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.....

open access: Gynecologic Oncology Case Reports - A case of endometrial cancer in the context of a BRCA2 mutation and double heterozygosity for Lynch syndrome

ScienceDirect.com - Gynecologic Oncology Case Reports - A case of endometrial cancer in the context of a BRCA2 mutation and double heterozygosity for Lynch syndrome

 "....While endometrial cancer diagnosed under the age of 50 is not included in the Revised Bethesda Guideline, evidence suggests that these individuals should be evaluated for Lynch syndrome (Resnick et al., 2009). The patient presented was diagnosed with endometrial cancer at the age of 41 and genetic testing revealed triple heterozygosity for BRCA2, MLH1 and MSH6 mutations."

 Introduction

Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant cancer susceptibility syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, MLH1, MSH2, and less frequently MSH6 and PMS2. MMR mutation carriers are predisposed primarily to colorectal cancer and endometrial cancer, with an increased frequency of stomach, ovary, pancreas, upper urinary tract, brain, small bowel, and skin consistently reported. This hereditary syndrome accounts for approximately 2–3% of colorectal cancers and 1–4% of endometrial cancers in the United States (Lynch and de la Chapelle, 2003). Depending on the MMR gene involved, women with Lynch syndrome can have up to an 80% lifetime risk of developing colorectal cancer, and a 20–60% risk of endometrial cancer.

Germline mutations in BRCA1 or BRCA2 (BRCA1/2) cause hereditary breast ovarian cancer syndrome. Female carriers of BRCA1/2 mutations have excessive risks for both breast and ovarian cancer, with lifetime breast cancer estimates ranging from 45% to 84%, and lifetime ovarian cancer estimates ranging from 11% to 62%, depending upon the population studied. BRCA1/2 kindreds are also noted to have an increased frequency of prostate cancer, and in BRCA2 kindreds, increased frequencies of pancreatic cancer and melanoma are observed. The frequency of BRCA1 or BRCA2 mutations in the general population is estimated to be 1 in 300 to 1 in 800, respectively (King et al., 2003).

While there are kindreds with more than one cancer susceptibility syndrome and/or mutation reported in the literature ( [Thiffault et al., 2004] and [Smith et al., 2008]), they are not often encountered in routine clinical settings........

Highlights

► Endometrial cancer with BRCA2 mutation and double heterozygosity for Lynch syndrome.
► Loss of MLH1 and PMS2 by immunohistochemical stain.
► MSH1 and MSH6 gene mutations by genomic sequencing.

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.

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors.

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors.:

Abstract
Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG→GCG) leading to a substitution of lysine to alanine in codon 618, has variously been interpreted as a pathogenic mutation, a variant of unknown significance, and a benign polymorphism. .........................We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold. Our systematic assessment approach may be useful for variants in other genes.

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.

(click on pdf for full paper) Gynecologic Oncology Case Reports: A Case of Endometrial Cancer in the Context of a BRCA2 Mutation and Double Heterozygosity for Lynch Syndrome

Gynecologic Oncology Case Reports | Articles in Press | ScienceDirect.com

A Case of Endometrial Cancer in the Context of a BRCA2 Mutation and Double Heterozygosity for Lynch Syndrome

In Press, Accepted Manuscript, Available online 15 March 2012
Ping Gong, Sarah Charles, Norman Rosenblum, Zoe Wang, Agnieszka K. Witkiewicz

 Show preview  |   PDF (458 K)   |   Related articles  |  Related reference work articles    

Highlights

► Endometrial cancer with BRCA2 mutation and double heterozygosity for Lynch syndrome 

► Loss of MLH1 and PMS2 by immunohistochemical stain 

► MSH1 and MSH6 gene mutations by genomic sequencing

An American founder mutation in MLH1 (Lynch Syndrome mutation) International Journal of Cancer - Wiley Online Library

Abstract

Mutations in the mismatch repair genes cause Lynch syndrome (LS), conferring high risk of colorectal, endometrial and some other cancers. After the same splice site mutation in the MLH1 gene (c.589-2A>G) had been observed in four ostensibly unrelated American families with typical LS cancers, its occurrence in comprehensive series of LS cases (Mayo Clinic, Germany and Italy) was determined. It occurred in 10 out of 995 LS mutation carriers (1.0%) diagnosed in the Mayo Clinic diagnostic laboratory. It did not occur among 1,803 cases tested for MLH1 mutations by the German HNPCC consortium, while it occurred in three probands and an additional five family members diagnosed in Italy. In the U.S., the splice site mutation occurs on a large (∼4.8 Mb) shared haplotype that also harbors the variant c.2146G>A, which predicts a missense change in codon 716 referred to here as V716M. In Italy, it occurs on a different, shorter shared haplotype (∼2.2 Mb) that does not carry V716M. The V716M variant was found to be present by itself in the U.S., German and Italian populations with individuals sharing a common haplotype of 280 kb, allowing us to calculate that the variant arose around 5,600 years ago (225 generations; 95% confidence interval 183–272). The splice site mutation in America arose or was introduced some 450 years ago (18 generations; 95% confidence interval 14–23); it accounts for 1.0% all LS in the Unites States and can be readily screened for.

