repair (MMR) proteins have been recommended. This study aims to evaluate the incidence of MMR deficiency and germline mutation in endometrial cancer Thai patients. METHODS: Immunohistochemistry for MMR proteins, including MLH1, MSH2, MSH6 and PMS2 were tested in 166 surgical specimens. Patients who had MMR deficiencies were offered genetic counseling and a germline testing using gene-panel next generation sequencing. RESULTS: Fifty-eight of 166 patients (34.9%) had one or more MMR deficiencies which were: MLH1 and PMS2 in 42 patients (25.3%), MSH2 and MSH6 in 11 patients (6.6%), and MSH6 in 5 patients (3.0%). Of the 40 patients (24.1%) who met the revised Bethesda guidelines, 19 patients (47.5%) had MMR deficiency. In contrast, MMR deficiency was found in 39 of the 126 patients (31.0%) who did not meet the revised Bethesda guidelines. A total of 27 patients with MMR deficiencies agreed to have germline genetic testing. Germline MMR mutations were detected in 5 patients (18.5%) including MSH6 (n=2), PMS2 (n=2), and MLH1 mutations (n=1). Incidental germline mutations in other genes were detected in 3 patients (1 BRCA1, 1 PTEN, and 1 BARD1). Among 5 Lynch syndrome patients, 2 patients (40%) did not meet the revised Bethesda guidelines. Eight patients who met the revised Bethesda Guidelines but having MMR proficiency had genetic testing, but no germline mutation was detected. CONCLUSION: MMR deficiencies were detected in 34.9% of the endometrial cancer patients. Germline mutations were diagnosed in 3.0% of this cohort (5/166 patients). Lynch syndrome screening with MMR immunohistochemistry should be considered in all patients regardless of personal or family history of Lynch syndrome-related cancers.

Lynch syndrome associated endometrial carcinomas in Western Australia: an analysis of universal screening by mismatch repair protein immunohistochemistry.

BACKGROUND: In 2016 universal screening with mismatch repair protein immunohistochemistry in all newly diagnosed endometrial carcinomas was introduced in Western Australia. OBJECTIVE: To compare the prevalence of Lynch syndrome associated endometrial carcinomas between 2016 and 2019 with a historical control (2015). Additionally, to compare the number of cases appropriately referred for genetic assessment. METHODS: A cross-sectional study of cases presented at the Western Australia gynecologic oncology tumor board was carried out. The primary outcome was the prevalence of Lynch syndrome associated endometrial carcinomas. A secondary outcome was the number of cases appropriately referred for genetic assessment. The following variables were extracted: date of birth; age at diagnosis; vital status; tumor mismatch repair protein expression status (retained or lost) and if lost, the specific mismatch repair protein deficiency; patients who were referred to a genetic clinic; and family history, if recorded. Data were collected from the clinical databases of the Familial Cancer Program at Genetic Services of Western Australia and WOMEN Center, to determine whether patients were appropriately referred for genetic evaluation and to ascertain the results of genetic testing. RESULTS: Between 2016 and 2019, there were 1040 new endometrial carcinomas. Tumors of 883 (85%) patients underwent mismatch repair protein immunohistochemistry compared with 117 of 199 patients (59%) in 2015 (χ2 73.14, p<0.001). Of 883 tumors tested, 242 (27%) showed loss of mismatch repair protein expression. In 2015, 30 (26%) tumors of 117 tested showed loss of mismatch repair protein expression. During the 4 years of universal screening, 13 (1.5%) of 883 patients screened were diagnosed with Lynch syndrome compared with 2 (1.7%) of 117 in 2015 (Fisher's exact test 0.04, p=0.69). In 2015, 11 (37%) of 30 patients with loss of mismatch repair protein expression were not referred for genetic assessment compared with 36 (17%) of 209 patients in the universal screening group (χ2 6.28, p=0.02). No cases of Lynch syndrome were diagnosed in patients aged over 70 years. CONCLUSIONS: Universal immunohistochemical screening did not increase the proportion of Lynch syndrome associated endometrial carcinomas identified, although the study was underpowered to detect small differences. There was an improvement in appropriate referrals for genetic assessment.

