Small Bowel Adenocarcinoma Frequently Exhibits Lynch Syndrome–associated Mismatch Repair Protein Deficiency But Does Not Harbor Sporadic MLH1 Deficiency

Xia, Michelle; Singhi, Aatur D.; Dudley, Beth; Brand, Randall E.; Nikiforova, Marina N.; Pai, Reetesh K.

doi:10.1097/pai.0000000000000389

Cited by 9 publications

(17 citation statements)

References 34 publications

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“…In fact, tumors with mismatch repair protein deficiency are unlikely to be associated with key cancer-predisposing conditions, such as with Crohn's disease, celiac disease, and FAP. 30 Mismatch repair protein deficiency can occur in 7 to 35% of SBA, 8 but abnormal MSH2 and MSH6 occur much more frequently, compared with colorectal cancer. 30 Even patients without a family history of Lynch's syndrome can have deficiencies in this pathway, with the exception of MLH1, which has not been observed to be sporadic.…”

Section: Genetics and Molecular Biologymentioning

confidence: 99%

“…30 Mismatch repair protein deficiency can occur in 7 to 35% of SBA, 8 but abnormal MSH2 and MSH6 occur much more frequently, compared with colorectal cancer. 30 Even patients without a family history of Lynch's syndrome can have deficiencies in this pathway, with the exception of MLH1, which has not been observed to be sporadic. 30 Defects in MSH1, MSH2, MSH6, and PMS2, either as direct gene mutation or promoter methylation, are all associated with microsatellite instability, which are specific DNA repeats that reflect the ability to accumulate multiple mutations, due to the lack of correcting mechanisms.…”

Section: Genetics and Molecular Biologymentioning

confidence: 99%

“…30 Even patients without a family history of Lynch's syndrome can have deficiencies in this pathway, with the exception of MLH1, which has not been observed to be sporadic. 30 Defects in MSH1, MSH2, MSH6, and PMS2, either as direct gene mutation or promoter methylation, are all associated with microsatellite instability, which are specific DNA repeats that reflect the ability to accumulate multiple mutations, due to the lack of correcting mechanisms. The four mismatch repair proteins typically form a protein complex that recognizes mismatched bases that may occur during DNA replication or from DNA damage.…”

Section: Genetics and Molecular Biologymentioning

confidence: 99%

“…29 Mismatch repair protein deficient tumors have been compared between small bowel and colorectal adenocarcinoma, and their clinical and pathological characteristics are similar. 30 Other genes associated with known genetic syndromes, such as STK11, that codes a serine/threonine kinase in cell homeostasis pathway in PJS 14 and SMAD4 and BMPR1A that code membrane receptors in transforming growth factor beta (TGF-B) pathway in JPS, may also have a role in the polyp formation that could lead to invasive cancer. Sporadic mutations in those without the genetic syndrome, however, are not well understood.…”

Section: Genetics and Molecular Biologymentioning

confidence: 99%

“…3,23,[42][43][44] Mucinous features can occur in 28 to 42% of tumors, 30,43 and signet cell features can be found in 23 to 37% of tumors. 4,30 With respect to immunophenotype, lower gastrointestinal adenocarcinoma typically stains positive for villin, CK20, and CDX2, but negative for CK7. Duodenal tumors, however, can sometimes have gastric and pancreatic-biliary phenotypes in both morphology and immunohistochemistry.…”

Section: Clinical Presentation and Diagnosismentioning

confidence: 99%

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Small Bowel Adenocarcinoma

Chen

Vaccaro

2018

Clinics in Colon and Rectal Surgery

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Small bowel adenocarcinoma is a clinically and anatomically distinct gastrointestinal cancer that lacks prospective data to support its optimal management. Patients with inflammatory bowel disease and inherited conditions that cause gastrointestinal polyps are at especially high risk. Due to a lack of effective surveillance programs resulting in missed or delayed diagnoses only when symptoms develop, this disease is generally discovered at an advanced stage. Surgical resection is the only treatment modality with a chance of cure. Currently accepted treatment considerations are often generalized from large bowel and pancreatic-biliary cancers, due to some anatomic and clinical parallels. Additional research, however, is desperately needed to characterize the unique molecular differences of this disease to better prognosticate patients and establish rational clinical trials that would improve their outcomes.

