paywalled: Patients with Lynch Syndrome Mismatch Repair Gene Mutations Are at Higher Risk for Not Only Upper Tract Urothelial Cancer but Also Bladder Cancer

Patients with Lynch Syndrome Mismatch Repair Gene Mutations Are at Higher Risk for Not Only Upper Tract Urothelial Cancer but Also Bladder Cancer

Abstract

Background

Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is caused by mutations in mismatch repair (MMR) genes. An increased risk for upper tract urothelial carcinoma (UTUC) has been described in this population; however, data regarding the risk for bladder cancer (BCa) are sparse.

Objective

To assess the risk of BCa in MMR mutation carriers and suggest screening and management recommendations.

Design, setting, and participants

Cancer data from 1980 to 2007 were obtained from the Familial Gastrointestinal Cancer Registry in Toronto for 321 persons with known MMR mutations: mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); mutS homolog 6 (E. coli) (MSH6); and PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2).

Outcome measurements and statistical analysis

Standardized incidence ratios from the Ontario Cancer Registry, using the Surveillance Epidemiology and End Results public database, were used to compare cancer risk in patients with MMR mutations with the Canadian population. Microsatellite instability analysis and immunohistochemistry (IHC) of the MMR proteins were also performed and the results compared with matched sporadic bladder tumors.

Results and limitations

Eleven of 177 patients with MSH2 mutations (6.21%, p < 0.001 compared with the Canadian population) were found to have BCa, compared with 3 of 129 patients with MLH1 mutations (2.32%, p > 0.05). Of these 11 tumors, 81.8% lacked expression of MSH2 on IHC, compared with the matched sporadic cases, which all displayed normal expression of MSH2 and MLH1. The incidence of UTUC among MSH2 carriers was 3.95% (p < 0.001), and all tumors were found to be deficient in MSH2 expression on IHC. Mutations in the intron 5 splice site and exon 7 of the MSH2 gene increased the risk of urothelial cancer. Limitations include possible inflated risk estimates due to ascertainment bias.

Conclusions

LS patients with MSH2 mutations are at an increased risk for not only UTUC but also BCa and could be offered appropriate screening.

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Figures and tables from this article:

Fig. 1. Tumor sections at ×200 magnification: (A) abnormal MSH2 expression—nuclear expression is lost in the tumor, with normal nuclear staining in the adjacent tissue; (B) normal MLH1 expression—normal strong nuclear expression in the tumor and normal tissue.

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Table 1. Distribution of patients with mismatch repair mutations

M:F = male-to-female; MLH1 = mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli); MSH2 = mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli); MSH6 = mutS homolog 6 (E. coli); PMS2 = PSM2 postmeiotic segregation increased 2 (S. cerevisiae).

View Within Article

Table 2. Total incidence of urothelial cancers due to MLH1 and MSH2

MLH1 = mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli); MSH2 = mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli); NS = not significant.

View Within Article

Table 3. Urothelial cancers in patients with confirmed MSH2 mutations and comparison with matched sporadic bladder cancer patients

− = absent expression; +  = normal expression; CR = colorectal; Dx = diagnosis; EM = endometrial; F = female; GA = gastric; HG = high grade; IHC = immunohistochemistry; LG = low grade; LS = Lynch syndrome; M = male; MSH2 = mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli); MSI = microsatellite instability; MSI-H = high microsatellite instability; MSS = microsatellite stable; OR = occupational risk; OV = ovarian; RP = renal pelvis; U = ureter.Patients H1 and H2 are related.

