• cholangiocarcinoma (CCA)
• resistance in cholangiocarcinoma
• single-cell and spatial transcriptomic perspective
• targeted therapies
• treatment of cholangiocarcinoma

• ARID1A
• CD8
• Colorectal cancer
• Heterogeneous expression
• Immunotherapy

• 82373372 National Natural Science Foundation of China
• YQ2022H017 Natural Science Funding of Heilongjiang

• biomarker
• cholangiocarcinoma
• gallbladder cancer
• hepatobiliary malignancy
• targeted therapy

• Humans
• Cholangiocarcinoma/drug therapy
• Bile Ducts
• Immune Checkpoint Inhibitors
• Bile Duct Neoplasms/drug therapy
• Bile Ducts, Intrahepatic

• chemotherapy
• clinical trials
• immunotherapy
• small bowel adenocarcinoma
• systematic review
• target therapy

• DNA damage repair
• homologous recombination
• immune checkpoint inhibitors
• mismatch repair
• oncology

• Cell Cycle
• DNA Damage/genetics
• DNA End-Joining Repair/genetics
• DNA Mismatch Repair/genetics
• DNA Repair/genetics
• Homologous Recombination/genetics
• Humans
• Immune Checkpoint Inhibitors/therapeutic use
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/pathology
• Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use

• Fundação de Amparo à Pesquisa do Estado de São Paulo

• CTLA-4
• PD-1
• PD-L1
• cancer treatment
• checkpoint inhibitors
• immunotherapy
• toxicity

• Animals
• Antineoplastic Agents, Immunological/adverse effects
• Antineoplastic Agents, Immunological/therapeutic use
• Diffusion of Innovation
• Humans
• Immune Checkpoint Inhibitors/adverse effects
• Immune Checkpoint Inhibitors/therapeutic use
• Immunotherapy/adverse effects
• Molecular Targeted Therapy
• Neoplasms/drug therapy
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasms/pathology
• Time Factors
• Treatment Outcome

• EGFR
• HER2
• Immune checkpoint inhibitors
• Immunotherapy
• NTRK
• Small bowel adenocarcinoma
• Targeted therapy

• Adjuvant therapy
• Checkpoint inhibitors
• FGFR
• IDH

• Adenocarcinoma
• Biomarkers
• Lymphocyte
• Medullary
• Microsatellite instability
• Prognosis
• Small intestine
• Tumor-infiltrating

Significant progress has been made in our understanding of the molecular lesions responsible for tumor cells to exhibit uncontrolled growth while circumventing normal mechanisms of apoptosis and their ability to migrate and invade normal tissues while evading recognition and destruction by the immune system. This understanding has enabled the development of therapies specifically targeted to these lesions coupled to innovative treatment regimens to most effectively use these new targeted therapies with precision in selected subpopulations of patients. Innovation at the scientific and clinical levels has been appropriately embraced and supported at the FDA, resulting in regulatory innovation to facilitate and adapt to the Precision Medicine environment.

Advances in innovative technology, including next-generation sequencing, have allowed comprehensive genomic analysis and the elucidation of the genomic aspect of intratumor heterogeneity (ITH). Moreover, models of the evolution of the cancer genome have been proposed by integrating these analyses. Cancer has been considered to accumulate genetic abnormalities for clonal evolution in time and space, and these evolutionary patterns vary depending on the organs of primary sites. Selection pressure is an important determinant of such evolutionary patterns. With weak selection pressure, more diverse clones coexist, and heterogeneity increases. Heterogeneity is maximized when there is no selection pressure; in other words, neutral evolution occurs. Some types of cancer such as lung cancer evolve in conditions that have maintained close to neutral evolution and produce diverse variants. This ITH is a key factor contributing to the lethal outcome of cancer, therapeutic failure, and drug resistance. This factor reaffirms the complexity and subtle adaptability of cancer. It is expected that further understanding of ITH and cancer genome evolution will facilitate the development of new therapeutic strategies to overcome ITH.

• cancer genome evolution
• intratumor heterogeneity
• targeted therapy

Colorectal carcinomas with high-frequency microsatellite instability (MSI-H) account for 15% of all colorectal cancers, including 12% of sporadic cases and 3% of cancers associated with Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer syndrome, HNPCC). Lynch syndrome is an autosomal dominant hereditary cancer syndrome, caused by germline mutations in mismatch repair genes, including MLH1, MSH2, MSH6 and PMS2.

Published articles from peer-reviewed journals were obtained from PubMed, Google Scholar and Clinicaltrials.gov. Based on the recent research data, we provide an update on the MSI testing, along with the evolving role of MSI in diagnosis, prognosis and treatment of colorectal cancers.

Studies have led to significant advances in the molecular pathogenesis and clinicopathological characteristics of MSI-H colorectal cancers. Emerging evidence suggests that colorectal cancers with MSI-H show different outcome and treatment response from those with microsatellite stable (MSS) tumors. Therefore, MSI testing is essential not only in the genetic context, but it may also have important prognostic and predictive value of response to chemotherapy and immunotherapy.

Many experts and professional authorities have recommended a universal MSI testing in all individuals newly diagnosed with colorectal cancers.

