Rare germline variants in pancreatic cancer and multiple primary cancers: an autopsy study.

Publisher: Lippincott Williams & Wilkins Country of Publication: England NLM ID: 9300837 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1473-5709 (Electronic) Linking ISSN: 09598278 NLM ISO Abbreviation: Eur J Cancer Prev Subsets: MEDLINE

Publication: London : Lippincott Williams & Wilkins
Original Publication: Oxford, UK : Rapid Communications of Oxford, c1991-

Pancreatic Neoplasms*/epidemiology ; Pancreatic Neoplasms*/genetics ; Neoplasms, Multiple Primary*; Male ; Humans ; Aged ; Mismatch Repair Endonuclease PMS2/genetics ; Mismatch Repair Endonuclease PMS2/metabolism ; MutS Homolog 2 Protein/genetics ; MutS Homolog 2 Protein/metabolism ; Autopsy ; Retrospective Studies ; DNA-Binding Proteins/metabolism ; DNA Mismatch Repair ; Germ Cells/metabolism ; MutL Protein Homolog 1/genetics ; MutL Protein Homolog 1/metabolism ; Pancreatic Neoplasms

Background: There is a lack of information on rare germline variants of pancreatic cancer-predisposing genes. Risk genes for multiple primary cancers may overlap with those for pancreatic cancer.
Methods: A retrospective study of autopsy cases with a negative family history in the Japanese single nucleotide polymorphism for geriatric research database examined rare germline variants in the protein-coding regions of 61 genes. Targeted sequencing of these genes was performed and classified for pathogenicity using the American College of Medical Genetics and Genomics guidelines. Polyphen-2, SIFT and LoFtool algorithms were used to predict damage to protein function.
Results: Of the 189 subjects used (90 cancer and 99 non-cancer controls), 72 patients had pancreatic cancer (23 had multiple primary cancers) and 18 had no pancreatic cancer in multiple primary cancers. APC, BRCA2, BUB1B, ENG and MSH6 were associated with cancer predisposition, and pathogenic/likely pathogenic (P/LP) variants occurred in 6% [pancreatic cancer (4/72); all-cancer (5/90)] and 54% (49/90) carried only variants of uncertain significance (VUS) among cancer patients. Of these VUS, in pancreatic cancer patients, four DNA mismatch repair (MMR) genes ( MLH1, MSH2, MSH6 and PMS2 ), and POLQ in men were significantly associated (odds ratio = 3.83; P  = 0.025; P  = 0.027, respectively). The most abundant predictor of functionally damaging variants was POLQ .
Conclusions: The frequency of P/LP variants in patients with sporadic pancreatic cancer suggests the need for genetic evaluation of individuals with no family history. VUS of MMR genes ( MLH1, MSH2, MSH6 and PMS2 ) and POLQ may be useful in predicting genetic trends in the potential risk of pancreatic cancer, especially in individuals lacking P/LP.
(Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

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EC 3.6.1.3 (Mismatch Repair Endonuclease PMS2)
EC 3.6.1.3 (MutS Homolog 2 Protein)
0 (DNA-Binding Proteins)
EC 3.6.1.3 (MutL Protein Homolog 1)

Date Created: 20230310 Date Completed: 20230404 Latest Revision: 20231213

20231215

PMC10063194

10.1097/CEJ.0000000000000787

36896836