View Within Article

Table 4. Urothelial cancers in patients with confirmed MLH1 mutations

− = absent expression; +  = normal expression; CR = colorectal; HG = high grade; IHC = immunohistochemistry; LG = low grade; LS = Lynch syndrome; M = male; MLH1 = mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli); MSI = microsatellite instability; MSI-H = high microsatellite instability; OR = occupational risk; RP = renal pelvis.

paywalled: Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients - Kantelinen - Human Mutation - Wiley Online Library

Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients - Kantelinen - Human Mutation

Abstract

Mismatch repair (MMR) malfunction causes the accumulation of mismatches in the genome leading to genomic instability and cancer. The inactivation of an MMR gene (MSH2, MSH6, MLH1 or PMS2) with an inherited mutation causes Lynch syndrome (LS), a dominant susceptibility to cancer. MMR gene variants of uncertain significance (VUS) may be pathogenic mutations which cause LS, may result in moderately increased cancer risks, or may be harmless polymorphisms. Our study suggests that an inherited MMR VUS individually assessed as proficient may, however, in a pair with another MMR VUS found in the same colorectal cancer (CRC) patient have a concomitant contribution to the MMR deficiency. Here, eight pairs of MMR gene variants found in cancer patients were functionally analyzed in an in vitro MMR assay. Although the other pairs do not suggest a compound deficiency, the MSH2 VUS pair c.380A>G/c.982G>C (p.Asn127Ser/p.Ala328Pro), which nearly halves the repair capability of the wild type MSH2 protein, is presumed to increase the cancer risk considerably. Moreover, two MSH6 variants, c.1304T>C (p.Leu435Pro) and c.1754T>C (p.Leu585Pro), were shown to be MMR deficient. The role of one of the most frequently reported MMR gene VUS, MSH2 c.380A>G (p.Asn127Ser), is especially interesting, since its concomitant defect with another variant could finally explain its recurrent occurrence in CRC patients.

American Society for Clinical Pathology: Molecular Testing in Colorectal Cancer (Lynch Syndrome/MLH1, MSH2, MSH6, PMS2/MSI-H/KRAS/BRAF.....)

Blogger's Note: focus (obviously) on colorectal cancer, however, the cancer spectrum of Lynch Syndrome is noted in this paper as well as the shortcomings of the Bethesda Guidelines

 Molecular Testing in Colorectal Cancer

Conclusion

In summary, current standard-of-care molecular testing of CRC is aimed at detecting Lynch syndrome and KRAS mutations. However, with recent rapid development of biological agents targeted against components of the EGFR signaling cascade in the treatment of CRCs, mutational analysis of the genes in the EGFR signaling pathway may become a standard of care for patients with CRC in the near future. Ideally, identifying molecular prognostic and predictive factors may allow us to identify high-risk patients with stage II CRC who will benefit from chemotherapy after surgery. In addition, this may allow us to determine patients’ eligibility for targeted biological therapies.

paywalled: Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study : The Lancet Oncology

Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study : The Lancet Oncology

Methods
"Resections done for small and large bowel cancer between January, 2002, and January, 2011, were retrieved. We systematically analysed non-tumorous mucosa from carriers of a Lynch syndrome mutation (set 1: ten patients) and control patients without Lynch syndrome (set 1: nine patients) for MMR protein expression (MLH1, MSH2, and EPCAM) with immunohistochemistry.....

abstract: Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature.

Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature.

Hum Pathol. 2012 Apr 17;


Abstract

Immunohistochemical detection of DNA mismatch repair proteins and polymerase chain reaction detection of microsatellite instability have enhanced the recognition of mismatch repair-deficient neoplasms in patients with Lynch syndrome and, consequently, led to the identification of tumors that have not been included in the currently known Lynch syndrome tumor spectrum.

Here, we report 4 such unusual tumors. Three of the 4, a peritoneal mesothelioma, a pancreatic acinar cell carcinoma, and a pancreatic well-differentiated neuroendocrine tumor, represented tumor types that, to the best of our knowledge, have not been previously reported in Lynch syndrome. The fourth tumor was an adrenocortical carcinoma, which has rarely been reported previously in Lynch syndrome. Three of our 4 patients carried a pathogenic germ-line mutation in a mismatch repair gene. The unusual tumor in each of the 3 patients showed loss of the mismatch repair protein corresponding to the mutation. The fourth patient did not have mutation information but had a history of colonic and endometrial carcinomas; both lacked MSH2 and MSH6 proteins. Interestingly, none of the 4 unusual tumors revealed microsatellite instability on polymerase chain reaction testing, whereas an appendiceal carcinoma from 1 of the study patients who was tested simultaneously did. The recognition of such tumors expands the repertoire of usable test samples for the workup of high-risk families.

