Cure Alveolar Soft Part Sarcoma International (iCureASPS)

“Tumor mutational burden (TMB) is a genomic biomarker with the potential to make a significant impact on the landscape of cancer immunotherapy. This emerging marker measures the number of mutations within a tumor genome and has already been shown to be associated with improved responses to checkpoint inhibitor immunotherapies in lung cancer, melanoma and bladder cancer.”

https://www.foundationmedicine.com/blog ... esponse-to

TO THE EDITOR:
Inhibitors of programmed death 1 (PD-1) protein or its ligand (PD-L1) have shown remarkable clinical benefit in many cancers.1 One emerging biomarker of response to anti–PD-1 therapy is the tumor mutational burden (i.e., the total number of mutations per coding area of a tumor genome). This finding is supported by the clinical activity of anti–PD-1 therapy in colorectal cancer with mismatch repair deficiency, a tumor subtype with a high tumor mutational burden, as compared with the colorectal cancer subtype with mismatch repair proficiency, which has a significantly lower tumor mutational burden and a poor response to these agents.2,3


https://www.nejm.org/doi/full/10.1056/NEJMc1713444

Was the CMMRD ( constitutional mismatched repair defiencey )because of the ALL ( acute lymphoblastic leukemia ) or was it present in the sibling’s ASPS makeup?


ALL is known as a CMMRD cancer ,that can lead to secondary cancers .

https://www.stjude.org/disease/constitu ... iency.html

My discussion early this year .

First reported case of alveolar soft part sarcoma in constitutional mismatch repair deficiency syndrome tumor spectrum - diagnosed in one of the siblings with constitutional mismatch repair deficiency”

http://www.cureasps.org/forum/viewtopic ... ent#p12042


The link to

“First reported case of alveolar soft part sarcoma in constitutional mismatch repair deficiency syndrome tumor spectrum - diagnosed in one of the siblings with constitutional mismatch repair deficiency”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379899/

Thought this medical write up gave light to the topic of MMR, and more in-depth explanations of how some tumor mutational ( burdens ) happen.
Testing of MSI is still being revamped and possibly comparing a highly studied cancer(colon) to a poorly understood ASPS, will begin to give light for our treatment options / protocol to some of our folks . : )


Abstract
Defects in the DNA mismatch repair (MMR) proteins, result in a phenotype called microsatellite instability (MSI), occurring in up to 15% of sporadic colorectal cancers. Approximately one quarter of colon cancers with deficient MMR (dMMR) develop as a result of an inherited predisposition syndrome, Lynch syndrome (formerly known as HNPCC). It is essential to identify patients who potentially have Lynch syndrome, as not only they, but also family members, may require screening and monitoring. Diagnostic criteria have been developed, based primarily on Western populations, and several methodologies are available to identify dMMR tumours, including immunohistochemistry and microsatellite testing. These criteria have provided evidence supporting the introduction of reflex testing. Yet, it is becoming increasingly clear that tests have a limited sensitivity and specificity and may yet be superseded by next generation sequencing. In this review, the limitations of diagnostic criteria are discussed, and current and emerging screening technologies explained. There is now useful evidence supporting the prognostic and predictive value of dMMR status in colorectal tumours, but much less is known about their value in extracolonic tumours, that may also feature in Lynch syndrome. This review assesses current literature relating to dMMR in endometrial, ovarian, gastric and melanoma cancers, which it would seem, may benefit from large-scale clinical trials in order to further close the gap in knowledge between colorectal and extracolonic tumours.

Keywords: Lynch syndrome, deficient mismatch repair, microsatellite instability, prognostic, predictive

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583524/

Introduction
DNA mismatch repair (MMR) is a very highly conserved cellular process, involving many proteins, resulting in the identification, and subsequent repair of mismatched bases, likely to have arisen during DNA replication, genetic recombination or chemical or physical damage (Fig. 1). The MMR genes play additional roles in double-strand break repair, apoptosis and recombination. The four key genes identified to date are mutL homologue 1 (MLH1), mutS homologue 2 (MSH2), mutS homologue 6 (MSH6) and postmeiotic segregation increased 2 (PMS2), so named because of their homology to the E. coli MMR genes. The MSH2 and MSH6 proteins form a heterodimeric complex (mutSα) which is involved in the initial identification of mismatched bases, and initiates DNA repair. Binding to the mismatch results in an ATP-dependent conformational change, which subsequently recruits mutLα, a heterodimer comprising of MLH1 and PMS2. Other proteins are recruited to complete the DNA repair, but are not discussed further in this review. The repair complexes ensure that it is the newly synthesised strand of DNA which is targeted for repair, not the parental strand.

Posted -

“Tue Aug 21, 2018 2:19 pm“

D.ap wrote: ↑Tue Aug 21, 2018 2:19 pm Introduction
DNA mismatch repair (MMR) is a very highly conserved cellular process, involving many proteins, resulting in the identification, and subsequent repair of mismatched bases, likely to have arisen during DNA replication, genetic recombination or chemical or physical damage (Fig. 1). The MMR genes play additional roles in double-strand break repair, apoptosis and recombination. The four key genes identified to date are mutL homologue 1 (MLH1), mutS homologue 2 (MSH2), mutS homologue 6 (MSH6) and postmeiotic segregation increased 2 (PMS2), so named because of their homology to the E. coli MMR genes. The MSH2 and MSH6 proteins form a heterodimeric complex (mutSα) which is involved in the initial identification of mismatched bases, and initiates DNA repair. Binding to the mismatch results in an ATP-dependent conformational change, which subsequently recruits mutLα, a heterodimer comprising of MLH1 and PMS2. Other proteins are recruited to complete the DNA repair, but are not discussed further in this review. The repair complexes ensure that it is the newly synthesised strand of DNA which is targeted for repair, not the parental strand.

Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium.

Abstract
BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited.

METHODS: We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented.

RESULTS: Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families (p=0.0007). All children with CMMRD had café-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p<0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive.

DISCUSSION: CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children.

https://www.ncbi.nlm.nih.gov/m/pubmed/24440087/

* café-au-lait spots https://www.healthline.com/health/cafe-au-lait-spots