The same genetic variant found in different individuals can cause a range of diverse phenotypes, from no discernible clinical phenotype to severe disease, even among related individuals. Such variants can be said to display incomplete penetrance, a binary phenomenon where the genotype either causes the expected clinical phenotype or it does not, or they can be said to display variable expressivity, in which the same genotype can cause a wide range of clinical symptoms across a spectrum. Both incomplete penetrance and variable expressivity are thought to be caused by a range of factors, including common variants, variants in regulatory regions, epigenetics, environmental factors, and lifestyle. Many thousands of genetic variants have been identified as the cause of monogenic disorders, mostly determined through small clinical studies, and thus, the penetrance and expressivity of these variants may be overestimated when compared to their effect on the general population. With the wealth of population cohort data currently available, the penetrance and expressivity of such genetic variants can be investigated across a much wider contingent, potentially helping to reclassify variants that were previously thought to be completely penetrant. Research into the penetrance and expressivity of such genetic variants is important for clinical classification, both for determining causative mechanisms of disease in the affected population and for providing accurate risk information through genetic counseling. A genotype-based definition of the causes of rare diseases incorporating information from population cohorts and clinical studies is critical for our understanding of incomplete penetrance and variable expressivity. This review examines our current knowledge of the penetrance and expressivity of genetic variants in rare disease and across populations, as well as looking into the potential causes of the variation seen, including genetic modifiers, mosaicism, and polygenic factors, among others. We also considered the challenges that come with investigating penetrance and expressivity.

https://www.frontiersin.org/articles/10.3389/fgene.2022.920390/pdf

Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts

DNA damage repair (DDR) pathways are essential to ensure the accurate transmission of genetic material. However, different endogenous and exogenous factors challenge genomic integrity. Mechanisms involved in the alterations of DDR pathways mainly include genetic inactivation and epigenetic mechanisms. The development and progression of carcinomas are closely associated with DDR pathway aberrations, including the epigenetic silencing of gene O6-alkylguanine-DNA methyltransferase (MGMT); deficiencies of mismatch repair (MMR) genes, including MutL homolog 1 (MLH1), MutS protein homologue (MSH)-2 (MSH2), MSH6, and PMS1 homolog 2; the mismatch repair system component (PMS2); and mutations of homologous recombination repair (HRR) genes, such as the breast cancer susceptibility gene 1/2 (BRCA1/2). Understanding the underlying mechanisms and the correlations between alterations to DDR pathways and cancer could improve the efficacy of antitumor therapies. Emerging evidence suggests that survival is higher in patients with DDR-deficient tumors than in those with DDR-proficient tumors. Thus, DDR alterations play a predictive and prognostic role in anticancer therapies. Theoretical studies on the co-administration of DDR inhibitors and other anticancer therapies, including chemotherapy, radiotherapy, immunotherapy, endocrine therapy, and epigenetic drugs, hold promise for cancer treatments. In this review, we focus on the basic mechanisms, characteristics, current applications, and combination strategies of DDR pathways in the anticancer field.

/pdf/alterations-of-dna-damage-repair-in-cancer-from-mechanisms-1wfuw9zj7n.pdf

Alterations of DNA damage repair in cancer: from mechanisms to applications.

Family-Specific Variants and the Limits of Human Genetics

Constitutional epimutation of the two major mismatch repair genes, MLH1 and MSH2, has been identified as an alternative mechanism that predisposes to the development of Lynch syndrome. In the present work, we aimed to investigate the prevalence of MLH1 constitutional methylation in colorectal cancer (CRC) patients with abnormal expression of the MLH1 protein in their tumors. In a series of 38 patients who met clinical criteria for Lynch syndrome genetic testing, with loss of MLH1 expression in the tumor and with no germline mutations in the MLH1 gene (35/38) or with tumors presenting the BRAF p.Val600Glu mutation (3/38), we screened for constitutional methylation of the MLH1 gene promoter using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in various biological samples. We found four (4/38; 10.5%) patients with constitutional methylation in the MLH1 gene promoter. RNA studies demonstrated decreased MLH1 expression in the cases with constitutional methylation when compared with controls. We could infer the mosaic nature of MLH1 constitutional hypermethylation in tissues originated from different embryonic germ layers, and in one family we could show that it occurred de novo. We conclude that constitutional MLH1 methylation occurs in a significant proportion of patients who have loss of MLH1 protein expression in their tumors and no MLH1 pathogenic germline mutation. Furthermore, we provide evidence that MLH1 constitutional hypermethylation is the molecular mechanism behind about 3% of Lynch syndrome families diagnosed in our institution, especially in patients with early onset or multiple primary tumors without significant family history.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.1285

