Possible association of postmeiotic segregation increased 2 (PMS 2) gene deletion and myelodysplastic syndrome.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e17021-e17021
Author(s):  
Trushil Shah ◽  
Gregory James Gerstner ◽  
Jaini Sutaria
Keyword(s):  
Colon Cancer ◽  
Myelodysplastic Syndrome ◽  
Gene Deletion ◽  
Chromosome 7 ◽  
Trisomy 8 ◽  
Dna Mismatch ◽  
Gradual Onset ◽  
Increased Risk ◽  
Postmeiotic Segregation ◽  
Pms2 Gene

e17021 Background: Postmeiotic segregation Increased 2 (PMS2) gene is one of the gene family members found in clusters on chromosome 7 involved in DNA mismatch repair. Mutations in this gene are associated with hereditary nonpolyposis colorectal cancer and Turcot syndrome. PMS-2 defects are not extensively studied and hence there is still considerable potential to detect new hemato-oncological associations with same. Chromosome 7 defects are the most commonly associated genetic abnormalities associated with myelodysplastic syndrome (MDS). Here, we describe a case of a patient with known PMS 2 gene deletion presenting with early onset MDS. Methods: A 52 year old caucasian female came in to our oncology clinic for evaluation after being diagnosed with DCIS of right breast. She underwent surgical resection followed by tamoxifen and surviellance mamograms. She developed gradual onset of fatigue, prompting follow-up laboratory tests which revealed WBC of 8,600, Hgb of 8.5, MCV of 101, and Plt 383,000. B12, folate, and iron studies were normal. Bone marrow biopsy revealed cellularity 80% and cytogenetics with trisomy 8.This lead to diagnosis of myelodysplastic syndrome, refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS). Patient is currently treated with supportive transfusions after lack of benefit of darbopoietin (baseline epo level 67). Family history is pertinent for a son who died at age 21 from colon cancer and a daughter diagnosed at age 22 with colon cancer, who survives. Her daughter subsequently tested positive for G750 PMS-2 from her father and complete deletion of PMS2 from her mother (our patient). Results: PMS2 gene deletion might predispose patients to MDS. Conclusions: Given the common link with chromosome 7 abnormalities, it is therefore possible that there is an associated increased risk of MDS in PMS-2 patients. While our patient did not have any general abnormalities by karyotype, current assays and general karyotyping are of potentially limited value unless specific mutation points are identified. Therefore, additional evaluations may be necessary to better identify at-risk patients.

Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation

Blood ◽  
2004 ◽  
Vol 104 (3) ◽  
pp. 822-828 ◽  
Author(s):  
Judith Offman ◽  
Gerhard Opelz ◽  
Bernd Doehler ◽  
David Cummins ◽  
Ozay Halil ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Factor ◽  
Myelodysplastic Syndrome ◽  
Mismatch Repair ◽  
Organ Transplantation ◽  
Myeloid Leukemia ◽  
Dna Mismatch Repair ◽  
Dna Mismatch ◽  
Increased Risk ◽  
Acute Myeloid

AbstractImmunosuppression after organ transplantation is an acknowledged risk factor for skin cancer and lymphoma. We examined whether there was also an excess of leukemia in patients after transplantation and whether this might be related to a particular immunosuppressive treatment. Data from more than 170 000 patients indicated that organ transplantation is associated with a significantly increased risk for acute myeloid leukemia (AML). AML was more frequent after heart transplantation and lung transplantation than after kidney transplantation and was associated with immunosuppression by azathioprine, a thiopurine prodrug. Cellular resistance to thiopurines is associated with DNA mismatch repair (MMR) deficiency. We demonstrate that thiopurine treatment of human cells in vitro selects variants with defective MMR. Consistent with a similar selection in patient bone marrow, in 7 of 7 patients, transplant-related AML/myelodysplastic syndrome (MDS) exhibited the microsatellite instability (MSI) that is diagnostic for defective MMR. Because MSI occurs infrequently in de novo AML, we conclude that the selective proliferation of MMR-defective, azathioprine-resistant myeloid cells may contribute significantly to the development of AML/MDS in patients who have received organ transplants. Identifying azathioprine as a risk factor for AML/MDS suggests that discontinuing the use of azathioprine as an immunosuppressant might reduce the incidence of posttransplantation AML/MDS.

