Constitutional mismatch repair deficiency and Lynch syndrome among consecutive Arab Bedouins with colorectal cancer in Israel

Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary disorders characterised by a highly increased risk of cancer development. This is due to germline aberrations in the mismatch repair (MMR) genes, which results in a high mutational load in tumours of these patients, including insertions and deletions in genes bearing microsatellites. This generates microsatellite instability and cause reading frameshifts in coding regions that could lead to the generation of neoantigens and opens up avenues for neoantigen targeting immune therapies prophylactically and therapeutically. However, major obstacles need to be overcome, such as the heterogeneity in tumour formation within and between LS and CMMRD patients, which results in considerable variability in the genes targeted by mutations, hence challenging the choice of suitable neoantigens. The machine-learning methods such as NetMHC and MHCflurry that predict neoantigen- human leukocyte antigen (HLA) binding affinity provide little information on other aspects of neoantigen presentation. Immune escape mechanisms that allow MMR-deficient cells to evade surveillance combined with the resistance to immune checkpoint therapy make the neoantigen targeting regimen challenging. Studies to delineate shared neoantigen profiles across patient cohorts, precise HLA binding algorithms, additional therapies to counter immune evasion and evaluation of biomarkers that predict the response of these patients to immune checkpoint therapy are warranted.

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Constitutional mismatch repair deficiency in childhood colorectal cancer harboring a de novo variant in the MSH6 gene: a case report

BMC Gastroenterology ◽

10.1186/s12876-021-01646-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Keinosuke Hizuka ◽

Shin-ichiro Hagiwara ◽

Takatoshi Maeyama ◽

Hitoshi Honma ◽

Masanobu Kawai ◽

...

Keyword(s):

Colorectal Cancer ◽

Mismatch Repair ◽

De Novo ◽

Pathological Examination ◽

Compound Heterozygous ◽

Mismatch Repair Deficiency ◽

Repair Deficiency ◽

Compound Heterozygous Variants ◽

De Novo Variant ◽

Constitutional Mismatch Repair Deficiency

Abstract Background Constitutional mismatch repair deficiency (CMMRD) is caused by biallelic pathogenic variants in one of the mismatch repair genes, and results in early onset colorectal cancer, leukemia, brain tumors and other childhood malignancies. Here we report a case of CMMRD with compound heterozygous variants in the MSH6 gene, including a de novo variant in multiple colorectal cancers. Case presentation An 11-year-old girl, who presented with multiple spots resembling café-au-lait macules since birth, developed abdominal pain, diarrhea and bloody stool over two months. Colonoscopy revealed multiple colonic polyps, including a large epithelial tumor, and pathological examination revealed tubular adenocarcinoma. Brain magnetic resonance imaging (MRI) showed an unidentified bright object (UBO), commonly seen in neurofibromatosis type 1 (NF1). Genetic testing revealed compound heterozygous variants, c. [2969T > A (p.Leu990*)] and [3064G > T (p.Glu1022*)] in the MSH6 gene; c.2969T > A (p.Leu990*) was identified as a de novo variant. Conclusions We present the first report of a CMMRD patient with a de novo variant in MSH6, who developed colorectal cancer in childhood. CMMRD symptoms often resemble NF1, as observed here. Physicians should become familiar with CMMRD clinical phenotypes for the screening and early detection of cancer.

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Intensive surveillance endoscopy for multiple gastrointestinal tumors in a patient with constitutional mismatch repair deficiency: case report

BMC Gastroenterology ◽

10.1186/s12876-021-01902-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Takayuki Ando ◽

Takahiko Nakajima ◽

Rei Fukuda ◽

Keiko Nomura ◽

Yo Niida ◽

...

Keyword(s):

Colorectal Cancer ◽

Rectal Cancer ◽

Mismatch Repair ◽

Mismatch Repair Deficiency ◽

Aggressive Approach ◽

Repair Deficiency ◽

Partial Colectomy ◽

Surveillance Endoscopy ◽

Constitutional Mismatch Repair Deficiency ◽

Intensive Surveillance

Abstract Background Constitutional mismatch repair deficiency (CMMRD) is an extremely rare autosomal recessive hereditary disease characterized by the absence of mismatch repair gene activity from birth, which results in brain tumors, colonic polyposis, gastrointestinal cancers, and lymphomas later in life. An aggressive approach, including colectomy or proctocolectomy, is recommended for the treatment of colorectal cancer. Additionally, partial colectomy with subsequent endoscopic surveillance may be an alternative strategy due to poor patient’s condition, although there is no evidence of surveillance endoscopy after partial colectomy for CMMRD. Case presentation A 13-year-old male patient with a history of T-lymphoblastic lymphoma underwent total gastrointestinal endoscopy, which revealed rectal cancer, colorectal polyposis, and duodenal adenoma. Differential diagnosis included constitutional mismatch repair deficiency according to its scoring system and microsatellite instability, and subsequent germline mutation testing for mismatch repair genes confirmed the diagnosis of constitutional mismatch repair deficiency based on a homozygous mutation in mutS homolog 6 (MSH6). The patient and his family refused colectomy due to the high risk of malignancies other than colorectal cancer, which could require radical surgery. Therefore, the patient underwent low anterior resection of the rectosigmoid colon for rectal cancer and intensive surveillance endoscopy for the remaining colon polyposis. During the 3-year period after initial surgery, 130 polyps were removed and the number of polyps gradually decreased during 6-months interval surveillance endoscopies, although only one polyp was diagnosed as invasive adenocarcinoma (pT1). Conclusions Our experience of short surveillance endoscopy illustrates that this strategy might be one of options according to patient’s condition.

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