Assessment of microsatellite instability and genetic analysis of mismatch repair genes in sporadic endometrial cancer: identification of different subsets of patients and a MLH1 founder mutation in Sardinia

10528 Background: Mutations in mismatch repair genes are responsible for Lynch syndrome. Estimating the penetrance of cancer related to MSH2 A636P, a founder mutation identified in Ashkenazi Jewish population, has clinical implications. Methods: The mutation was genotyped in all subjects of the MECC study, a population-based case-control study carried out in North Israel during 1998–2004 that included 2,112 cases of pathology-confirmed colorectal cancer (CRC) and 2,060 population controls. Approximately 50% of the subjects were of Ashkenazi Jewish origin. Family history of cancer (among first and second degree relatives) was obtained by personal interview. Penetrance of MSH2 A636P was estimated from relatives using a kin-cohort approach by the marginal maximum likelihood method, estimating cumulative risk among carriers and noncarriers. Results: Thirteen MSH2 A636P carriers were identified, all among CRC cases. Their relatives formed a cohort of 138 subjects contributing 8,802 person years (py); 14 of 138 had CRC (173 per 100,000) and 5 endometrial cancer (112 per 100,000). The cohort of relatives of noncarriers summed 46,257 subjects contributing 2.8M py; 582 had CRC (20 per 100,000) and 142 endometrial cancer (EC)(10 per 100,000). For carriers, the cumulative risk to age 70 of CRC was 0.44 (0.19–0.90) and that of EC was 0.29 (0–0.84). The cumulative risk of any cancer related with Lynch syndrome was 0.66 (0.47–0.93). These estimates of penetrance were not substantially modified if the cohorts were restricted to first degree relatives, to Ashkenazi Jews, or when relatives of controls were excluded. Compared to noncarriers, the hazard ratios were 28.7 (2.8–112) for CRC, 9.1 (0–181) for EC and 19 (6.4–50) for Lynch syndrome cancers. Conclusions: The MSH2 A636P missense mutation is highly penetrant, with a cumulative risk of cancers related to Lynch syndrome that is similar to other truncating mutations in mismatch repair genes. These results have implications for the tailored management of patients with this Ashkenazi founder mutation. No significant financial relationships to disclose.

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Microsatellite instability and expression of mismatch repair genes in sporadic endometrial cancer coexisting with colorectal or breast cancer

Oncology Reports ◽

10.3892/or.13.1.11 ◽

2005 ◽

Cited By ~ 2

Author(s):

Katsumi Takano ◽

Yoshihito Ichikawa ◽

Ei Ueno ◽

Michitaka Ohwada ◽

Mitsuaki Suzuki ◽

...

Keyword(s):

Breast Cancer ◽

Endometrial Cancer ◽

Microsatellite Instability ◽

Mismatch Repair ◽

Mismatch Repair Genes ◽

Repair Genes

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Correlation of mismatch repair genes immunohistochemistry and microsatellite instability status in HNPCC-associated tumours

Pathology ◽

10.1080/0031302021000035965-2 ◽

2002 ◽

Vol 34 (6) ◽

pp. 541-547 ◽

Cited By ~ 58

Author(s):

Andrew Ruszkiewicz ◽

Graeme Bennett ◽

James Moore ◽

Jim Manavis ◽

Barney Rudzki ◽

...

Keyword(s):

Microsatellite Instability ◽

Mismatch Repair ◽

Mismatch Repair Genes ◽

Repair Genes

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Mismatch Repair Genes and Microsatellite Instability as Molecular Markers for Gynecological Cancer Detection

Experimental Biology and Medicine ◽

10.1177/153537020222700805 ◽

2002 ◽

Vol 227 (8) ◽

pp. 579-586 ◽

Cited By ~ 14

Author(s):

Roman Miturski ◽

Michał Bogusiewicz ◽

Carmella Ciotta ◽

Margherita Bignami ◽

Marek Gogacz ◽

...

Keyword(s):

Endometrial Cancer ◽

Mismatch Repair ◽

Cancer Detection ◽

Xeroderma Pigmentosum ◽

Gynecological Cancer ◽

Epidemiological Studies ◽

Mismatch Repair Genes ◽

The Past ◽

Repair Genes

Due to major developments in genetics over the past decade, molecular biology tests are serving promising tools in early diagnosis and follow-up of cancer patients. Recent epidemiological studies revealed that the risk for each individual to develop cancer is closely linked to his/her own genetic potentialities. Some populations that are defective in DNA repair processes, for example in Xeroderma pigmentosum or in the Lynch syndrome, are particularly prone to cancer due to the accumulation of mutations within the genome. Such populations would benefit from the development of tests aimed at identifying people who are particularly at risk. Here, we review some data suggesting that the inactivation of mismatch repair is often found in endometrial cancer and we discuss molecular-based strategies that would help to identify the affected individuals in families with cases of glandular malignancies.

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Is It Time to Abandon Microsatellite Instability As a Pre-Screen for Selecting Families for Mutation Testing for Mismatch Repair Genes?

Journal of Clinical Oncology ◽

10.1200/jco.2005.05.3207 ◽

2006 ◽

Vol 24 (12) ◽

pp. 1960-1962 ◽

Cited By ~ 7

Author(s):

Gareth D. Evans ◽

Fiona Lalloo ◽

Tony Mak ◽

Doug Speake ◽

James Hill

Keyword(s):

Microsatellite Instability ◽

Mismatch Repair ◽

Mutation Testing ◽

Mismatch Repair Genes ◽

Repair Genes

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Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability

Cancers ◽

10.3390/cancers12113319 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3319

Author(s):

Madhura Deshpande ◽

Phillip A. Romanski ◽

Zev Rosenwaks ◽

Jeannine Gerhardt

Keyword(s):

Microsatellite Instability ◽

Mismatch Repair ◽

Treatment Strategies ◽

Mismatch Repair Genes ◽

Gynecologic Malignancies ◽

Gynecological Cancers ◽

Traditional Treatment ◽

Increased Risk ◽

Deficient Mismatch Repair ◽

Repair Genes

Mutations in mismatch repair genes leading to mismatch repair (MMR) deficiency (dMMR) and microsatellite instability (MSI) have been implicated in multiple types of gynecologic malignancies. Endometrial carcinoma represents the largest group, with approximately 30% of these cancers caused by dMMR/MSI. Thus, testing for dMMR is now routine for endometrial cancer. Somatic mutations leading to dMMR account for approximately 90% of these cancers. However, in 5–10% of cases, MMR protein deficiency is due to a germline mutation in the mismatch repair genes MLH1, MSH2, MSH6, PMS2, or EPCAM. These germline mutations, known as Lynch syndrome, are associated with an increased risk of both endometrial and ovarian cancer, in addition to colorectal, gastric, urinary tract, and brain malignancies. So far, gynecological cancers with dMMR/MSI are not well characterized and markers for detection of MSI in gynecological cancers are not well defined. In addition, currently advanced endometrial cancers have a poor prognosis and are treated without regard to MSI status. Elucidation of the mechanism causing dMMR/MSI gynecological cancers would aid in diagnosis and therapeutic intervention. Recently, a new immunotherapy was approved for the treatment of solid tumors with MSI that have recurred or progressed after failing traditional treatment strategies. In this review, we summarize the MMR defects and MSI observed in gynecological cancers, their prognostic value, and advances in therapeutic strategies to treat these cancers.

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