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. 2024 Nov:8:e2400419.
doi: 10.1200/PO-24-00419. Epub 2024 Nov 22.

Genomic Alterations in DNA Mismatch Repair Genes Across Different Cancer Types

Vijaykumar R Holla  1 , Michael P Kahle  1 , Sun-Hee Kim  1 , Arash Ronaghy  2 , Richard K Yang  3 , Keyur P Patel  3 , Mark J Routbort  3 , Michael J Overman  4 , Ecaterina E Dumbrava  2 , Kenna R Mills Shaw  1 , Daniel D Karp  2 , Funda Meric-Bernstam  2
Affiliations

Genomic Alterations in DNA Mismatch Repair Genes Across Different Cancer Types

Vijaykumar R Holla et al. JCO Precis Oncol. 2024 Nov.

Abstract

Purpose: PD-1 inhibition is effective in patients with mismatch repair deficient (dMMR) solid tumors in a tumor-agnostic fashion. However, dMMR testing by immunohistochemistry (IHC) is not routinely performed across tumor types. By contrast, next-generation sequencing (NGS) for somatic genomic alterations is frequently performed across tumor types. We hypothesized that NGS would identify patients with alterations in mismatch repair (MMR) genes and that these patients would have higher rates of MMR protein loss by IHC. This would support the utility of IHC reflex testing after NGS and potential matching to approved therapeutic options.

Methods: From January 2016 to December 2021, 15,701 patients with solid tumors received NGS covering the MMR genes, and 4,994 patients had both IHC and NGS. Sequencing results were analyzed for mutations in MMR genes, tumor type distribution, and concordance with IHC results when available.

Results: Six hundred and ninety-eight (4.4%) of 15,701 patients had mutations in one of the MMR genes. Mutations were found across tumor types. Three hundred and seventeen (6.3%) of 4,994 patients displayed IHC loss for at least one MMR protein. 33.8% patients (110/325) patients with MMR mutations had dMMR, compared with just 4.4% (207/4,669) patients without mutations (P < .001); dMMR rate varied by mutation type.

Conclusion: Mutations in MMR genes are found in multiple tumor types where IHC testing is not routine. Reflex IHC testing of patients carrying MMR gene mutations, especially those known or inferred to be inactivating, may identify more patients with dMMR and matched treatment options. However, dedicated IHC screening is needed to capture majority of the patients.

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Conflict of interest statement

Disclosure

  1. FMB reports consulting/advisory board fees from AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, Daiichi Sankyo Co. Ltd., Calibr (a division of Scripps Research), DebioPharm, Ecor1 Capital, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., GT Apeiron, Genentech Inc., Harbinger Health, IBM Watson, Incyte, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, LegoChem Bio, Lengo Therapeutics, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Protai Bio Ltd, Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks, Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals, Theratechnologies, Zentalis; Sponsored research to her institution from Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co.; Honoraria (speaking engagement) from Dava Oncology; Travel reimbursement from European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO), Cholangiocarcinoma Foundation, Dava Oncology.

  2. EED reports Research or grant funding from Bayer HealthCare Pharmaceuticals Inc, Immunocore LTD, Amgen, Aileron Therapeutics, Compugen Ltd, TRACON Pharmaceuticals Inc, Unum Therapeutics, Gilead Immunomedics, BOLT Therapeutics, Aprea Therapeutics, Bellicum Pharmaceuticals, PMV Pharma, Triumvira Immunologics, Seagen Inc, Mereo BioPharma 5 Inc, Sanofi, Rain Oncology, Astex Therapeutics, Sotio, Poseida, Mersana Therapeutics, Genentech, Boehringer Ingelheim, Dragonfly Therapeutics, A2A Pharmaceuticals; Advisory Board fees from BOLT Therapeutics, Mersana Therapeutics, Orum Therapeutics, Summit Therapeutics, Fate Therapeutics, PMV Pharma; Speaker honoraria from PMV Pharma; Travel, Accommodations, Expenses from ASCO, LFSA Association, Rain Oncology, Banner MD Anderson Cancer Center, Triumvira Immunologics.

  3. DDK reports travel accomodation from Phosplatin Therapeutics; Consulting fees from Black Beret Life Sciences; Advisory board fees from Affigen and Phosplatin Therapeutics.

  4. The other authors do not declare any conflict of interest.

Figures

Figure 1:
Figure 1:
Next generation sequencing (NGS) profile of patients for mismatch repair (MMR) genes. A) Overall mutation sub-type distribution in our cohort. B) Mutation distribution in individual MMR genes C) Frequency of MMR gene mutations in different tumor types. D) Co-alterations with MMR genes found in select patients. *** (p<0.001), * (p<0.05), Not significant (ns),
Figure 2:
Figure 2:
Immunohistochemistry profile of patients and its association with MMR gene mutations. A) Frequency of tumor type distribution of IHC testing and their results in our cohort. B) A flowchart diagram showing the relationship IHC results to mutation in MMR genes. Results show strong association of IHC loss to MMR gene mutations. C) Pie chart depiction of MMR gene mutation to IHC results. A direct association of MMR gene mutations to IHC loss of MMR proteins.
Figure 3.
Figure 3.
Distribution of MMR gene mutation subtypes and IHC A) Pie chart depiction of missense vs frameshift/truncation/indel/splice mutations with IHC results. Patients with frameshift/truncation/indel/splice mutations (78/123, 63.4%) are more associated with IHC loss than missense mutations (32/202, 15.8%). B) Flow chart of patients with MMR gene mutations with and without IHC results. Frameshift and truncation mutations are more associated with IHC loss of MMR proteins than missense mutations.
See this image and copyright information in PMC

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