mismatch repair cancer syndrome

Mismatch repair cancer syndrome (MMRCS) is a rare autosomal recessive childhood cancer predisposition syndrome [10]. It is characterized by the development of four main tumor types:

• Hematologic malignancies
• Brain/central nervous system tumors
• Colorectal tumors
• Multiple intestinal polyps, and other malignancies including embryonic tumors and rhabdomyosarcoma

This syndrome is caused by biallelic DNA mismatch repair mutations [1], which lead to a deficiency in the mismatch repair (MMR) process during DNA replication. As a result, there is a rapid accumulation of mutations, leading to the development of cancers [12].

People with MMRCS may also develop multiple noncancerous growths (adenomas) in the colon that are likely to become cancerous over time [4]. The syndrome is associated with an increased risk of developing various types of cancer, including colorectal cancer and brain tumors.

It's worth noting that MMRCS is a rare condition, and more research is needed to fully understand its characteristics and implications. However, it is clear that this syndrome poses a significant risk for the development of multiple types of cancer in affected individuals.

References:

[1] - Mismatch repair cancer syndrome (MMRCS) is a cancer syndrome associated with biallelic DNA mismatch repair mutations. [4] - People with CMMRD syndrome may develop multiple noncancerous (benign) growths (adenomas) in the colon that are likely to become cancerous (malignant) over time. [10] - Mismatch repair cancer syndrome-2 (MMRCS2) is an autosomal recessive childhood cancer predisposition syndrome characterized by hematologic malignancy, brain tumors, colorectal tumors and multiple intestinal polyps, and other malignancies including embryonic tumors and rhabdomyosarcoma. [12] - Constitutional mismatch repair deficiency (CMMRD) syndrome (OMIM #276300) 1 is a cancer predisposition syndrome associated with inheritance of biallelic pathogenic variants in mismatch repair (MMR) genes.

Mismatch repair cancer syndrome, also known as Lynch syndrome or hereditary non-polyposis colorectal cancer (HNPCC), can exhibit a range of signs and symptoms. While not everyone with the condition will experience all of these, being aware of them can help with early detection and management.

Common Signs and Symptoms:

• Cafe-au-lait spots: These are flat, oval-shaped patches on the skin that are lighter than the surrounding area.
• Axillary freckling: Freckles in the armpit area.
• Hyperpigmented spots: Areas of skin that are darker than the surrounding area.
• Multiple adenomatous colon polyps: Growths in the colon that can become cancerous over time.

Other Possible Symptoms:

• Unexplained weight loss
• Tiredness
• Fever that does not go away
• Night sweats
• Loss of appetite
• Aches, pains, lumps or swelling that have no clear cause

Important Note: These symptoms can also be present in other conditions, and the presence of one or more of these signs does not necessarily mean you have mismatch repair cancer syndrome. If you're concerned about your health, it's essential to consult with a healthcare professional for proper evaluation and diagnosis.

References:

• [5] - Multiple noncancerous (benign) growths (adenomas) in the colon that are likely to become cancerous (malignant) over time.
• [7] - Many patients show signs reminiscent of neurofibromatosis type I (NF1; 162200), particularly multiple cafe-au-lait macules (summary by Baas et al., 2013).
• [15] - Cafe-au-lait spot; Axillary freckling; Hyperpigmented spots; ...

Mismatch Repair Cancer Syndrome, also known as Lynch Syndrome, is a genetic disorder that increases the risk of developing certain types of cancer. Diagnostic tests for this condition involve evaluating the presence of mutations in the genes responsible for mismatch repair.

Clinical Testing

Clinical testing typically involves two methods: immunohistochemistry (IHC) and microsatellite instability (MSI) analysis [1]. IHC is a laboratory test that detects the absence or reduction of certain proteins involved in mismatch repair, such as MLH1, MSH2, MSH6, and PMS2. MSI analysis measures the level of genetic instability in tumor tissues.

Genetic Testing

In addition to clinical testing, genetic testing is also used to diagnose Lynch Syndrome [4]. This involves analyzing a blood sample for mutations in the MLH1, MSH2, MSH6, and PMS2 genes. Genetic testing can confirm the presence of a mutation in one of these genes.

Other Diagnostic Methods

Other diagnostic methods include NGS (Next-Generation Sequencing) and PCR-based testing [5]. NGS is a comprehensive genetic test that analyzes multiple genes simultaneously, including those involved in mismatch repair. PCR-based testing involves amplifying specific DNA sequences to detect mutations.

Screening Tools

Reflex immunohistochemistry (rIHC) for mismatch repair protein expression can be used as a screening tool to detect Lynch Syndrome [2]. Tissue-based microsatellite instability analysis and IHC are also accepted screening tools to evaluate the risk of developing this condition.

In summary, diagnostic tests for Mismatch Repair Cancer Syndrome involve clinical testing using IHC and MSI analysis, genetic testing to identify mutations in specific genes, and other methods such as NGS and PCR-based testing. These tests can help confirm a diagnosis of Lynch Syndrome and inform treatment decisions.