Evaluation of a nationwide Dutch guideline to detect Lynch syndrome in patients with endometrial cancer.

OBJECTIVE: In the Netherlands a nationwide guideline was introduced in 2016, which recommended routine Lynch syndrome screening (LSS) for all women with endometrial cancer (EC) <70 years of age. LSS consists of immunohistochemical (IHC) staining for loss of mismatch repair (MMR) protein expression, supplemented with MLH1 methylation analysis if indicated. Test results are evaluated by the treating gynaecologist, who refers eligible patients to a clinical geneticist. We evaluated the implementation of this guideline. METHODS: From the nation-wide pathology database we selected all women diagnosed with EC < 70 years of age, treated from 1.6.2016-1.6.2017 in 14 hospitals. We collected data on the results of LSS and follow up of cases with suspected LS. RESULTS: In 183 out of 204 tumours (90%) LSS was performed. In 41 cases (22%) MMR protein expression was lost, in 25 cases due to hypermethylation of the MLH1 promotor. One patient was known with a pathogenic MLH1 variant. The option of genetic counselling was discussed with 12 of the 15 remaining patients, of whom three declined. After counselling by the genetic counsellor nine patients underwent germline testing. In two no pathogenic germline variant was detected, two were diagnosed with a pathogenic PMS2 variant, and five with a pathogenic MSH6 variant, in concordance with the IHC profiles. CONCLUSION: Coverage of LSS was high (90%), though referral for genetic counselling could be improved. Gynaecologists ought to be aware of the benefits and possible drawbacks of knowing mutational status, and require training in discussing this with their patients.

Prevalence of Lynch syndrome in women with mismatch repair-deficient ovarian cancer.

BACKGROUND: There are limited data on the prevalence of Lynch syndrome (LS) in women with primary ovarian cancer with mismatch repair deficiency (MMR-D) by immunohistochemistry (IHC). MATERIALS AND METHODS: Three hundred and eight cases of primary ovarian, fallopian, and peritoneal cancer between January 2012 and December 2019 were evaluated for MMR-D by IHC. The incidence of LS in this cohort was evaluated. RESULTS: MMR-D by IHC was identified in 16 of 308 (5.2%) (95% CI: 3.2%-8.3%) primary ovarian-related cancers. Most cases with MMR-D were endometrioid (n = 11, 68.7%); (95% CI: 44.2%-86.1%). MSH2/MSH6 protein loss was detected in eight cases (50.0%); (95% CI: 28.0%-72.0%) and MLH1/PMS2 protein loss was detected in four cases (25.0%); (95% CI: 9.7%-50.0%). MSH6 protein loss was detected in two cases (12.5%); (95% CI: 2.2%-37.3%) and PMS2 protein loss was detected in two cases (12.5%); (95% CI: 2.2%-37.3%). All four cases with MLH1/PMS2 protein loss had MLH1 promotor hypermethylation. All 12 women with ovarian cancer suggestive of LS underwent germline testing and 8 (66.6%); (95% CI: 38.8%-86.5%) were confirmed to have LS. CONCLUSIONS: Most ovarian cancers with somatic MMR-D were confirmed to have LS in this cohort. Germline testing for LS in addition to BRCA1/2 for all women with an epithelial ovarian cancer would be efficient and would approach 100% sensitivity for identifying Lynch syndrome. Utilization of a multigene panel should also be considered, given the additional non-Lynch germline mutation identified in this cohort.

Lynch syndrome with exclusive skin involvement: time to consider a molecular definition?

