Lynch Syndrome and Somatic Mismatch Repair Variants in Pancreas Cancer

Catherine A. O鈥機onnor; Emily Harrold; David Lin; Henry Walch; Andrea Gazzo; Megha Ranganathan; Sarah Kane; Fergus Keane; Joshua Schoenfeld; Drew Moss; Deborah M. Thurtle-Schmidt; Sarah P. Suehnholz; Debyani Chakravarty; Fiyinfolu Balogun; Anna Varghese; Kenneth Yu; David Kelsen; Alicia Latham; Britta Weigelt; Wungki Park; Zsofia Stadler; Eileen M. O鈥橰eilly

doi:10.1001/jamaoncol.2024.3651

Key Points

Question听 What are the clinicogenomic features and associated treatment outcomes of Lynch syndrome鈥揳ssociated pancreas cancer (PC), and how can microsatellite (MS) status testing be optimized in PC?

Findings听 In this cross-sectional study of 55 patients with PC, MS instability (MSI-H) arose in PC due to somatic and germline oncogenesis and was associated with response to immune checkpoint blockade therapy. Orthogonal testing, including the use of artificial intelligence classifiers, informed MS status in approximately 20% of PC cases and was valuable for low-cellularity specimens.

Meaning听 The study results suggest that orthogonal MS testing is critical to identify MSI-H in PC and patients with MSI-H PC should be treated with immune checkpoint blockade therapy.

Abstract

Importance听 Microsatellite (MS) instability (MSI-H) occurs frequently in Lynch syndrome (LS)鈥揳ssociated tumors and is associated with response to immune checkpoint blockade (ICB) therapy. MSI-H is conferred by germline or somatic variants in mismatch repair genes. The contribution of somatic oncogenesis to MSI-H in pancreatic cancer (PC) is unknown.

Objective听 To evaluate an LS-related PC cohort to define clinicogenomic features, describe somatic MSI-H cases (germline negative), characterize response to ICB, and guide preferred MS testing methods.

Design, Setting, and Participants听 This single-institution, retrospective analysis was conducted from March 2012 to July 2023 at Memorial Sloan Kettering Cancer Center and included 55 patients with PC and either an LS germline pathogenic variant (gPV) or somatic mismatch repair (MMR) variant.

Main Outcomes and Measures听 Composite MMR and MS status determined using orthogonal methods. An artificial intelligence classifier was used to account for low-cellularity specimens. Demographic and clinical data were abstracted from medical record. Zygosity status and somatic comutation landscape analyzed.

Results听 Fifty-five patients (23 women [42%]) had PC and an MMR variant: 32 (58%) had LS (LS cohort) and 23 (42%) had a somatic MMR variant (no germline pathogenic variant, somatic MMR cohort). In the LS cohort, 10 (31%) had gMSH2, 9 (28%) gMSH6, 8 (25%) gPMS2, 4 (13%) gMLH1, 1 (3%) gEPCAM. The median age at diagnosis was 68 years (range, 45-88 years). For composite MS status, 17 (59%) were MSI-H, 12 (41%) MS stable, and 3 MS unknown. Five cases were reclassified as MSI-H by the artificial intelligence classifier. In the somatic MMR cohort, 11 (48%) had MSH6, 7 (30%) MLH1, 3 (13%) MSH2, and 2 (9%) PMS2. The median age at diagnosis was 72 years (range, 66-85 years). For composite MS status, 10 (43%) were MSI-H, 11 (48%) MS stable, and 2 (9%) MS indeterminate. Six cases were reclassified as MSI-H by the artificial intelligence classifier. For the LS and somatic MMR cohorts, 20 received ICB (n鈥�=鈥�17 MSI-H). The median ICB duration was 27.7 months (95% CI, 11.5 to not reached); the disease control rate was 80%.

Conclusion听 The results of this cross-sectional study suggest that MSI-H occurs due to LS or somatic oncogenesis in PC. Orthogonal MS testing is key in PC; the artificial intelligence classifier reclassified approximately 20% of cases, most of which were low cellularity. ICB for patients with LS or somatic MSI-H PC provided significant benefit.

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September 16, 2024

Lynch syndrome in patients with advanced/metastatic pancreatic cancer revealed by cancer genomic medicine in Japan

takuma hayashi, MBBS, DMSci, GMRC, PhD. | National Hospital Organization, Kyoto Medical Center3

Microsatellite Instability (MSI) testing for instability of repetitive sequences in the genome and immunohistochemical staining of the mismatch repair (MMR) proteins that cause MSI are covered by insurance and are widely used in clinical practice as companion diagnostics (CDx) for immune checkpoint inhibitors (ICIs) for solid tumors and as auxiliary diagnostics for Lynch syndrome, a hereditary tumor with an autosomal dominant inheritance pattern.

