Lynch syndrome, molecular mechanisms and variant classification
Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
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Lynch syndrome, molecular mechanisms and variant classification. / Abildgaard, Amanda B.; Nielsen, Sofie; Bernstein, Inge; Stein, Amelie; Lindorff-Larsen, Kresten; Hartmann-Petersen, Rasmus.
I: British Journal of Cancer, Bind 128, 2023.Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
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TY - JOUR
T1 - Lynch syndrome, molecular mechanisms and variant classification
AU - Abildgaard, Amanda B.
AU - Nielsen, Sofie
AU - Bernstein, Inge
AU - Stein, Amelie
AU - Lindorff-Larsen, Kresten
AU - Hartmann-Petersen, Rasmus
PY - 2023
Y1 - 2023
N2 - Patients with the heritable cancer disease, Lynch syndrome, carry germline variants in the MLH1, MSH2, MSH6 and PMS2 genes, encoding the central components of the DNA mismatch repair system. Loss-of-function variants disrupt the DNA mismatch repair system and give rise to a detrimental increase in the cellular mutational burden and cancer development. The treatment prospects for Lynch syndrome rely heavily on early diagnosis; however, accurate diagnosis is inextricably linked to correct clinical interpretation of individual variants. Protein variant classification traditionally relies on cumulative information from occurrence in patients, as well as experimental testing of the individual variants. The complexity of variant classification is due to (1) that variants of unknown significance are rare in the population and phenotypic information on the specific variants is missing, and (2) that individual variant testing is challenging, costly and slow. Here, we summarise recent developments in high-throughput technologies and computational prediction tools for the assessment of variants of unknown significance in Lynch syndrome. These approaches may vastly increase the number of interpretable variants and could also provide important mechanistic insights into the disease. These insights may in turn pave the road towards developing personalised treatment approaches for Lynch syndrome.
AB - Patients with the heritable cancer disease, Lynch syndrome, carry germline variants in the MLH1, MSH2, MSH6 and PMS2 genes, encoding the central components of the DNA mismatch repair system. Loss-of-function variants disrupt the DNA mismatch repair system and give rise to a detrimental increase in the cellular mutational burden and cancer development. The treatment prospects for Lynch syndrome rely heavily on early diagnosis; however, accurate diagnosis is inextricably linked to correct clinical interpretation of individual variants. Protein variant classification traditionally relies on cumulative information from occurrence in patients, as well as experimental testing of the individual variants. The complexity of variant classification is due to (1) that variants of unknown significance are rare in the population and phenotypic information on the specific variants is missing, and (2) that individual variant testing is challenging, costly and slow. Here, we summarise recent developments in high-throughput technologies and computational prediction tools for the assessment of variants of unknown significance in Lynch syndrome. These approaches may vastly increase the number of interpretable variants and could also provide important mechanistic insights into the disease. These insights may in turn pave the road towards developing personalised treatment approaches for Lynch syndrome.
KW - NONPOLYPOSIS COLORECTAL-CANCER
KW - SUSCEPTIBILITY GENE-MUTATIONS
KW - AMINO-ACID SUBSTITUTIONS
KW - MISMATCH-REPAIR
KW - MICROSATELLITE INSTABILITY
KW - FUNCTIONAL-ANALYSIS
KW - MISSENSE VARIANTS
KW - PROTEIN FUNCTION
KW - QUALITY-CONTROL
KW - HMUTS-ALPHA
U2 - 10.1038/s41416-022-02059-z
DO - 10.1038/s41416-022-02059-z
M3 - Review
C2 - 36434153
VL - 128
JO - The British journal of cancer. Supplement
JF - The British journal of cancer. Supplement
SN - 0007-0920
ER -
ID: 328801443