Clinically Silent Carriers in Families with Myelodysplastic Syndrome Due to GATA2 Mutations

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1264-1264
Author(s):  
Blanche P Alter ◽  
Neelam Giri ◽  
Katherine R Calvo ◽  
Irina Maric ◽  
Diane C Arthur ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Family Members ◽  
Lymphoid Cells ◽  
Refractory Anemia ◽  
Cell Transplant ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Variable Expression ◽  
Increased Risk

Abstract Abstract 1264 Patients with familial myelodysplastic syndrome (MDS) associated with mutations in GATA2 are at increased risk of MDS and acute myeloid leukemia (AML). Specific clinical syndromes recently found to be due to mutations in GATA2 include MonoMAC (monocytopenia and mycobacterial infection), Emberger (MDS with severe lymphedema), and DCML (defects in dendritic cells, monocytes, and B and NK lymphoid cells). Features shared by many patients with these GATA2-associated syndromes include monocytopenia, markedly decreased B and NK cells, and clinical immunodeficiency manifested as warts and mycobacteria and fungal infections. MDS and/or AML occur with multilineage dyspoieses, particularly prominent in the megakaryocyte lineage (micromegakaryocytes, small mononuclear megakaryocytes, and large megakaryocytes with multiple separated nuclei). Several reports mention family members who are “asymptomatic,” without further details. We identified mutations in GATA2 in two of three families with familial MDS. In both families, one apparently healthy parent was found to have a GATA2 mutation; only in-depth laboratory examinations uncovered subtle findings consistent with familial GATA2 mutation in these clinically silent carriers. Family 1: The proband presented at age 15 with pancytopenia, and was found to have MDS and monosomy 7; he died from post-BMT complications including aspergillosis. His brother was found to have leukopenia, neutropenia and macrocytosis at age 13 during an infection with H1N1 influenza; the leukopenia and macrocytosis persisted. Six months later, repeat bone marrow showed early refractory anemia; the next year his marrow had myeloid dyspoiesis and dysplastic megakaryocytes; FISH showed −7 in 2.3% of cells, leading to classification as MDS-RCC. In retrospect, both boys had absolute monocytopenia (<100/uL). GATA2 sequencing of samples from the surviving brother and his 51 y.o. mother identified a deleterious mutation (c.1116_1130del15, p.C373del5). The mother had breast cancer at age 50, but otherwise was asymptomatic. Closer clinical examination revealed lower limb lymphedema, while laboratory studies revealed lymphopenia (360/uL), monocytopenia (110/uL), low lymphocyte subsets, especially CD19 (3/uL) and MCV = 100fL. Her marrow did not show overt dyspoiesis in myeloid or erythroid lineages; among mostly normal megakaryocytes there were occasional atypical forms, including some with hypolobulated or separated lobes; G-banded karyotyping and interphase FISH for −7/7q- were normal. She would not have been suspected to have GATA2-related MDS based on her clinical status, and is thus a silent carrier. Family 2: Three children in this family were diagnosed with MDS. The oldest had a history of warts and pancytopenia at age 18; his marrow showed MDS with trisomy 8. His brother was a compatible transplant donor, but he had mild pancytopenia and monocytopenia; his marrow had MDS and trisomy 8. Their sister was diagnosed at age 14 with MDS and trisomy 8; she, too, had monocytopenia. All 3 were transplanted. Subsequently, a mutation - c.1187G>A, p.R396Q - was found in GATA2, in all 3 brothers and their healthy father. He had normal blood counts (monocytes 500/uL) and immunoglobulins, but low B-cells in peripheral blood (CD20 23/uL) and bone marrow. His normocellular marrow had occasional atypical megakaryocytes with separated lobes, hypolobulation, and mononuclear and micromegakaryocytes. He, too, would not have been suspected to have GATA2-related MDS, and is also a clinically silent carrier. These two families indicate that familial GATA2-related MDS is a dominantly-inherited syndrome. In our two families, dominant inheritance was not initially considered, in part because the genetically affected parent was clinically asymptomatic. It is unclear whether GATA2 MDS shows “anticipation,” in which the younger generation is more severely affected than the parental generation. It is important that GATA2 be evaluated in families with apparently inherited childhood MDS, since the variable expression might lead inadvertently to selecting an asymptomatic GATA2 mutation carrier as a stem cell transplant donor. Genetic counseling needs to be provided with regard to risk to other family members. In addition, only long-term follow-up and surveillance of the clinically silent carriers will determine whether they remain unaffected. Disclosures: No relevant conflicts of interest to declare.

