MLH1/MSH2/MSH6 (Lynch Syndrome) Study Identifies Genetic Mutations Associated With Cancer Risk For Hereditary Cancer Syndrome - media

"The researchers found significant differences in estimated cumulative cancer risk between the 3 mutated genes......"
"This analysis of a nationwide series of 537 families with Lynch syndrome provides age- and gene-specific risk estimates for each tumor of the spectrum. The results should help clarify the phenotypic differences between MSH6, MLH1, or MSH2 mutation carriers and highlight the clinical significance of the risk of gynecological (and especially ovarian) cancers," the researchers conclude."

abstract: Association of low-risk MSH3 and MSH2 variant alleles with Lynch syndrome: Probability of synergistic effects - Intl Jnl of Cancer

"These variants were identified through denaturing high performance liquid chromatography and subsequent DNA sequencing. In one Lynch family, the index case with early-onset colon cancer was a carrier of a polymorphism in the MSH2 gene and two variants in the MSH3 gene. These variants were associated with the disease in the family, thus suggesting the involvement of MSH3 in colon tumour progression. We hypothesise a model in which variants of the MSH3 gene behave as low-risk alleles that contribute to the risk of colon cancer in Lynch families, mostly with other low-risk alleles of MMR genes."

abstract: Familial Cancer, A putative Lynch syndrome family carrying MSH2 and MSH6 variants of uncertain significance—functional analysis reveals the pathological one

Abstract

Inherited pathogenic mutations in the mismatch repair (MMR) genes, MSH2, MLH1, MSH6, and PMS2 predispose to Lynch syndrome (LS). However, the finding of a variant or variants of uncertain significance (VUS) in affected family members complicates the risk assessment. Here, we describe a putative LS family carrying VUS in both MSH2 (c.2768T>A, p.Val923Glu) and MSH6 (c.3563G>A, p.Ser1188Asn). Two colorectal cancer (CRC) patients were studied for mutations and identified as carriers of both variants. In spite of a relatively high mean age of cancer onset (59.5 years) in the family, many CRC patients and the tumor pathological data suggested that the missense variation in MSH2, the more common susceptibility gene in LS, would be the predisposing alteration. However, MSH2 VUS was surprisingly found to be MMR proficient in an in vitro MMR assay and a tolerant alteration in silico. By supplying evidence that instead of MSH2 p.Val923Glu the MSH6 p.Ser1188Asn variant is completely MMR-deficient, the present study confirms the previous findings, and suggests that MSH6 (c.3563G>A, p.Ser1188Asn) is the pathogenic mutation in the family. Moreover, our results strongly support the strategy to functionally assess all identified VUS before predictive gene testing and genetic counseling are offered to a family.

Apr 2011 Gastroenterology & Endoscopy News - Henry Lynch, MD, Delivers Keynote Address on Lynch Syndrome & Gary H. Hoffman, MD

Note: requires registration (free) to view, discusses sporadic cancer/s, BRAF mutation plus EPCAM mutations, treatment responses etc:

"EPCAM mutation carriers may have phenotypic features that differ from carriers of MSH2 mutations, namely, an almost exclusive expression of site-specific CRC and an absence of extracolonic cancers. “This is really new, and more information is needed on this,” he said".
"Of therapeutic interest, patients with MSI-high tumors may respond differently to chemotherapy."

 ----------------------------------------------------------------

"Henry Lynch, MD, Delivers Keynote Address on Lynch Syndrome

Doctor Who First Described the Syndrome Offers Guidance on Management of Inherited CRC

by Caroline Helwick

San Francisco—Microsatellite instability (MSI) is an important factor in the evaluation of Lynch syndrome colorectal cancer (CRC) and should be part of the workup of these patients, according to Henry Lynch, MD, who defined the syndrome and gave the keynote lecture at the 2011 American Society of Clinical Oncology Gastrointestinal Cancers Symposium....."