As yet, however, there are no data to support the inclusion of these tumors into general screening guidelines for detecting Lynch syndrome, nor are there data to warrant surveillance for these tumors in patients with Lynch syndrome.

abstract: Uroepithelial (bladder/ureter) and kidney carcinoma in Lynch syndrome (MSH2)

Uroepithelial and kidney carcinoma in Lynch syndrome [Fam Cancer. 2012] - PubMed - NCBI
 

Fam Cancer. 2012 Apr 4

Abstract

Increased risk for urological tumors has been observed in mutation carriers with Lynch syndrome (LS). In this study, we evaluated the clinical features of uroepithelial (bladder and ureter) and kidney cancers in 974 Finnish mutation carriers. Altogether 30 patients had a total of 34 urological tumors: 12 ureter, 12 bladder, and 10 kidney cancers. Urological tumor was the only tumor in 9 (30 %) patients, and metachronous other tumor occurred in 21 (70 %). The occurrence of uroepithelial cancers was significantly higher in MSH2 mutation carriers (6 %) than in MLH1 carriers (2 %) and MSH6 mutation carriers (0 %).

The mean ages of patients at the time of diagnosis were: bladder cancer, 57 years; ureter cancer, 58 years; and kidney cancer, 64 years. Overall 5-year survival rates were 70 % in bladder cancer, 81 %  in ureter cancer, and 75 % in kidney cancer.

Cancer-specific 5-year survival rates were 70 %  in bladder cancer, 91 %  in ureter cancer, and 100 % in kidney cancer.

In conclusion, early age of onset was observed in patients with uroepithelial tumors, but not in patients with kidney cancer. The frequency of uroepithelial tumors was significantly higher in MSH2 mutation carriers than in MLH1 carriers. Further studies with larger numbers of patients, however, are needed to evaluate the potential benefit of surveillance of urological tumors in LS.

abstract: Role of the Msh2 gene (Lynch Syndrome) in genome maintenance and development in mouse fetuses.

Role of the Msh2 gene in genome maintenance and development in mouse fetuses

These results indicate that elevated mutation levels have little effect on the development of the fetus, even if a mutator phenotype appears at the organogenesis stage.

 Abstract
In an attempt to evaluate the roles of the mismatch repair gene Msh2 in genome maintenance and in development during the fetal stage, spontaneous mutations and several developmental indices were studied in Msh2-deficient lacZ-transgenic mouse fetuses.

ICGC Data Portal - search using MSH2 gene as an example

ICGC Data Portal (search results MSH2)

abstract: (Lynch Syndrome) Colorectal and Other Cancer Risks for Carriers and Noncarriers From Families With a DNA Mismatch Repair Gene Mutation: A Prospective Cohort Study [Epidemiology] multi-national study

 Blogger's Note: some stats deleted for ease of reading, see abstract (or paid subscription for full details; interesting stat on female breast cancer


Colorectal and Other Cancer Risks for Carriers and Noncarriers From Families With a DNA Mismatch Repair Gene Mutation: A Prospective Cohort Study [Epidemiology]:

Purpose
To determine whether cancer risks for carriers and noncarriers from families with a mismatch repair (MMR) gene mutation are increased above the risks of the general population.

Patients and Methods
We prospectively followed a cohort of 446 unaffected carriers of an MMR gene mutation (MLH1, n = 161; MSH2, n = 222; MSH6, n = 47; and PMS2, n = 16) and 1,029 their unaffected relatives who did not carry a mutation every 5 years at recruitment centers of the Colon Cancer Family Registry. For comparison of cancer risk with the general population, we estimated country-, age-, and sex-specific standardized incidence ratios (SIRs) of cancer for carriers and noncarriers.
Results
Over a median follow-up of 5 years, mutation carriers had an increased risk of

colorectal cancer (20.48),
endometrial cancer (30.62),  
ovarian cancer (18.81),
renal cancer (11.22),
pancreatic cancer ( 10.68), 
gastric cancer (9.78),  
urinary bladder cancer (9.51), and  
female breast cancer ( 3.95;).