ctDNA as a prognostic factor in operable colon cancer patients: a systematic review and meta-analysis

2020 ◽  
Author(s):  
Emre Yekedüz ◽  
Elif Berna Köksoy ◽  
Hakan Akbulut ◽  
Yüksel Ürün ◽  
Güngör Utkan
Keyword(s):  
Colon Cancer ◽  
Prognostic Factor ◽  
Cancer Patients ◽  
Meta Analysis ◽  
Circulating Tumor Dna ◽  
Random Effects Model ◽  
Inverse Variance ◽  
Increased Risk ◽  
Significant Step ◽  
Tumor Dna

Aim: Using circulating tumor DNA (ctDNA) instead of historical clinicopathological factors to select patients for adjuvant chemotherapy (ACT) may reduce inappropriate therapy. Material & methods: MEDLINE was searched on March 31, 2020. Studies, including data related to the prognostic value of ctDNA in the colon cancer patients after surgery and after ACT, were included. The generic inverse-variance method with a random-effects model was used for meta-analysis. Results: Four studies were included for this meta-analysis. ctDNA-positive colon cancer patients after surgery and ACT had a significantly increased risk of recurrence compared with ctDNA-negative patients. Conclusions: ctDNA is an independent prognostic factor, and this meta-analysis is a significant step for using ctDNA instead of historical prognostic factors in the adjuvant setting.

scholarly journals NCMP-17. MISMATCH REPAIR MUTATIONS AND THE CENTRAL NERVOUS SYSTEM: A CASE SERIES OF GERMLINE MUTATIONS AND CNS MALIGNANCY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii126-ii126
Author(s):  
Amber Ruiz ◽  
Jerome Graber
Keyword(s):  
Treatment Response ◽  
Mismatch Repair ◽  
Case Series ◽  
Germline Mutations ◽  
Molecular Characteristics ◽  
Loss Of Function ◽  
Dna Mismatch ◽  
Mutational Burden ◽  
Increased Risk ◽  
Tumor Mutational Burden

Abstract Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.

scholarly journals Routes of Clonal Evolution into Complex Karyotypes in Myelodysplastic Syndrome Patients with 5q Deletion

2018 ◽  
Vol 19 (10) ◽  
pp. 3269 ◽  
Author(s):  
Simone Feurstein ◽  
Kathrin Thomay ◽  
Winfried Hofmann ◽  
Guntram Buesche ◽  
Hans Kreipe ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Clonal Evolution ◽  
Suppressor Gene ◽  
Trisomy 8 ◽  
Multicolor Fish ◽  
Catastrophic Event ◽  
Evolution And Development ◽  
Gene Tp53

