Reference Detail

Ref Type

Journal Article

PMID

(31008436)

Authors

Middha S, Yaeger R, Shia J, Stadler ZK, King S, Guercio S, Paroder V, Bates DDB, Rana S, Diaz LA, Saltz L, Segal N, Ladanyi M, Zehir A, Hechtman JF

Title

Majority of B2M-Mutant and -Deficient Colorectal Carcinomas Achieve Clinical Benefit From Immune Checkpoint Inhibitor Therapy and Are Microsatellite Instability-High.

Journal	Vol	Issue	Date	Pages	Journal Short Title
JCO precision oncology	3		2019		JCO Precis Oncol

URL

Abstract Text

Microsatellite instability-high (MSI-H) colorectal carcinomas (CRCs) show high rates of response to immune checkpoint inhibitors (IOs). B2M mutations and protein loss have been proposed as causes of resistance to IOs, yet they are enriched in MSI-H CRC. We aimed to characterize B2M-mutant, IO-naive CRC.All CRCs with results for Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets, a next-generation sequencing assay that interrogates > 400 genes for mutations as well as MSI status, were surveyed for B2M mutations. All B2M-mutant CRCs were assessed for expression of B2M, major histocompatibility complex class I, and programmed death-1 ligand (PD-L1) via immunohistochemistry and average CD3+ and CD8+ tumor-infiltrating lymphocyte counts against a control group of MSI-H B2M wild-type CRCs.Fifty-nine (3.4%) of 1,751 patients with CRC harbored B2M mutations, with 84% (77 of 92) of the mutations predicted to be truncating. B2M mutations were significantly enriched in MSI-H CRCs, with 44 (24%) of 182 MSI-H CRCs harboring B2M mutations (P < .001). Thirty-two of 44 B2M-mutant CRCs with available material (73%) had complete loss of B2M expression, whereas all 26 CRCs with wild-type B2M retained expression (P < .001). B2M mutation status was not associated with major histocompatibility complex class I expression, KRAS or BRAF mutation, tumor-infiltrating lymphocyte level, or PD-L1 expression after adjustment for MSI status. Of 13 patients with B2M-mutant CRC who received programmed death-1 or PD-L1 IOs, 11 (85%) achieved clinical benefit, defined as stable disease or partial response using Response Evaluation Criteria in Solid Tumors criteria.B2M mutations occur in approximately 24% of MSI-H CRCs and are usually associated with loss of B2M expression. Most patients with B2M-mutant MSI-H CRC with loss of protein expression obtain clinical benefit from IOs.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description
B2M	E64*	nonsense	unknown	B2M E64* results in a premature truncation of the B2m protein at amino acid 64 of 119 (UniProt.org). E64* has been identified in the scientific literature (PMID: 31008436), but has not been biochemically characterized and therefore, its effect on B2m protein function is unknown (PubMed, Jan 2023).
B2M	E89*	nonsense	unknown	B2M E89* results in a premature truncation of the B2m protein at amino acid 89 of 119 (UniProt.org). E89* has been identified in sequencing studies (PMID: 31008436), but has not been biochemically characterized and therefore, its effect on B2m protein function is unknown (PubMed, Oct 2023).
B2M	L10P	missense	unknown	B2M L10P lies within the signal peptide region of the B2m protein (UniProt.org). L10P has been identified in the scientific literature (PMID: 31008436), but has not been biochemically characterized and therefore, its effect on B2m protein function is unknown (PubMed, Jan 2023).
B2M	L13P	missense	unknown	B2M L13P lies within the signal peptide region of the B2m protein (UniProt.org). L13P has been identified in the scientific literature (PMID: 31008436), but has not been biochemically characterized and therefore, its effect on B2m protein function is unknown (PubMed, Jan 2023).
B2M	R117*	nonsense	unknown	B2M R117* results in a premature truncation of the B2m protein at amino acid 117 of 119 (UniProt.org). R117* is associated with decreased B2m expression in patient samples (PMID: 31008436), but has not been biochemically characterized and therefore, its effect on B2m protein function is unknown (PubMed, Oct 2023).
B2M	T93Hfs*2	frameshift	unknown	B2M T93Hfs2 indicates a shift in the reading frame starting at amino acid 93 and terminating 2 residues downstream causing a premature truncation of the 119 amino acid B2m protein (UniProt.org). T93Hfs2 has been identified in sequencing studies (PMID: 31008436), but has not been biochemically characterized and therefore, its effect on B2m protein function is unknown (PubMed, Jan 2023).
B2M	T93Lfs*10	frameshift	unknown	B2M T93Lfs10 indicates a shift in the reading frame starting at amino acid 93 and terminating 10 residues downstream causing a premature truncation of the 119 amino acid B2m protein (UniProt.org). T93Lfs10 has been identified in sequencing studies (PMID: 31008436), but has not been biochemically characterized and therefore, its effect on B2m protein function is unknown (PubMed, Jan 2023).
B2M	V69Wfs*34	frameshift	unknown	B2M V69Wfs34 indicates a shift in the reading frame starting at amino acid 69 and terminating 34 residues downstream causing a premature truncation of the 119 amino acid B2m protein (UniProt.org). V69Wfs34, combined with S16Afs*27, demonstrates a loss of B2m protein expression via immunohistochemistry in a patient sample (PMID: 31008436), but has not been biochemically characterized and therefore, its effect on B2m protein function is unknown.
B2M	Y30*	nonsense	unknown	B2M Y30* results in a premature truncation of the B2m protein at amino acid 30 of 119 (UniProt.org). Y30* has been identified in the scientific literature (PMID: 31008436), but has not been biochemically characterized and therefore, its effect on B2m protein function is unknown (PubMed, Oct 2023).
B2M	Y87*	nonsense	unknown	B2M Y87* results in a premature truncation of the B2m protein at amino acid 87 of 119 (UniProt.org). Y87* has been identified in the scientific literature (PMID: 31008436), but has not been biochemically characterized and therefore, its effect on B2m protein function is unknown (PubMed, Apr 2021).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
B2M mutant	colorectal cancer	predicted - sensitive	unspecified PD-1 antibody	Clinical Study - Cohort	Actionable	In a clinical study, a cohort of colorectal cancer patients harboring B2M mutations demonstrated a clinical benefit of either a partial response or stable disease in 85% (11/13) when treated with a PD-1 or PD-L1 inhibitor (PMID: 31008436).	31008436
B2M mutant	colorectal cancer	predicted - sensitive	unspecified PD-L1 antibody	Clinical Study - Cohort	Actionable	In a clinical study, a cohort of colorectal cancer patients harboring B2M mutations demonstrated a clinical benefit of either a partial response or stable disease in 85% (11/13) when treated with a PD-1 or PD-L1 inhibitor (PMID: 31008436).	31008436