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.

Cancer Risks for the Relatives of Colorectal Cancer Cases with a Methylated MLH1 Promoter Region: Data from the Colorectal Cancer Family Registry

Blogger's Note: focus on MLH1

".....The cohort consisted of 3,128 first- and second-degree relatives of the 233 MLH1-methylated CRC cases with no MMR or MUTYH gene mutations.

The standardized incidence ratio (SIR) for CRC was 1.60 [95% confidence interval (CI), 1.22–2.16] for first-degree relatives and 1.08 (0.74–1.60) for second-degree relatives.

The SIR for gastric cancer was 2.58 (1.52–4.71) for first-degree relatives and 4.52 (2.23–10.61) for second-degree relatives and, for ovarian cancer, it was 2.16 (1.29–3.86) for first-degree relatives.

The risk of liver cancer was also increased significantly in first-degree relatives but the estimate was on the basis of only two cases.

These data imply that relatives of CRC cases with MLH1 methylation may be at increased risk of CRC and stomach cancer and possibly ovarian and liver cancer, suggesting that there may be a heritable factor for CRC and other cancers associated with MLH1 methylation in non–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.

open access: Evidence of constitutional MLH1 epimutation associated to transgenerational inheritance of cancer susceptibility - Human Mutation

Blogger's Note: see references in paper to ovarian cancer; BRAF mutations


Epimutation , epimutation meaning , definition of epimutation , what is epimutation - A heritable change in gene expression that does not affect the actual base pair sequence of DNA . The first sign of cellular abnormality in some tumors is an epimutation—a change in heritable chromatin marks , such as an increase or decrease in the density of DNA methylation.
 ................................................................
"In addition, two patients were included in the study because of personal medical past history (endometrial cancer at the age of 24, and multiple sebaceous tumors associated with ovary cancer at the age of 44, respectively) strongly suggesting Lynch syndrome. The mean age of patients at diagnosis of the first Lynch syndrome-related cancer was 46 years (range, 24–74)."

"In conclusion, we have shown that constitutional epimutations in MMR genes constitute a rare cause of Lynch syndrome. However, they are associated to a real risk of transgenerational inheritance of cancer susceptibility. Moreover, tumors from patients with constitutional MLH1 epimutation can display BRAF mutations, mimicking MSI-H sporadic tumors. Altogether, these findings may have important implications for future diagnostic strategies and genetic counseling."

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)....."

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."

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.

Multiple synchronous primary ovarian malignancies in a patient with a MLH-1 mutation: Impact on potential fertility preservation (MLH1 is one of the Lynch Syndrome genes) including commentary

"EOC associated with HNPCC syndrome differs compared to sporadic cases with mean age at diagnosis of 42.7"


(Note: Definition synchronous: occurring or existing at the same time)

  Abstract:

Introduction

While the majority of epithelial ovarian cancer (EOC) is due to sporadic mutations, approximately 10% of cases are secondary to hereditary germ line mutations: 85–90% of tumors are caused by BRCA1 and BRCA2 gene mutations while hereditary non-polyposis colorectal cancer (HNPCC), or Lynch syndrome, accounts for the remainder [1].

HNPCC patients may have synchronous primary tumors at the time of prophylactic or therapeutic surgery, involving the colon, ovary, uterus or a combination thereof. We present an unusual case of a patient with HNPCC syndrome and three primary ovarian neoplastic processes without coexisting colon or uterine malignancies, and underscore the importance of hysterectomy and bilateral salpingo-oophorectomy in cancer-associated mutation carriers from Lynch syndrome families........cont'd




Also: link to referenced article:
Cancer 

Fertility preservation in young women with epithelial ovarian cancer 
Volume 115, Issue 18, 15 September 2009, Pages 4118-4126  

METHODS: Women aged ≤50 years with stage IA or IC epithelial ovarian cancer who were registered in the Surveillance, Epidemiology, and End Results database were examined.......cont'd

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

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.