We found no evidence of their noncarrier relatives having an increased risk of any cancer, including CRC (1.02).

Conclusion 
 We confirmed that carriers of an MMR gene mutation were at increased risk of a wide variety of cancers, including some cancers not previously recognized as being a result of MMR mutations, and found no evidence of an increased risk of cancer for their noncarrier relatives.

The molecular basis of EPCAM expression loss in Lynch syndrome-associated tumors : Modern Pathology

The molecular basis of EPCAM expression loss in Lynch syndrome-associated tumors

Abstract

Germline deletions affecting the Epithelial cell adhesion molecule (EPCAM) gene lead to silencing of MSH2 and cause Lynch syndrome. We have recently reported that lack of EPCAM expression occurs in many, but not all tumors from Lynch syndrome patients with EPCAM germline deletions. The differences in EPCAM expression were not related to the localization of EPCAM germline deletions. We therefore hypothesized that the type of the second somatic hit, which leads to MSH2 inactivation during tumor development, determines EPCAM expression in the tumor cells. 

To test this hypothesis and to evaluate whether lack of EPCAM expression can already be detected in Lynch syndrome-associated adenomas, we analyzed four carcinomas and two adenomas from EPCAM germline deletion carriers for EPCAM protein expression and allelic deletion status of the EPCAM gene region by multiplex ligation-dependent probe amplification. 

In four out of six tumors we observed lack of EPCAM expression accompanied by biallelic deletions affecting the EPCAM gene. In contrast, monoallelic retention of the EPCAM gene was observed in the remaining two tumors with retained EPCAM protein expression. These results demonstrate that EPCAM expression in tumors from EPCAM deletion carriers depends on the localization of the second somatic hit that inactivates MSH2. 

Moreover, we report lack of EPCAM protein expression in a colorectal adenoma, suggesting that EPCAM immunohistochemistry may detect EPCAM germline deletions already at a precancerous stage.

Polymorphisms in MSH2 gene and risk of gastric cancer, and interactions with lifestyle factors in a Chinese population ( IVS10+12G>A and IVS12−6T>C )

Polymorphisms inMSH2gene and risk of gastric cancer, and interactions with lifestyle factors in a Chinese population

Background:
Although polymorphisms in DNA mismatch repair (MMR) gene MSH2 have been associated with risks of many cancers, little is known about their etiology role in gastric cancer (GC) and the potential interacting role with lifestyle factors known to damage DNA.

Conclusion:
The IVS10+12G>A and IVS12−6T>C polymorphisms in MSH2 gene appear to be associated with risk of GC in this Chinese population. Risk for GC, stratified by related genotypes, was further modified by drinking, high pickled food or fried food intake. Larger prospective studies are needed to confirm these findings.

open access: BMC Cancer - Predictive models for mutations in mismatch repair genes: implication for genetic counseling in developing countries (Lynch Syndrome)

 Background

Lynch syndrome (LS) is the most common form of inherited predisposition to colorectal cancer (CRC), accounting for 2–5% of all CRC. LS is an autosomal dominant disease characterized by mutations in the mismatch repair genes mutL homolog 1 (MLH1), mutS
homolog 2 (MSH2), postmeiotic segregation increased 1 (PMS1), post-meiotic segregation increased 2 (PMS2) and mutS homolog 6 (MSH6). Mutation risk prediction models can be incorporated into clinical practice, facilitating the decision-making process and identifying
individuals for molecular investigation. This is extremely important in countries with limited economic resources. This study aims to evaluate sensitivity and specificity of five predictive models for germline mutations in repair genes in a sample of individuals with suspected
Lynch syndrome.

