A new mutL homolog 1 c.1896+5G>A germline mutation detected in a Lynch syndrome‐associated lung and gastric double primary cancer patient

Abstract

Background Mismatch‐repair genes (MMRs) ensure high fidelity in genome editing. Loss of function mutation of MMRs will lead to instability of the genome and increase the incidence of cancers. Human mutL homolog 1 (MLH1) is a member of the MMRs, and its mutation is found in Lynch syndrome (LS). In addition to the high incidence of colorectal cancer, LS patients often have other primary cancers. Here, a case of LS‐associated lung and gastric double primary cancer was reported. Methods Diagnosis of lung and gastric double primary cancer was mainly based on clinical findings, imaging examination, and histopathological data. The tumor tissues and blood samples were collected, and then genomic DNA was extracted and 450 cancer‐related gene alteration screening was conducted by next‐generation sequencing and the functional verification of a mutant gene was carried out using the PCR method. Results We detected the epidermal growth factor receptor L858R, MSH2 R929* and telomerase reverse transcriptase amplification in the lung cancer specimen; CDH1 c.1320+1G>T mutation in the gastric cancer (GC) specimen; and MLH1 c.1896+5G>A germline mutation in the lung and GC specimens by 450 cancer‐related gene mutations detection using next‐generation sequencing technology. MLH1c.1896+5G>A is a novel germline mutation, and it was verified by the PCR subsequently. It was found that it could affect the splicing of intron 16. Nine relatives of three‐generation of the patient were examined and the MLH1 c.1896+5G>A mutation and pedigree analysis were performed. The father's sister without cancer also carries this mutation. Conclusion Diagnosis of LS was mainly depended on the following: the cancer histories of his relatives, multi‐primary cancers of lung and stomach in his own body, MLH1 and MSH2 gene mutations detected in the cancer tissues. The clinical significance of this new MLH1 c.1896+5G>A germline mutation detected in the LS‐associated double primary cancer patient needed further study.

RETRACTED: Identification of an Immunologic Signature of Lung Adenocarcinomas Based on Genome-Wide Immune Expression Profiles

“…MMRs are intracellular mismatch repair mechanisms. Their loss of function leads to irreparable DNA replication errors, thus leading to high generation of gene mutations (Chen X. et al, 2019 ). When tumor cells are mismatch repair-deficient (dMMR) and microsatellite instability is present, many gene mutations will accumulate in tumor cells, and some neoantigens may be recognized and attacked by the immune system, thereby achieving better immunotherapy effects.…”

Overview on population screening for carriers with germline mutations in mismatch repair (MMR) genes in China

“…After giving birth to hysterectomy. 30–35 96.2 [ 3 , 5 , 12 – 14 , 25 , 35 , 37 ] Gastric cancer NR Male MLH1 or MSH2 >32.8 Female MLH1 or MSH2 >27.1 Mean: 56-58.5 MLH1 or MSH2 : 56 MSH6 : 63 PMS2 : 70–78 Gastroscopy every 3–5 years and remove Helicobacter pylori completely 30–35 or 40–45 61–64 [ 2 , 8 , 9 , 21 , 30 , 35 ] Lung cancer NR NR 68.5 Appropriate imaging examination screen and surveillance for carriers NR NR [ 2 , 11 , 35 ] Ovarian cancer MLH1 :38 MLH2:47 MLH1 or MSH2 : 11–24 MSH6 :3-10 PMS2 : 6 Mean: 45-46 MLH1 or MSH2 : 44 PMS2 : 42 Vaginal ultrasound and CA125 detection, bilateral fallopian tube-ovarian resection after childbirth 30–35 52.5–59 [ 11 , 33 , 35 , 37 ] Small bowel cancer NR MLH1 or MSH2 : 3–6 ...…”

“…More than 90 % of the variants only existed in Chinese ethnicity, showing an ethnic-specific nature [ 1 ]. In 2019, a new MLH1 c.1896 + 5G > A germline mutation was found in the Chinese LS-related lung and gastric cancer [ 2 ]. MMR mutation carriers susceptibly develop colorectal cancer (CRC) and other extracolorectal malignant tumors.…”

Hatali Eşleşme Genleri̇nden Mlh1, Pms2, Msh6, Msh2’i̇n Mi̇de Kanserleri̇nde İmmünhi̇stoki̇myasal Ekspresyonu; Bi̇r Doku Mi̇kroarray Çalişmasi

“…MMR genes are necessary for the genome to be copied accurately in cell proliferation and if there is a deficiency, mutation risk increases by 100 times compared with a healthy cell (14,15). Base mismatch, genomic repair defects caused by MMRS (mistmach repair genes) mutation can lead to an increase in the genome instability which can be observed in gastric, endometrial, and ovarian cancers (16).…”