paywalled: Recurrent and founder mutations in the PMS2 gene - Clinical Genetics

Recurrent and founder mutations in the PMS2 gene - Tomsic - Clinical Genetics

Germline mutations in PMS2 are associated with Lynch syndrome (LS), the most common known cause of hereditary colorectal cancer.

Mutation detection in PMS2 has been difficult due to the presence of several pseudogenes, but a custom-designed long-range PCR strategy now allows adequate mutation detection. Many mutations are unique. However some mutations are observed repeatedly, across individuals not known to be related, due to the mutation being either recurrent, arising multiple times de novo at hot spots for mutations, or of founder origin, having occurred once in an ancestor. Previously, we observed 36 distinct mutations in a sample of 61 independently ascertained Caucasian probands of mixed European background with PMS2 mutations.

Eleven of these mutations were detected in more than one individual not known to be related and of these, six were detected more than twice. These six mutations accounted for 31 (51%) ostensibly unrelated probands. Here we performed genotyping and haplotype analysis in four mutations observed in multiple probands and found two (c.137G>T and exon 10 deletion) to be founder mutations, one (c.903G>T) a probable founder, and one (c.1A>G) where founder mutation status could not be evaluated. We discuss possible explanations for the frequent occurrence of founder mutations in PMS2.

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.

abstract: Insertion of an SVA element, a non-autonomous retrotransposon, in PMS2 intron 7 as a novel cause of Lynch syndrome.

Insertion of an SVA element, a non-autonomous retrotransposon, in PMS2 intron 7 as a novel cause of Lynch syndrome.:

Hum Mutat. 2012 Mar 27;


Abstract

Heterozygous germline mutations in the mismatch repair gene PMS2 predispose carriers for Lynch syndrome, an autosomal dominant predisposition to cancer. Here, we present a LINE-1-mediated retrotranspositional insertion in PMS2 as a novel mutation type for Lynch syndrome. This insertion, detected with Southern blot analysis in the genomic DNA of the patient, is characterized as a 2.2 kb long 5' truncated SVA_F element. The insertion is not detectable by current diagnostic testing limited to MLPA and direct Sanger sequencing on genomic DNA. The molecular nature of this insertion could only be resolved in RNA from cultured lymphocytes in which nonsense-mediated RNA decay was inhibited. Our report illustrates the technical problems encountered in the detection of this mutation type. Especially large heterozygous insertions will remain unnoticed because of preferential amplification of the smaller wild-type allele in genomic DNA, and are probably underreported in the mutation spectra of autosomal dominant disorders.

press release: Myriad Study Finds High Prevalence of Mutations in the PMS2 Gene (Lynch syndrome)

Myriad Study Finds High Prevalence of Mutations in the PMS2 Gene

"This study demonstrates the importance of the analyzing the PMS2 gene to fully comprehend a patient's Lynch syndrome status."

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

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.

full free access: (2010) MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer

Background

Approximately 10% of Lynch syndrome families have a mutation in MSH6 and fewer families have a mutation in PMS2. It is assumed that the cancer incidence is the same in families with mutations in MSH6 as in families with mutations in MLH1/MSH2 but that the disease tends to occur later in life, little is known about families with PMS2 mutations. This study reports on our findings on mutation type, cancer risk and age of diagnosis in MSH6 and PMS2 families..........cont'd

"Lynch syndrome is an autosomal dominantly inherited cancer syndrome characterised by early onset epithelial cancers. Patients with Lynch syndrome have an increased risk of developing malignancies during their lifetime, at a mean age of disease onset that is significantly lower than that observed in the general population. In addition to the high risk of developing CRC, Lynch syndrome patients are also at risk of developing malignancies in a variety of organs that include the uterus, small bowel, stomach, ovary, bladder, pancreas and the urinary tract [2,3]."

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"

Table 1 : Mismatch repair deficient colorectal cancer in the era of personalized treatment : Nature Reviews Clinical Oncology