"Lynch syndrome (LS) is the most common form of inherited predisposition to colorectal cancer (CRC), accounting for 2–5% of all CRC [1]. Colorectal cancer in LS differs from sporadic cases by an earlier age of diagnosis (mean age approximately 44 years), a predominance of proximally-sited colon cancers (60–70%) and an increased propensity to
synchronous or metachronous CRCs (25%) [2,3]. Individuals with LS have an 80% probability of developing CRC at 65 years, and they are at an elevated risk of developing a second primary CRC [4] as well as at an increased risk for extra-colonic malignancies, including endometrial, gastric, small bowel, urological tract, ovary, pancreas and brain cancer
[5]."

 Conclusions

The Barnetson, PREMM, MMRpro and Wijnen models present similar AUC. The AUC of the Myriad model is statistically inferior to the four other models. 

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

abstract: Frequency of Rearrangements in Lynch Syndrome Cases Associated with MSH2: Characterization of a New Deletion Involving both EPCAM and the 5′ Part of MSH2

".......The tumors of the carriers show high-level MSI and MSH2 protein loss. The clinical correlation provided evidence that the type of mutation and the extension of the deletions involving the MSH2 gene could have different implications in cancer predisposition. Thus, the identification of EPCAM-MSH2 rearrangements and their comprehensive characterization should be included in the routine mutation screening protocols for Lynch syndrome."

abstract - Identification of Cancer Patients with Lynch Syndrome: Clinically Significant Discordances and Problems in Tissue-Based Mismatch Repair Testing

abstract: Synchronous gynecologic malignancy and preliminary results of Lynch syndrome (Korean women)

METHODS:

Thirty six women with synchronous gynecologic tumors of endometrial and ovarian cancer were identified among patients being treated at our institution.

CONCLUSION:

In this study, the frequency of Lynch syndrome associated immunohistochemical staining (MLH1, MSH2, and MSH6) group was estimated as 9% (3/32) among Korean women with synchronous gynecologic tumors.

abstract: Pancreatic cancer and a novel MSH2 germline alteration

CONCLUSIONS:

The MSH2 P349L may increase the risk for pancreatic cancer beyond the usual mutations in DNA mismatch repair genes; however, studies of additional families with the identical missense alteration are needed to confirm this initial impression.

Hereditary Cancer in Clinical Practice |open access: Novel germline MSH2 mutation in Lynch syndrome patient surviving multiple cancers (ovarian cancer as first cancer)

Case report
Hereditary Cancer in Clinical Practice 2012, 10:1 doi:10.1186/1897-4287-10-1
Published: 10 January 2012

Abstract (provisional)

Lynch syndrome (LS) individuals are predisposed to a variety of cancers, most commonly colorectal, uterine, urinary tract, ovarian, small bowel, stomach and biliary tract cancers. The risk of extracolonic manifestations appears to be highest in MSH2 mutations carriers. We present a carrier case with a novel MSH2 gene mutation that clearly demonstrates the broad extent of LS phenotypic expression and highlights several important clinical aspects. Current evidence suggests that colorectal tumors from LS patients tend to have better prognoses than their sporadic counterparts, however survival benefits for other cancers encountered in LS are unclear.
In this article we describe a family with a novel protein truncating mutation of c.2388delT in the MSH2 gene, particularly focusing on one individual carrier affected with multiple primary cancers who is surviving 25 years on. Our report of multiple primary tumors occurring in the 12-25 years interval might suggest these patients do not succumb to other extracolonic cancers, provided they are regularly followed-up.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

 "Firstly, the patient over time presented with five primary cancers (in different organs) all of them, except that of breast, typical for the tumor spectrum of LS.   Early-stage ovarian mucinous carcinoma was the first manifestation of LS spectrum in the proband. The lifetime risk of ovarian cancer in Lynch syndrome is approximately 10-12% [12], with higher risks (36%) reported in MSH2 carriers [13]. Recent estimates of age-specific cumulative cancer risks in Lynch syndrome families suggest lower than published elsewhere ovarian cancers risk (24% ovarian cancer risk in MSH2) [14]. MMR-deficient ovarian cancers are biologically and clinically different from BRCA deficient cancers, the former overrepresented by non-serous histology types, early-stage and early-onset disease [12, 15]...."