Muir-Torre syndrome (MTS) is clinically characterized by the occurrence of skin, usually sebaceous, and visceral tumors in the same individual. The most common underlying mechanism is a constitutional defect of the mismatch repair (MMR) genes that cause Lynch syndrome (LS). Herewithin we report on a 76 years-old male patient heterozygous for a pathogenic MSH2 missense substitution who presented with a striking cutaneous phenotype in the absence of typical LS visceral tumors. The patient developed 20 skin tumors, including sebaceous adenomas/carcinomas and keratoacanthomas. Two skin tumors showed immunohistochemical loss of MSH2 and MSH6 expression. There was no apparent family history of neoplasia. Based on the variable involvement of the skin and internal organs, we suggest that the definition of tumor associations that are often observed as variants of inherited tumor syndromes, such as MTS, should be guided by the underlying molecular bases. In addition, the presence of multiple sebaceous tumors, especially if showing MMR deficiency, appears to be a very strong indicator of a constitutional MMR gene defect. The reasons underlying the high phenotypic variability of cutaneous phenotypes associated with constitutional MMR defects are yet to be determined.

Survivorship Guidance for Patients with Colorectal Cancer.

OPINION STATEMENT: Effective therapy for treatment of colorectal cancer includes comprehensive and evidence-based therapies that may include a combination of surgery, chemotherapy, targeted therapy, and/or radiation. However, in order to provide patients with the highest quality of care, providers must consider all aspects of survivorship care including: surveillance for recurrence/second primaries, genetic counseling, psychosocial/physical late effects of cancer and its therapies, and preventative lifestyle strategies. Health systems, providers, and researchers need to identify systematic methods of addressing the unique needs of the survivorship population that include multidisciplinary teams including supportive oncology (i.e., psychologists, social workers), specialties (i.e., cardiology), and primary care physicians.

Recent Advances in Lynch Syndrome: Diagnosis, Treatment, and Cancer Prevention.

Identification of individuals with inherited predispositions to cancer, including Lynch syndrome, can help prevent cancer and cancer-related death by allowing for the uptake of specific cancer prevention and screening as well as the use of therapies directed toward the underlying neoplastic process for individuals with advanced cancer. In the 25 years since the discovery of microsatellite instability (MSI) and the first recognition of germline mismatch repair (MMR) gene variants as the etiologic basis of Lynch syndrome, there has been tremendous progress in the understanding of the spectrum of cancer risk associated with Lynch syndrome as well as in cancer prevention and risk-reduction strategies. The past few years, in particular, have brought transformative changes in the treatment of Lynch syndrome-associated cancers with immune checkpoint inhibitors. In parallel, advances in next-generation sequencing (NGS) technologies now allow rapid and scalable somatic and germline sequencing that promises to help identify Lynch syndrome in individuals who otherwise lack classic phenotypes. Last, real progress is being made to understand more sophisticated methods of precision cancer prevention, including chemotherapeutic prevention agents (e.g., aspirin) and strategies that leverage the immune system to facilitate primary cancer prevention in otherwise-healthy Lynch syndrome carriers.

Screening for Lynch syndrome using risk assessment criteria in patients with ovarian cancer.

OBJECTIVE: Lynch syndrome is a cancer predisposition syndrome caused by germline mutation of DNA mismatch repair (MMR) genes. Lynch syndrome only causes about 0.4% of cases of ovarian cancer, which suggests that universal screening may not be cost-efficient. However, the frequency of Lynch syndrome in ovarian cancer is unclear in the Asian population. The goal of the study was to investigate a screening strategy using family history. METHODS: The subjects were 129 patients with ovarian cancer. Clinical and family history were collected using a self-administered questionnaire, and Society of Gynecologic Oncology (SGO) criteria 2007 and PREMM5 were used for risk assessment. Microsatellite instability, immunohistochemistry, and methylation of MMR genes were analyzed. RESULTS: Of the 129 cases, 25 (19.4%) met the SGO criteria, and 4 of these 25 had MSI-high and MMR deficiency. Two cases had loss of MSH2 and MSH6, indicating MSH2 mutation, and the other two had loss of MLH1 and PMS2, including one without MLH1 methylation indicating MLH1 mutation. These results show that screening using family history can detect Lynch syndrome in 12.0% (3/25) of ovarian cancer cases. The 3 cases were positive for PREMM5, but negative for Amsterdam II criteria and revised Bethesda guidelines. Genetic testing in one case with MSH2 and MSH6 deficiency confirmed the diagnosis of Lynch syndrome with MSH2 mutation. CONCLUSION: This is the first study of screening for Lynch syndrome in ovarian cancer using clinical and family history in an Asian population. This approach may be effective for diagnosis in these patients.