• Cancer treatment
• Chemotherapy
• Colorectal cancer
• Immunotherapy
• Lynch syndrome
• Microsatellite instability
• Mismatch repair

• lung cancer
• mutation
• next-generation sequencing
• programmed death ligand-1
• sarcomatoid cancer

• gastrointestinal cancer
• hypermutation
• immune checkpoint inhibitor
• microsatellite instability
• precision medicine

• R01 CA160688 NCI NIH HHS

Lynch syndrome is an autosomal-dominant disorder caused by defective DNA mismatch repair (MMR) genes and is associated with increased risk of malignancies in multiple organs. Small-intestinal adenocarcinomas are common initial manifestations of Lynch syndrome. To define the incidence and characteristics of Lynch syndrome-related small-intestinal adenocarcinomas, meticulous familial and clinical histories were obtained from 195 patients with small-intestinal adenocarcinoma, and MMR protein immunohistochemistry, microsatellite instability, MLH1 methylation, and germline mutational analyses were performed. Lynch syndrome was confirmed in eight patients (4%), all of whom had synchronous/metachronous malignancies without noticeable familial histories. Small-intestinal adenocarcinomas were the first clinical manifestation in 37% (3/8) of Lynch syndrome patients, and second malignancies developed within 5 years in 63% (5/8). The patients with accompanying Lynch syndrome were younger (≤50 years; P=0.04) and more likely to have mucinous adenocarcinomas (P=0.003), and tended to survive longer (P=0.11) than those with sporadic cases. A meticulous patient history taking, MMR protein immunolabeling, and germline MMR gene mutational analysis are important for the diagnosis of Lynch syndrome-related small-intestinal adenocarcinomas. Identifying Lynch syndrome in patients with small-intestinal adenocarcinoma can be beneficial for the early detection and treatment of additional Lynch syndrome-related cancers, especially in patients who are young or have mucinous adenocarcinomas.

• DNA mismatch repair
• Lynch syndrome
• hereditary nonpolyposis colorectal cancer syndrome
• microsatellite instability
• small intestinal adenocarcinoma

• Colonic neoplasms
• Colorectal neoplasms
• DNA mismatch repair
• Hereditary nonpolyposis
• Immunotherapy
• Microsatellite instability

• Colonic neoplasms
• Colorectal neoplasms
• DNA mismatch repair
• Hereditary nonpolyposis
• Immunotherapy
• Microsatellite instability

• DNA Mismatch Repair
• Humans
• Immunotherapy
• Microsatellite Instability
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/immunology
• Programmed Cell Death 1 Receptor/antagonists & inhibitors

• Lynch syndrome
• familial gastrointestinal cancer
• genetic testing
• multigene panel testing

• Adenocarcinoma
• Lung cancer
• Microsatellite instability
• Mismatch repair

• Adenocarcinoma/drug therapy
• Adenocarcinoma/genetics
• Adenocarcinoma/secondary
• Adult
• Aged
• Antibodies, Monoclonal, Humanized/adverse effects
• Antibodies, Monoclonal, Humanized/therapeutic use
• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/therapeutic use
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• DNA Mismatch Repair
• Disease-Free Survival
• Female
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neoplasm Metastasis/drug therapy
• Neoplasm Metastasis/genetics
• Programmed Cell Death 1 Receptor/antagonists & inhibitors

• CA57345 NCI NIH HHS
• R01 CA067941 NCI NIH HHS
• R37 CA043460 NCI NIH HHS
• U01 CA067941 NCI NIH HHS
• CA16058 NCI NIH HHS
• P30CA006973 NCI NIH HHS
• P50 CA062924 NCI NIH HHS
• P30 CA006973 NCI NIH HHS
• CA67941 NCI NIH HHS
• CA43460 NCI NIH HHS
• CA163672 NCI NIH HHS
• P50CA062924 NCI NIH HHS
• R37 CA057345 NCI NIH HHS
• P30 CA016058 NCI NIH HHS
• R01 CA057345 NCI NIH HHS
• K23 CA163672 NCI NIH HHS

Inherited mutations in the DNA mismatch repair genes (MMR) can cause MMR deficiency and increased susceptibility to colorectal and endometrial cancer. Microsatellite instability (MSI) is the defining molecular signature of MMR deficiency. The clinical classification of identified MMR gene sequence variants has a direct impact on the management of patients and their families. For a significant proportion of cases sequence variants of uncertain clinical significance (also known as unclassified variants) are identified, constituting a challenge for genetic counselling and clinical management of families. The effect on protein function of these variants is difficult to interpret. The presence or absence of MSI in tumours can aid in determining the pathogenicity of associated unclassified MMR gene variants. However, there are some considerations that need to be taken into account when using MSI for variant interpretation. The use of MSI and other tumour characteristics in MMR gene sequence variant classification will be explored in this review.

Lynch syndrome is the most common cause of hereditary colon cancer, and accounts for as much as 3% of all colon and endometrial cancers. The identification and management of individuals with Lynch syndrome have evolved over the past 20 years, yet the syndrome remains vastly underdiagnosed. It is important for clinicians to recognize individuals and families who are at risk in order to be able to manage them appropriately and reduce their morbidity and mortality from this condition. This review will touch on the history of Lynch syndrome, the current knowledge of genotype–phenotype correlations, the cancers associated with Lynch syndrome, and management of individuals who are gene carriers.

• Lynch syndrome
• hereditary cancer
• hereditary nonpolyposis colorectal cancer
• immunohistochemistry
• microsatellite instability
• mismatch repair
• mismatch repair genes