 

 

 

 

 

open access: Evidence for breast cancer as an integral part of Lynch Syndrome (MLH1/MSH2 - small study/review) - Genes, Chromosomes and Cancer

"...While early onset, right-sided CRC represents the hallmark cancer of Lynch syndrome (Lynch et al., 1993; Lynch and Smyrk, 1996; Aarnio et al., 1999), extracolonic cancers such as tumors of the stomach (Aarnio et al., 1997), upper urinary tract, small bowel (Rodriguez-Bigas et al., 1998), hepatobiliary tract, sebaceous gland (Muir-Torre variant of Lynch syndrome), and glioblastomas (Turcot variant; Hamilton et al., 1995) may occur in addition. Women from Lynch syndrome families are at a significantly increased risk for gynecologic malignancies, namely endometrial and ovarian carcinoma. In fact, the lifetime risk for endometrial (Watson et al., 1994; Aarnio et al., 1995; Aarnio et al., 1999) and ovarian cancers (Watson et al., 2001) is estimated at 30–60% and 12%, respectively, compared with 3 and 2%, respectively, in the general population. An elevated risk for breast cancer in Lynch syndrome has been suggested in several studies, but the issue remains controversial (Risinger et al., 1996; Scott et al., 2001; Vasen et al., 2001; Muller et al., 2002; de Leeuw et al., 2003; Oliveira Ferreira et al., 2004; Watson and Riley, 2005; Westenend et al., 2005; Blokhuis et al., 2008; Shanley et al., 2009)....."

The founder Ashkenazi Jewish mutations in the MSH2 and MSH6 genes in Israeli patients with gastric and pancreatic cancer

Abstract

The genetic basis for gastric and pancreatic cancer is largely undetermined.
These cancers are overrepresented in hereditary non polyposis colon cancer (HNPCC), inherited cancer syndrome attributed to germline mutations primarily in the MSH2, MLH1 and MSH6 genes.
Among Ashkenazi Jewish HNPCC cases, recurring mutations in the MSH2 (1906G>C; A636P) and MSH6 (c.3984_3987dupGTCA; c.3959_3962delCAAG) genes can be detected. The MSH6*c.3984_3987dupGTCA mutation was recently detected in an Ashkenazi family with inherited gastric cancer. We hypothesized that it may be possible to detect the recurring MSH2 and MSH6 mutations in Jewish individuals with familial and sporadic gastric and pancreatic cancer.
To test this notion, we genotyped 143 unrelated Jewish Israeli patients with gastric (n = 23) and pancreatic (n = 120) cancer. The majority of cases (100/143–70%) were Ashkenazi Jews, and 10% (n = 16)—of mixed Ashkenazi-non Ashkenazi Jewish ancestry, and most participants (n = 96–67.1%) had a positive family history of cancer. Genotyping the MSH2*A636P mutation was performed by PCR followed by restriction enzyme digest, and the MSH6*c.3984_3987dupGTCA and c.3959_3962delCAAG mutations were detected by fragment size analysis by capillary electrophoresis and sequencing. None of the participants harbored any of the genotyped MSH2 or MSH6 mutations.
We conclude that the recurring Ashkenazi MSH2 and MSH6 mutations contribute little if any to sporadic and familial gastric and pancreatic cases in Israeli patients"

The predicted truncation from a (ovarian) cancer-associated variant of the MSH2 initiation codon alters activity of the MSH2-MSH6 mismatch repair complex

Abstract

Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes. MMR recognizes and repairs DNA mismatches and small insertion/deletion loops. Carriers of MMR gene variants have a high risk of developing colorectal, endometrial, ovarian, and other extracolonic carcinomas. We report on an ovarian cancer patient who carries a germline MSH2 c.1A>C variant which alters the translation initiation codon. Mutations affecting the MSH2 start codon have been described previously for LS-related malignancies. However, the patients often lack a clear family history indicative of LS and their tumors often fail to display microsatellite instability, a hallmark feature of LS...."(technical)