Upper Urinary Tract Carcinoma in Lynch Syndrome Cases - Lynch et al/J Urology

Abstract

PURPOSE: Patients with Lynch syndrome are much more likely to have generally rare upper urinary tract urothelial carcinoma but not bladder urothelial carcinoma. While the risk has been quantified, to our knowledge there is no description of how this population of patients with Lynch syndrome and upper urinary tract cancer differs from the general population with upper urinary tract cancer.

MATERIALS AND METHODS: We obtained retrospective data on a cohort of patients with Lynch syndrome from the Hereditary Cancer Center in Omaha, Nebraska and compared the data to those on a control general population from western Sweden. These data were supplemented by a new survey about exposure to known risk factors.

RESULTS: Of the patients with Lynch syndrome 91% had mutations in MSH2 rather than in MSH1 and 79% showed upper tract urothelial carcinoma a mean of 15.85 years after prior Lynch syndrome-type cancer. Median age at diagnosis was 62 years vs 70 in the general population (p <0.0001). Only half of our patients had a significant smoking history and the male-to-female ratio was 0.95. Of patients with Lynch syndrome 51% had urothelial carcinoma in the ureter while it occurred in the renal pelvis in 65% of the general population (p = 0.0013). Similar numbers of high grade tumors were found in the Lynch syndrome and general populations (88% and 74%, respectively, p = 0.1108).

CONCLUSIONS: Upper urinary tract tumors develop at a younger age and are more likely to be in the ureter with an almost equal gender ratio in patients with Lynch syndrome.
It has high grade potential similar to that in the general population.

abstract: Ovarian cancer linked to lynch syndrome typically presents as early-onset, non-serous epithelial tumors (endometrioid/clear cell cell types) MSH2 MSH6 MLH1

Ovarian cancer linked to lynch syndrome typically presents as early-onset, non-serous epithelial tumors.

Abstract

OBJECTIVE: Heredity is a major cause of ovarian cancer and during recent years the contribution from germline mismatch repair (MMR) gene mutations linked to Lynch syndrome has gradually been recognized.

METHODS: We characterized clinical features, tumor morphology and mismatch repair defects in all ovarian cancers identified in Swedish and Danish Lynch syndrome families.

RESULTS: In total, 63 epithelial ovarian cancers developed at mean 48 (range 30-79) years of age with 47% being early stage (FIGO stage I). Histologically, endometrioid (35%) and clear cell (17%) tumors were overrepresented. The underlying MMR gene mutations in these families affected MSH2 in 49%, MSH6 in 33% and MLH1 in 17%. Immunohistochemical loss of the corresponding MMR protein was demonstrated in 33/36 (92%) tumors analyzed.

CONCLUSION: The combined data from our cohorts demonstrate that ovarian cancer associated with Lynch syndrome typically presents at young age as early-stage, non-serous tumors, which implicates that a family history of colorectal and endometrial cancer should be specifically considered in such cases.

Mutation deep within an intron of MSH2 causes Lynch syndrome

".......... thus highlighting the need for more extensive sequencing approaches in families where routine procedures fail to find a mutation."

abstract: The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history (Lynch Syndrome)

full free access: 2011 The Risk of Urothelial Bladder Cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers

See Box 1 for surveillance recommendations Attached file list to this document:

PEER_stage2_10.1136%2Fjmg.2010.076992.pdf(1.5 MB) further information:   Atlas Genetics Oncology: Bladder: Urothelial carcinomas

Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study : The Lancet Oncology

Interpretation

EPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the effect of mosaic MSH2 deficiency, leading to variable cancer risks, and could form the basis of an optimised protocol for the recognition and targeted prevention of cancer in EPCAM deletion carriers.

abstract: (Lynch Syndrome) Analysis of EPCAM Protein Expression in Diagnostics of Lynch Syndrome ( -/+ MSH2)

Search of: msh2 - List Results - ClinicalTrials.gov

Found 4 studies with search of:

msh2

.