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Section: Genetics and Molecular Biologymentioning

confidence: 99%

Section: Genetics and Molecular Biologymentioning

confidence: 99%

Section: Genetics and Molecular Biologymentioning

confidence: 99%

Section: Genetics and Molecular Biologymentioning

confidence: 99%

Section: Clinical Presentation and Diagnosismentioning

confidence: 99%

See 3 more Smart Citations

Small Bowel Adenocarcinoma

Chen

Vaccaro

2018

Clinics in Colon and Rectal Surgery

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Frequency and clinicopathologic associations of DNA mismatch repair protein deficiency in ampullary carcinoma: Routine testing is indicated

Xue

Balcı

Mericoz

et al. 2020

Cancer

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BACKGROUND: The significance of DNA mismatch repair (MMR) deficiency in ampullary cancers (ACs) has not been established. METHODS: In total, 127 ACs with invasive carcinomas measuring ≥3 mmthat had adequate tissue were analyzed immunohistochemically. RESULTS: MMR loss was detected in 18% of ACs (higher than in colorectal cancers). Twelve tumors with MLH1-PMS2 loss were negative for BRAF V600E mutation, suggesting a Lynch syndrome association. MMR-deficient tumors (n = 23), comparedwith MMR-intact tumors (n = 104), showed a striking male predominance (male:female ratio, 4.7). Although the deficient tumors had slightly larger invasion size (2.7 vs 2.1 cm), they also had more expansile growth and less invasiveness, including less perineural invasion, and they ultimately had lower tumor (T) classification and less lymph node metastasis (30% vs 53%; P = .04). More important, patients who had MMR-deficient tumors had better clinical outcomes, with a 5-year overall survival rate of 68% versus 45% (P = .03), which was even more pronounced in those who had higher Tclassification (5-year overall survival, 69% vs 34%; P = .04). MMR deficiencyhad a statistically significant association with medullary phenotype, pushing-border invasion, and tumor-infiltrating immune cells, and it occurred more frequently in ampullary-duodenal type tumors. Programed cell death-ligand 1 (PD-L1) levels analyzed in the 22 MMR-deficient ACs revealed that all medullary carcinomas were positive. Nonmedullary MMR-deficient carcinomas expressed PD-L1 in 33% of tumors cells according to the criteria for a combined positive score ≥1, but all were negative according to the tumor proportion score≥1 method. CONCLUSIONS: In ACs, MMR deficiency is even more frequent (18%) than in colon cancer and often has a Lynch-suggestive profile, thus routine testing is warranted. Male gender, pushing-border infiltration, ampullary-duodenal origin, medullary histology, and tumor-related inflammation have a significantly higher association with MMR deficiency. MMR-deficient tumors have less aggressive behavior. PD-L1 expression is common in medullary-phenotype ACs, thus immunotherapy should be considered at least for this group.

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Clinical practice guidelines for duodenal cancer 2021

et al. 2022

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Duodenal cancer is considered to be a small intestinal carcinoma in terms of clinicopathology. In Japan, there are no established treatment guidelines based on sufficient scientific evidence; therefore, in daily clinical practice, treatment is based on the experience of individual physicians. However, with advances in diagnostic modalities, it is anticipated that opportunities for its detection will increase in future. We developed guidelines for duodenal cancer because this disease is considered to have a high medical need from both healthcare providers and patients for appropriate management. These guidelines were developed for use in actual clinical practice for patients suspected of having non-ampullary duodenal epithelial malignancy and for patients diagnosed with non-ampullary duodenal epithelial malignancy. In this study, a practice algorithm was developed in accordance with the Minds Practice Guideline Development Manual 2017, and Clinical Questions were set for each area of epidemiology and diagnosis, endoscopic treatment, surgical treatment, and chemotherapy. A draft recommendation was developed through a literature search and systematic review, followed by a vote on the recommendations. We made decisions based on actual clinical practice such that the level of evidence would not be the sole determinant of the recommendation. This guideline is the most standard guideline as of the time of preparation. It is important to decide how to handle each case in consultation with patients and their family, the treating physician, and other medical personnel, considering the actual situation at the facility (and the characteristics of the patient).

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Small Bowel Adenocarcinoma Frequently Exhibits Lynch Syndrome–associated Mismatch Repair Protein Deficiency But Does Not Harbor Sporadic MLH1 Deficiency

Cited by 9 publications

References 34 publications

Small Bowel Adenocarcinoma

Small Bowel Adenocarcinoma

Frequency and clinicopathologic associations of DNA mismatch repair protein deficiency in ampullary carcinoma: Routine testing is indicated

Clinical practice guidelines for duodenal cancer 2021

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