From December 2019 to June 2024, a total of 36,211 new treatments were investigated using cancer genome panel tests (FoundationOne庐 CDx test: n = 27,981 cases; OncoGuideTM NCC oncopanel test (Riken Genesis, Yokohama, Japan): n = 8,230 cases) in cancer genomic medicine conducted at the Japanese national universities.

A new treatment method was examined using cancer genome panel testing in 1981 Japanese patients with advanced/metastatic pancreatic cancer; MSI-High (i.e., Germline Mismatch Repair Variants positive) were detected in 67 patients with advanced/metastatic pancreatic cancer. Of the 67 patients of MSI-High positive advanced/metastatic pancreatic cancer, 66 patients with advanced/metastatic pancreatic cancer were diagnosed with Lynch syndrome, a hereditary tumor.

We have nothing to disclose.

Dr. T. Hayashi and Dr. I Konishi
National Hospital Organization Kyoto Medical Center

999

CONFLICT OF INTEREST: None Reported

September 16, 2024

Lynch syndrome in patients with advanced/metastatic pancreatic cancer revealed by cancer genomic medicine in Japan

takuma hayashi, MBBS, DMSci, GMRC, PhD. | National Hospital Organization, Kyoto Medical Center3

CONFLICT OF INTEREST: None Reported

September 15, 2024

Lynch syndrome in patients with advanced/metastatic pancreatic cancer revealed by cancer genomic medicine in Japan

takuma hayashi, MBBS, DMSci, GMRC, PhD. | National Hospital Organization, Kyoto Medical Center

CONFLICT OF INTEREST: None Reported

October 8, 2024

Controversies over germline and somatic mutations in DNA damage response (DDR) related pathways and Lynch syndrome

Bufu TangMD1鈥�, Yiou WangBM1鈥�, Peng LuoMD2* | China Medical University

Controversies over germline and somatic mutations in DNA damage response (DDR) related pathways and Lynch syndrome.
Article Type: Letter to the editor

Department of Radiation Oncology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China.
China Medical University, Shenyang 110122, China.
Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510000, China.

This Letter to the Editor is in response to:
[Lynch Syndrome and Somatic Mismatch Repair Variants in Pancreas Cancer/O鈥機onnor CA, Harrold E, Lin D, et al]
https:// doi:10.1001/jamaoncol.2024.3651/

Competing Interests
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

* Correspondences to:
Peng Luo,
Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong,510000 ,China.
Tel: 0086-18588447321
Email: luopeng@smu.edu.cn

鈥�: Bufu Tang and Yiou Wang have contributed equally to this work and share first authorship.

Word Count for Text: 251words鈥�
To the editor,
This article from O'Connor et al. describes their finding that MSI-H pancreatic cancer (PC) is frequently caused by germline, not somatic, mutations in mismatch repair (MMR) genes - particularly gMLH1 and gMSH2.1 MMR variants account for MSI-H in around 50% of PC patients. MSI-H PC patients appear to derive significant benefit from immune checkpoint blockade (ICB).

The association between germline and somatic mutations in DNA damage response (DDR) pathways and Lynch syndrome (LS) is an area of ongoing discussion. While several reports have described relationships between germline mutations in key DDR genes and LS, there is debate around which genes are critical.2 One such study found relatively frequent germline LS mutations in hereditary breast cancer (HBC) patients, especially MLH1 c.1321G>A, MSH2 c.260C>G and c.2178G>C, MSH6 c.3217C>T, and PMS2 c.1268C>G and c.86G>C variants. LS is proposed to principally arise from loss-of-function germline mutations in MLH1 and MSH2, with MSH6 and PMS2 alterations seen less commonly.

Another study assessed the ability of germline heterozygous and somatic bi-allelic variants to alter cellular phenotypes. Germline and somatic joint changes in MMR genes showed a cooperative effect on somatic MSI burden, though single alterations did not. While germline variants can impact cellular phenotypes and cancer development, this capacity usually depends on additional somatic changes or tissue-specific processes.3

In summary, the authors believe the integrated influence of multiple germline and somatic mutations across complementary pathways and genes is likely critical to understanding LS fully. Clarifying these complex interactions may help optimize application of immunotherapy for MSI-H cancers.
Statements & Declarations
Funding
Not applicable.

Acknowledgements
Not applicable.

References
1. O鈥機onnor CA, Harrold E, Lin D, et al. Lynch Syndrome and Somatic Mismatch Repair Variants in Pancreas Cancer. JAMA Oncology. 2024.
2. Nikitin AG, Chudakova DA, Enikeev RF, et al. Lynch Syndrome Germline Mutations in Breast Cancer: Next Generation Sequencing Case-Control Study of 1,263 Participants. Frontiers in oncology. 2020;10:666.
3. Buckley AR, Ideker T, Carter H, Harismendy O, Schork NJ. Exome-wide analysis of bi-allelic alterations identifies a Lynch phenotype in The Cancer Genome Atlas. Genome Medicine. 2018;10(1).

CONFLICT OF INTEREST: None Reported

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