Towards gene- and gender-based risk estimates in Lynch syndrome; age-specific incidences for 13 extra-colorectal cancer types.

BACKGROUND: In Lynch syndrome, inherited mismatch repair (MMR) defects predispose to colorectal cancer and to a wide spectrum of extra-colorectal tumours. Utilising a cohort study design, we aimed to determine the risk of extra-colorectal cancer and to identify yet unrecognised tumour types. METHODS: Data from 1624 Lynch syndrome mutation carriers in the Danish hereditary non-polyposis colorectal cancer register were used to estimate the sex- and age-specific incidence rate ratios (IRRs) for 30 extra-colorectal malignancies with comparison to the general population. RESULTS: Significantly increased IRRs were identified for 13 cancer types with differences related to gender, age and disease-predisposing gene. The different cancer types showed variable peak age incidence rates (IRs) with the highest IRs for ovarian cancer at age 30-49 years, for endometrial cancer, breast cancer, renal cell cancer and brain tumours at age 50-69 years, and for urothelial cancer, small bowel cancer, gastric cancer, pancreatic cancer and skin tumours after age 70. CONCLUSIONS: The broad spectrum of tumour types that develop at an increased incidence defines Lynch syndrome as a multi-tumour syndrome. The variable incidences in relation to age, gender and gene suggest a need for individualised surveillance.

Hereditary diffuse gastric cancer and lynch syndromes in a BRCA1/2 negative breast cancer patient.

INTRODUCTION: Genetic counseling and testing is recommended for women with a personal and/or family history of breast and other cancers (ovarian, pancreatic, male breast and others). Mutations in the BRCA1 and BRCA2 genes (BRCA1/2) are the most common causes of hereditary breast and ovarian cancer. Additional genetic counseling and testing with a multi-gene panel may be considered in breast cancer patients who tested negative for mutations in these two genes. In about 11% of BRCA1/2-negative patients, further genetic testing reveals pathogenic mutations in other high or moderate cancer risk genes. In 0.2% of cases, an individual may carry pathogenic mutations in more than one high penetrance gene (a double heterozygote). Finding one or more pathogenic mutations is important for cancer prevention in patients and/or their families. CASE PRESENTATION: Here we present a case of a breast cancer patient who did not have a pathogenic mutation in BRCA1/2 and had a family history of breast and stomach cancers. On an additional multi-gene panel testing, she was found to carry pathogenic mutations in the CDH1 and PMS2 genes, which cause Hereditary Diffuse Gastric Cancer and Lynch syndromes, respectively. To our knowledge, this is the first description of such a double heterozygote. DISCUSSION: Clinical manifestations, genetics, and management of both syndromes are reviewed, including prophylactic surgery and screening for unaffected family members. Management challenges for a mutation carrier with advanced breast cancer are discussed. Our case supports the clinical utility of additional multi-gene panel testing for breast cancer patients who do not have a pathogenic mutation in BRCA1/2 genes.

Lynch Syndrome and Endometrial Cancer.

In patients with Lynch syndrome, gynecologic cancer often can be the first presenting malignancy. In this review, we summarize the genetics of Lynch syndrome and review the various modalities of identifying patients at risk for this syndrome. The clinical characteristics of Lynch-associated endometrial cancer and screening and risk-reducing strategies also are described.

Epidemioclinical Feature of Early-Onset Colorectal Cancer at-Risk for Lynch Syndrome in Central Iran.