References:

[1] by GM O'Kane · 2017 · Cited by 39 — Reflex immunohistochemistry (rIHC) for mismatch repair (MMR) protein expression can be used as a screening tool to detect Lynch Syndrome (LS).

[2] by N Buza · 2016 · Cited by 86 — Clinical testing of tumor tissues for the presence of MMR gene deficiency is standard practice in clinical oncology, with immunohistochemistry and PCR-based ...

[4] A blood sample is sent to a genetic testing lab. The lab runs genetic tests that looks for changes in the MLH1, MSH2, MSH6, PMS2, and/or EPCAM genes.

[5] Apr 8, 2024 — For gastroesophageal and small bowel cancers, pathologists can use MSI PCR, MMR IHC, or NGS for diagnosis. In cases of endometrial cancer, MMR ...

Mismatch repair (MMR) deficiency is a genetic condition that increases the risk of developing various types of cancer, including colorectal, endometrial, and other cancers. In recent years, there has been significant progress in the development of targeted therapies for MMR-deficient cancers.

Immunotherapy

One promising approach to treating MMR-deficient cancers is immunotherapy, which harnesses the power of the immune system to attack cancer cells. Checkpoint inhibitors, such as nivolumab and ipilimumab, have been shown to be effective in treating various types of cancer, including those with MMR deficiency [1][2].

• A study involving patients with locally advanced rectal cancer found that treatment with neoadjuvant PD-1 blockade alone resulted in a clinical complete response [3].
• Another trial demonstrated the efficacy of nivolumab plus ipilimumab in patients with locally advanced dMMR colon cancer, with an acceptable safety profile and leading to a pathological response [4].

Targeted therapies

In addition to immunotherapy, targeted therapies have also been developed for MMR-deficient cancers. For example:

• Jemperli (dostarlimab) is a monoclonal antibody that targets the PD-1 receptor and has been approved by the FDA for the treatment of MSI-H or dMMR advanced colorectal cancer in patients whose cancer got worse after chemotherapy [5].
• Durvalumab, another checkpoint inhibitor, has shown clinical activity in patients with advanced mismatch repair-deficient and repair-proficient endometrial cancer [6].

Chemotherapy

While targeted therapies have emerged as promising treatments for MMR-deficient cancers, chemotherapy remains an important option for some patients. For example:

• Bendamustine with rituximab or single-agent chlorambucil are chemotherapies that may be used in older patients [7].
• Immunotherapy has demonstrated remarkable efficacy in metastatic colorectal cancers (mCRCs) with mismatch repair deficiency (MMRd)/microsatellite instability (MSI), but chemotherapy remains an important option for some patients [8].

In summary, the treatment of MMR-deficient cancer syndrome involves a range of approaches, including immunotherapy, targeted therapies, and chemotherapy. The choice of therapy depends on various factors, such as the type and stage of cancer, patient age, and overall health.

References:

[1] Westdorp et al. (2017) [2] [3] Diaz et al. (2023) [4] [5] FDA Approval: Jemperli (dostarlimab) [6] [7] Alouani et al. (2023) [8] [9] Clinical activity of durvalumab for patients with advanced mismatch repair-deficient and repair-proficient endometrial cancer.

Mismatch repair cancer syndrome (MMRCS), also known as Constitutional Mismatch Repair Deficiency (CMMRD) syndrome, is a rare autosomal recessive childhood cancer predisposition syndrome. When considering the differential diagnosis for MMRCS, several other conditions should be taken into account.

• Lynch Syndrome: This is another inherited condition that increases the risk of developing colorectal and other cancers. However, Lynch Syndrome typically presents with a different set of tumor types and an older age of onset compared to MMRCS [1][2].
• Colorectal Cancer: While colorectal cancer can be a feature of both MMRCS and Lynch Syndrome, the presence of multiple primary tumors and a family history of early-onset cancers should raise suspicion for MMRCS.
• Hemolytic Uremic Syndrome (HUS): This is a rare condition that can present with similar symptoms to MMRCS, including anemia, thrombocytopenia, and acute kidney injury. However, HUS typically does not involve cancer [3].
• Other Cancer Predisposition Syndromes: Conditions such as Familial Adenomatous Polyposis (FAP) and Juvenile Polyposis Syndrome can also increase the risk of developing colorectal cancer. However, these conditions typically do not present with the same level of cancer predisposition as MMRCS [4].

To differentiate between these conditions, a comprehensive evaluation including:

• Family History: A thorough review of the patient's family history to identify any patterns of cancer or other relevant medical conditions.
• Genetic Testing: Genetic testing for mutations in the MLH1, MSH2, MSH6, and PMS2 genes can help confirm the diagnosis of Lynch Syndrome. In contrast, genetic testing for CMMRD typically involves sequencing of these same genes, as well as other genes involved in mismatch repair.
• Tumor Characteristics: The presence of multiple primary tumors, particularly those involving the hematologic system, should raise suspicion for MMRCS.

It's essential to note that a definitive diagnosis of MMRCS can only be made through genetic testing and confirmation of biallelic germline mutations in one or more mismatch repair genes [5].

References:

[1] Context 4 [2] Context 6 [3] Context 7 [4] Context 8 [5] Context 9