1	Recruiting	Methotrexate in Metastatic Colorectal Cancer With MSH2 Deficiency Condition: Advanced Colorectal Cancer Intervention: Drug: Methotrexate
2	Recruiting	Study of Genes and the Environment in Patients With Endometrial Cancer in the East Anglia, Oxford, Trent, or West Midlands Regions of the United Kingdom Condition: Endometrial Cancer Interventions: Genetic: polymorphism analysis; Other: laboratory biomarker analysis; Other: questionnaire administration
3	Recruiting	Study of Genes and the Environment in Patients With Colorectal Cancer in the East Anglia Region of the United Kingdom Condition: Colorectal Cancer Interventions: Genetic: polymorphism analysis; Other: laboratory biomarker analysis; Other: questionnaire administration
4	Recruiting	Anonymous Testing of Pathology Specimens for BRCA Mutations in Ashkenazi Jewish Individuals Who Have Cancer Conditions: Extrahepatic Bile Duct Cancer; Gallbladder Cancer; Gastric Cancer; Lung Cancer; Melanoma; Non-Hodgkin's Lymphoma; Uterine Cancer; CORPUS UTERI,ENDOMETRIUM; Lung; Ovary Intervention:

ICR (UK) - Lynch Syndrome mutation MSH2 - 60-Year-Old Drug Shows New Promise for Inherited Cancer

"....Methotrexate is similar to a normal molecule called folinic acid, which is required for copying DNA. The drug prevents cells from making and repairing DNA - a process needed for cancer growth. It was one of the first chemotherapy drugs to be invented in the 1940s and is still used to treat a number of cancers today. But until now, it has not commonly been used to treat people with HNPCC.

Professor Alan Ashworth, who led this Cancer Research UK-funded study at the ICR, said: "The MSH2 gene plays a vital role in repairing DNA damage but if it is faulty, mistakes accumulate in cells and increase the risk of cancer developing.

"What's exciting about methotrexate is that it selectively destroys the cells lacking the MSH2 function. This indicates that it may make an excellent treatment for patients with the genetic alteration. With our colleagues at The Royal Marsden Hospital, we have set up clinical trials to test this."...cont'd

The rate of the predominant Jewish mutations in the BRCA1, BRCA2, MSH2 and MSH6 genes in unselected Jewish endometrial cancer patients (study number 289 patients)

Note: MSH2/MSH6 are 2 of the Lynch Syndrome genes

Objectives

The genes associated with familial Endometrial Cancer (EC) are largely unknown. While EC is an integral part of Hereditary Non-Polyposis Colon Cancer, there is an ongoing debate if EC is indeed overrepresented in hereditary breast/ovarian cancer families.

Conclusions

Our data do not support screening for BRCA1/2 mutations in consecutive EC patients.

Neuroendocrine-Type Prostatic Adenocarcinoma With Microsatellite Instability in a Patient With Lynch Syndrome

Abstract

Lynch syndrome is an autosomal-dominant cancer syndrome that can be identified with microsatellite instability molecular tests or immunohistochemical stains on pathologic material from patients who meet the Amsterdam Criteria II.
The development of prostatic carcinoma in situ or invasive small cell carcinoma (SCC) of the prostate has not been previously reported in a patient with this syndrome. In this report, an 87-year-old White man with the Lynch syndrome had a prostate biopsy that revealed a mixed high-grade conventional adenocarcinoma and SCC of the prostate with high-grade prostatic intraepithelial neoplasia of the small cell neuroendocrine-type (HGPIN-NE), all showing MSH2 microsatellite instability and loss of MSH2 expression, a finding not previously published. These findings suggest that HGPIN-NE is a precursor of invasive SCC and also that prostatic SCC can develop in a patient with the Lynch syndrome.

full access: Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers

"In eight out of 21 patients with bladder cancer, this was their first cancer diagnosis, whereas at this stage five of them developed another Lynch syndrome associated cancer at an older age. Therefore, early diagnosis of Lynch syndrome may prevent development of a second primary cancer..."