BACKGROUND: Colorectal cancer (CRC) is becoming one of the most complicated challenges of human health, particularly in developing countries like Iran. In this paper, we try to characterize CRC cases diagnosed < age 50 at-risk for Lynch syndrome within central Iran. MATERIALS AND METHODS: We designed a descriptive retrospective study to screen all registered CRC patients within 2000-2013 in Poursina Hakim Research Center (PHRC), a referral gastroenterology clinic in central Iran, based on being early-onset (age at diagnosis ≤50 years) and Amsterdam II criteria. We calculated frequencies and percentages by SPSS 19 software to describe clinical and family history characteristics of patients with early-onset CRC. RESULTS: Overall 1,659 CRC patients were included in our study of which 413 (24.9%) were ≤50 years at diagnosis. Of 219/413 successful calls 67 persons (30.6%) were reported deceased. Family history was positive for 72/219 probands (32.9%) and 53 families (24.2%) were identified as familial colorectal cancer (FCC), with a history of at-least three affected members with any type of cancer in the family, of which 85% fulfilled the Amsterdam II Criteria as hereditary non-polyposis colorectal cancer (HNPCC) families (45/219 or 20.5%). Finally, 14 families were excluded due to proband tumor tissues being unavailable or unwillingness for incorporation. The most common HNPCC-associated extracolonic- cancer among both males and females of the families was stomach, at respectively 31.8 and 32.7 percent. The most common tumor locations among the 31 probands were rectum (32.3%), sigmoid (29.0%), and ascending colon (12.9%). CONCLUSIONS: Given the high prevalence of FCC (~1/4 of early-onset Iranian CRC patients), it is necessary to establish a comprehensive cancer genetic counseling and systematic screening program for early detection and to improve cancer prognosis among high risk families.

Rheumatoid Arthritis as a Therapeutic Challenge in a Patient with Lynch Syndrome.

BACKGROUND: Lynch syndrome (LS) is an inherited colorectal cancer (CRC) syndrome accounting for about 3-5% of all cases and involves significantly higher risk of subsequent malignancies, colonic as well as extra-colonic. Increased risk of malignancies, especially lymphoid malignancies, have been described in patients with autoimmune diseases like rheumatoid arthritis (RA), systemic lupus erythematosus, and Sjögren's syndrome. Epidemiological studies demonstrated that hematopoietic, lung, skin, and prostate cancers are increased in RA, while breast and colon cancers are decreased, with an overall slight increase in all cancers. CASE REPORT: Our case demonstrates the development of CRC, endometrial cancer, and breast cancer as a presentation of LS in a patient with RA and presents a therapeutic challenge for RA treatment. CONCLUSIONS: We describe a patient with LS and RA presenting a therapeutic challenge because biologic agents commonly used to treat severe RA need to be used cautiously in patients with history of malignancy.

Clinical characterization and mutation spectrum in Caribbean Hispanic families with Lynch syndrome.

Lynch syndrome (LS) is an inherited form of colorectal cancer (CRC) caused by germline mutations in the mismatch repair (MMR) genes. It accounts for approximately 5% of all CRCs. The prevalence of LS among US Hispanics is unknown. The objective of this study was to describe the germline mutations of LS in Caribbean Hispanics from Puerto Rico and Dominican Republic. A total of 89 subjects were recruited through the Puerto Rico Familial Colorectal Cancer Registry and were classified according to Amsterdam and Bethesda clinical guidelines. For those tumors with lack of expression of MMR protein, gene sequencing was ordered. A total of 35 individuals with deficient MMR system were identified: 22 had MMR mutations and 13 had tumors with absent MMR protein expression. Our results show that the mutation spectrum of Caribbean Hispanic LS patients was composed mostly of MSH2 (66.7%) mutations, followed by MLH1 (25.0%). One mutation was identified in MSH6 (8.3%). A previously unidentified mutation in MLH1 gene c.2044_2045del was found in one Caribbean Hispanic family. MMR mutation-positive individuals were found to be more likely to have a prominent family history of CRC and tumors located at the proximal colon. Compared to MSH2 mutation carriers, MLH1 mutation-positive individuals were more likely to have a strong family history of CRC and LS associated cancers. Furthermore, insurance coverage for genetic testing was found to be limited in the study population with 65.1% of the individuals recruited were denied coverage. This report presents the first description of the mutation spectrum and clinicopathologic characteristics of LS Caribbean Hispanics patients.