Contribution of MLH1 constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH1 downregulation.

Background Germline defects in MLH1 , MSH2 , MSH6 and PMS2 predisposing for Lynch syndrome (LS) are mainly based on sequence changes, whereas a constitutional epimutation of MLH1 (CEM) is exceptionally rare. This abnormal MLH1 promoter methylation is not hereditary when arising de novo, whereas a stably heritable and variant-induced CEM was described for one single allele. We searched for MLH1 promoter variants causing a germline or somatic methylation induction or transcriptional repression. Methods We analysed the MLH1 promoter sequence in five different patient groups with colorectal cancer (CRC) (n=480) composed of patients with i) CEM (n=16), ii) unsolved loss of MLH1 expression in CRC (n=37), iii) CpG-island methylator-phenotype CRC (n=102), iv) patients with LS (n=83) and v) MLH1-proficient CRC (n=242) as controls. 1150 patients with non-LS tumours also served as controls to correctly judge the results. Results We detected 10 rare MLH1 promoter variants. One novel, complex MLH1 variant c.-63_-58delins18 is present in a patient with CRC with CEM and his sister, both showing a complete allele-specific promoter methylation and transcriptional silencing. The other nine promoter variants detected in 17 individuals were not associated with methylation. For four of these, a normal, biallelic MLH1 expression was found in the patients9 cDNA. Conclusion We report the second promoter variant stably inducing a hereditary CEM. Concerning the classification of promoter variants, we discuss contradictory results from the literature for two variants, describe classification discrepancies between existing rules for five variants, suggest the (re-)classification of five promoter variants to (likely) benign and regard four variants as functionally unclear.

https://jmg.bmj.com/content/jmedgenet/55/4/240.full.pdf

Comprehensive analysis of the MLH1 promoter region in 480 patients with colorectal cancer and 1150 controls reveals new variants including one with a heritable constitutional MLH1 epimutation.

Lynch syndrome is a hereditary cancer syndrome caused by a constitutional mutation in one of the mismatch repair genes. The implementation of predictive testing and targeted preventative surveillance is hindered by the frequent finding of sequence variants of uncertain significance in these genes. We aimed to determine the pathogenicity of previously reported variants (c.-28A>G and c.-7C>T) within the MLH1 5′untranslated region (UTR) in two individuals from unrelated suspected Lynch syndrome families. We investigated whether these variants were associated with other pathogenic alterations using targeted high-throughput sequencing of the MLH1 locus. We also determined their relationship to gene expression and epigenetic alterations at the promoter. Sequencing revealed that the c.-28A>G and c.-7C>T variants were the only potentially pathogenic alterations within the MLH1 gene. In both individuals, the levels of transcription from the variant allele were reduced to 50% compared with the wild-type allele. Partial loss of expression occurred in the absence of constitutional epigenetic alterations within the MLH1 promoter. We propose that these variants may be pathogenic due to constitutional partial loss of MLH1 expression, and that this may be associated with intermediate penetrance of a Lynch syndrome phenotype. Our findings provide further evidence of the potential importance of noncoding variants in the MLH1 5′UTR in the pathogenesis of Lynch syndrome.

Lynch Syndrome Associated with Two MLH1 Promoter Variants and Allelic Imbalance of MLH1 Expression

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Lynch Syndrome Associated with Two MLH1 Promoter Variants and Allelic Imbalance of MLH1 Expression