Myelodysplastic syndrome (MDS) can easily transform into acute myeloid leukemia (AML), a process which is often associated with clonal evolution and development of complex karyotypes. Deletion of 5q (del(5q)) is the most frequent aberration in complex karyotypes. This prompted us to analyze clonal evolution in MDS patients with del(5q). There were 1684 patients with low and intermediate-risk MDS and del(5q) with or without one additional cytogenetic abnormality, who were investigated cytogenetically in our department, involving standard karyotyping, fluorescence in situ hybridization (FISH) and multicolor FISH. We identified 134 patients (8%) with aspects of clonal evolution. There are two main routes of cytogenetic clonal evolution: a stepwise accumulation of cytogenetic events over time and a catastrophic event, which we defined as the occurrence of two or more aberrations present at the same time, leading to a sudden development of highly complex clones. Of the 134 patients, 61% underwent a stepwise accumulation of events whereas 39% displayed a catastrophic event. Patients with isolated del(5q) showed significantly more often a stepwise accumulation of events rather than a catastrophic event. The most frequent aberrations in the group of stepwise accumulation were trisomy 8 and trisomy 21 which were significantly more frequent in this group compared to the catastrophic event group. In the group with catastrophic events, del(7q)/-7 and del(17p)/-17 were the most common aberrations. A loss of 17p, containing the tumor suppressor gene TP53, was found significantly more frequent in this group compared to the group of stepwise accumulation. This leads to the assumption that the loss of TP53 is the driving force in patients with del(5q) who undergo a sudden catastrophic event and evolve into complex karyotypes.

scholarly journals Risk of primary gastrointestinal cancers following incident non-metastatic breast cancer: a Danish population-based cohort study

2020 ◽  
Vol 7 (1) ◽  
pp. e000413
Author(s):  
Kasper Adelborg ◽  
Dóra Körmendiné Farkas ◽  
Jens Sundbøll ◽  
Lidia Schapira ◽  
Suzanne Tamang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Colon Cancer ◽  
Cohort Study ◽  
Metastatic Breast Cancer ◽  
Stomach Cancer ◽  
Metastatic Breast ◽  
Population Based ◽  
Gastrointestinal Cancers ◽  
Increased Risk

ObjectiveWe examined the risk of primary gastrointestinal cancers in women with breast cancer and compared this risk with that of the general population.DesignUsing population-based Danish registries, we conducted a cohort study of women with incident non-metastatic breast cancer (1990–2017). We computed cumulative cancer incidences and standardised incidence ratios (SIRs).ResultsAmong 84 972 patients with breast cancer, we observed 2340 gastrointestinal cancers. After 20 years of follow-up, the cumulative incidence of gastrointestinal cancers was 4%, driven mainly by colon cancers. Only risk of stomach cancer was continually increased beyond 1 year following breast cancer. The SIR for colon cancer was neutral during 2–5 years of follow-up and approximately 1.2-fold increased thereafter. For cancer of the oesophagus, the SIR was increased only during 6–10 years. There was a weak association with pancreas cancer beyond 10 years. Between 1990–2006 and 2007–2017, the 1–10 years SIR estimate decreased and reached unity for upper gastrointestinal cancers (oesophagus, stomach, and small intestine). For lower gastrointestinal cancers (colon, rectum, and anal canal), the SIR estimate was increased only after 2007. No temporal effects were observed for the remaining gastrointestinal cancers. Treatment effects were negligible.ConclusionBreast cancer survivors were at increased risk of oesophagus and stomach cancer, but only before 2007. The risk of colon cancer was increased, but only after 2007.

A diet with lactosucrose supplementation ameliorates trinitrobenzene sulfonic acid-induced colitis in rats

2015 ◽  
Vol 6 (1) ◽  
pp. 161-171 ◽  
Author(s):  
Yan Zhou ◽  
Zheng Ruan ◽  
Xiaoli Zhou ◽  
Xiaoliu Huang ◽  
Hua Li ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Sulfonic Acid ◽  
Intestinal Inflammation ◽  
Trinitrobenzene Sulfonic Acid ◽  
Increased Risk ◽  
Chronic Intestinal Inflammation

Chronic intestinal inflammation contributes to an increased risk of colon cancer.

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