Relationship between smoking and multiple colorectal cancers in patients with Japanese Lynch syndrome: a cross-sectional study conducted by the Japanese Society for Cancer of the Colon and Rectum.

The positive correlation between smoking and cancer risk is well estimated in sporadic colorectal cancer, whereas little is known with regard to Lynch syndrome-associated colorectal cancer. A total of 118 familial colorectal cancer patients from the Hereditary Nonpolyposis Colorectal Cancer Registry and Genetic Testing Project of the Japanese Society for Cancer of the Colon and Rectum, were assessed to determine whether smoking alters the incidence of multiple colorectal cancers. In male patients with Lynch syndrome (n = 29), the incidence of multiple colorectal cancers in patients who had ever smoked (smoking duration: median of 19 years) was higher than that in those who never smoked (58.8% vs. 10.0%, P = 0.02). The cumulative risk for metachronous colorectal cancer was significantly higher in male Lynch syndrome patients who had previously smoked than in those who had never smoked (P = 0.03). Our data suggest that long-term cigarette smoking might be a strong risk factor for the development of multiple colorectal cancers in male Lynch syndrome patients.

Evaluation of clinical criteria for the identification of Lynch syndrome among unselected patients with endometrial cancer.

Clinical criteria, primarily young age of cancer onset and family history of signature cancers, have been developed to identify individuals at elevated risk for Lynch syndrome with the goals of early identification and cancer prevention. In 2007, the Society of Gynecologic Oncology (SGO)-codified criteria for women presenting with gynecologic cancers. These criteria have not been validated in a population-based setting. For 412 unselected endometrial cancers, immunohistochemical expression of DNA mismatch repair proteins and MLH1 methylation were assessed to classify tumors as sporadic or probable Lynch syndrome (PLS). In this cohort, 10.5% of patients were designated as PLS based on tumor testing. The sensitivity and specificity of the SGO criteria to identify these same cases were 32.6% [95% confidence interval (CI), 19.2-48.5] and 77% (95% CI, 72.7-81.8), respectively. With the exception of tumor location in the lower uterine segment, multivariate analysis of clinical features, family history, and pathologic variables failed to identify significant differences between the sporadic and PLS groups. A simplified cost-effectiveness analysis demonstrated that the SGO clinical criteria and universal tissue testing strategies had comparable costs per patient with PLS identified. In conclusion, the SGO criteria successfully identify PLS cases among women with endometrial cancer who are young or have significant family history of signature tumors. However, a larger proportion of patients with PLS who are older and have less significant family history are not detected by this screening strategy. Universal tissue testing may be necessary to capture more individuals at risk for having Lynch syndrome.

Prostate cancer incidence in males with Lynch syndrome.

PURPOSE: An increased risk of prostate cancer is currently not considered a part of the Lynch syndrome spectrum. The purpose of this study was to retrospectively examine prostate cancer incidence in the Lynch syndrome cohort at the Ohio State University in comparison with that in the general population. METHODS: We included all males diagnosed with Lynch syndrome from June 1998 to June 2012 at the Ohio State University and obtained baseline information including cancer history. If patients had not been seen in the 12 months before June 2012, they were contacted to document changes in their cancer history. We compared prostate cancer incidence among the Lynch syndrome families with that of the general population by using the Surveillance, Epidemiology, and End RESULTS registry 1999-2009. RESULTS: Of the 188 males identified with Lynch syndrome, 11 males were diagnosed with prostate cancer during the study period. The ratio of observed to expected numbers of prostate cancer cases resulted in a standardized rate ratio of 4.87 (95% confidence interval: 2.43-8.71). Impaired mismatch repair expression and microsatellite instability were seen in one out of two prostate cancer specimens available for testing. CONCLUSION: Males with Lynch syndrome had a nearly fivefold increased risk of developing prostate cancer but did not appear to have earlier onset or a more aggressive phenotype.