Background: Lynch syndrome (LS) is an autosomal dominant genetic disease caused by mutations in DNA mismatch repair (MMR) genes, leading to an increased risk of colorectal cancer and other malignancies. Tumors with MMR-deficiency often have microsatellite instability (MSI) and high mutational burden (TMB) which predict high response rate to immunotherapy. Therefore, accurate diagnosis of LS can create valuable opportunities for the clinical management of a broad spectrum of cancers.

Methods: We conducted next-generation sequencing to assess both somatic and germline mutations of the proband. LS diagnosis was confirmed by mismatch repair protein immunochemistry and germline genetic testing results. Furthermore, we applied Sanger sequencing to screen the candidate variant in his family members.

Results: Our proband is a 62-year-old Chinese diagnosed with invasive lung adenocarcinoma (pT1aN2M0, stage IIIA) in the right inferior lobe. Based on the near completely loss of PMS2 in cancer cells by MMR IHC, as well as instability of three MSI markers (NR21, BAT-26 and MONO-27), we suspected LS and performed a germline NGS panel analysis which revealed a G>A nucleotide substitution (c.1144+1G>A) located at the +1 position of intron 10 of the PMS2 gene. We also found that the proband has an oncogenic KRAS p.G13D somatic mutation and his young daughter with the same PMS2 variant has no cancer yet. To characterize the pathogenicity of this PMS2 germline variant, we conducted a comprehensive genetic analysis according to the ACMG/Sherloc guidelines. In silico analysis with three splice prediction programs suggested that the PMS2 c.1144+1G>A variant will generate aberrant splicing transcripts. The population data in the gnomAD web portal showed that the allele frequency of PMS2 c.1144+1G>A variant is 2/282496 without homozygotes, falling into the pathogenic range defined by the Sherloc guideline. Importantly, in a family with germline PMS2 c.1144+2T>A variant, which disrupts the same splice donor site as c.1144+1G>A, the cosegregation between this variant and LS-related cancers was clearly seen. Based on all these results, we classified the PMS2 c.1144+1G>A variant as likely pathogenic, and disruption of this specific PMS2 splicing site results in LS. Combination chemotherapy with cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and nivolumab (200 mg) was administered after surgery every 3 weeks for a total of 4 cycles to the patient. He achieved 16 months DFS. We then provided an up-to-date genetic counseling to the patient's daughter with the same PMS2 variant.

Conclusion: Our findings suggest that accurate LS diagnosis with modern pathology approaches including MSI/MMR-d testing and NGS sequencing offers extracolonic cancer patients the opportunity to reduce cancer-related morbidity and mortality through innovative treatments such as immunotherapy.

Citation Format: Quanli Han, Xiaomo Li, Tonghui Ma, Qi Wang, Zhi Cui. Molecular diagnosis and immunotherapy of a rare lung carcinoma patient associated with PMS2 c.1144+1G>A mutation-driven Lynch syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 803.