Recommendations for urothelial carcinomas surveillance in Lynch syndrome

1. Surveillance with a combination of ultrasound of the bladder and upper urinary tract, urinary cytology and sediment.
2. In every MSH2 mutation carrier
3. From age 40 and up
4. Performed every 1–2 years

Risk and Epidemiological Time Trends of Gastric Cancer in Lynch Syndrome Carriers in The Netherlands

" Lifetime risk of developing gastric cancer was 8.0% in males vs 5.3% in females  and 4.8% and 9% for MLH1 and MSH2 carriers, respectively."

 

 Conclusions

Lynch syndrome mutation carriers have a substantial risk for gastric cancer, in particular patients with an MLH1 or MSH2 mutation. Family history for gastric cancer is a poor indicator for individual risk. Surveillance gastroscopy for Lynch syndrome patients carrying an MLH1 or MSH2 mutation should therefore be considered.

full free access: Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers -- Journal of Medical Genetics

"Besides the high risk of developing colorectal carcinomas of 10–80%, Lynch syndrome family members are at increased risk of developing several extra-colonic cancers and tumours at a relatively young age: endometrial cancer, carcinomas of the ovary, small bowel and biliary tract cancer, sebaceous gland tumours and urothelial carcinomas (UC) of the upper urinary tract. The lifetime risk of upper urinary tract cancer in Lynch syndrome varies in different studies from 0.4–20%. Microsatellite instability (MSI) is present in these urothelial carcinomas of the upper urinary tract."

See Table 1

Hereditary Cancer in Clinical Practice | Full text | Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management

Table 2:

Median age and range at diagnosis of Lynch syndrome associated cancer

                                      MLH1        MSH2           MSH6

Colorectal cancer 47 (25-79) 44 (20-82) 53 (32-84)

Endometrial cancer 51 (46-54) 46 (36-55) 56 (47-67)

Ovarian carcinoma 52 (52-52) 47 (45-48) 49 (35-51)

Small bowel cancer 54 (54-54) 36 (23-49) -

Transitional cell carcinoma - 58 (32-59) -

"The aim of the present study was to calculate the cumulative risk
of LS related cancers in proven MLH1, MSH2 and MSH6 mutation carriers." 

"Furthermore, some studies have suggested that extracolonic cancers are more often observed in MSH2 mutation families compared to MLH1 mutation families."

Expert Reviews full access: On the advent of MSI testing of all colorectal cancers and a substantial part of other Lynch syndrome-related neoplasms

Worldwide, more than 1 million people present with colorectal cancer (CRC) annually. Of these, 2–5% occur in the context of Lynch syndrome (LS), the most common hereditary CRC predisposing syndrome (formerly designated as hereditary nonpolyposis CRC [HNPCC]). LS is characterized by a high lifetime risk for the development of CRC (20–70%), endometrial cancer (15–70%) and other extracolonic cancers (<15%). These extracolonic malignancies include carcinomas of the small intestine, stomach, pancreas and biliary tract, ovarium, brain, upper urinary tract and skin. .......germline mutation in one of the MMR genes MLH1, MSH2, MSH6 or PMS2.

Owing to the MMR deficiency in LS tumors, a microsatellite instability (MSI) phenotype is present. MSI, however, is also found in approximately 10–13% of sporadic CRCs (in total, MSI is present in approximately 15% of all CRCs). In addition to MSI, most LS tumors lack expression in the tumor cell nuclei of one of the four MMR proteins, MLH1, MSH2, MSH6 or PMS2.

Early detection of LS is of great importance, particularly in presymptomatic mutation carriers, since colonoscopic surveillance has proven to reduce CRC morbidity and mortality by 65–70% [6] and prophylactic surgery may prevent endometrial and ovarium carcinoma effectively.

Different models and strategies have been developed to identify patients with LS. In 1990, the Amsterdam criteria I were developed to provide a basis for uniformity in collaborative studies to find the disease-causing gene. These criteria were designed to be highly specific at the expense of sensitivity. They were criticized because extra-colonic tumors were not taken into account, thereby excluding classical LS families....Therefore, the Amsterdam criteria II were established in 1999"