Multilocus Inherited Neoplasia Allele Syndrome (MINAS): an update

Abstract

Multi-locus Inherited Neoplasia Allele Syndrome (MINAS) refers to individuals with germline pathogenic variants in two or more cancer susceptibility genes(CSGs). With increased use of exome/genome sequencing it would be predicted that detection of MINAS would become more frequent. Here we review recent progress in knowledge of MINAS. A systematic literature search for reports of individuals with germline pathogenic variants in 2 or more of 94 CSGs was performed. In addition, participants with multiple primary tumours who underwent genome sequencing as part of the Rare Disease arm of the UK 100,000 Genomes Project were interrogated to detect additional cases. We identified 385 MINAS cases (211 reported in the last 5 years, 6 from 100,000 genomes participants). Most (287/385) cases contained at least one pathogenic variant in either BRCA1 or BRCA2. 108/385 MINAS cases had multiple primary tumours at presentation and a subset of cases presented unusual multiple tumour phenotypes. We conclude that, as predicted, increasing numbers of individuals with MINAS are being have been reported but, except for individuals with BRCA1/BRCA2 MINAS, individual CSG combinations are generally rare. In many cases it appears that the clinical phenotype is that which would be expected from the effects of the constituent CSG variants acting independently. However, in some instances the presence of unusual tumour phenotypes and/or multiple primary tumours suggests that there may be complex interactions between the relevant MINAS CSGs. Systematic reporting of MINAS cases in a MINAS database (e.g. https://databases.lovd.nl/shared/diseases/04296) will facilitate more accurate prognostic predictions for specific CSG combinations.

Co-occurrence of VHL and SDHA Pathogenic Variants: A Case Report

“…Multi-locus inherited neoplasia allele syndrome (MINAS) is a relatively new entity that was initially reported in BRCA1 / BRCA2 -related cancers ( 21 ). With increasing adoption of next generation sequencing technologies for cancer susceptibility germline (CSG) testing, there has been a rise in reports of non- BRCA1 / BRCA2 related MINAS.…”

“…A recent study by McGuigan et al. reported that atypical tumor phenotypes comprised of about 15% of non- BRCA1 / BRCA2 MINAS cases, which could be secondary to complex interactions between the relevant CSGs ( 21 ).…”

“…Although a second pathogenic variant was not reported by the tumor molecular testing, it is possible that the second hit could not be detected due to limitation of the tumor-based molecular analyses. These include possibility of somatic second hit being present in the promoter or deep enhancer region, or promoter methylation (21). Loss of heterozygosity (LOH) analysis could not be performedin the patient's tumor type, as the laboratory only performs LOH analysis in ovarian tumors Multi-locus inherited neoplasia allele syndrome (MINAS) is a relatively new entity that was initially reported in BRCA1/BRCA2related cancers (21).…”

“…These include possibility of somatic second hit being present in the promoter or deep enhancer region, or promoter methylation (21). Loss of heterozygosity (LOH) analysis could not be performedin the patient's tumor type, as the laboratory only performs LOH analysis in ovarian tumors Multi-locus inherited neoplasia allele syndrome (MINAS) is a relatively new entity that was initially reported in BRCA1/BRCA2related cancers (21). With increasing adoption of next generation sequencing technologies for cancer susceptibility germline (CSG) testing, there has been a rise in reports of non-BRCA1/BRCA2 related MINAS.…”

Good genotype-phenotype relationships in rare disease are hard to find

“…Multi-locus inherited neoplasia allele syndrome (MINAS) is an example of this. Individuals can develop multiple neoplasms because they have pathogenic variants in multiple cancer genes [6]. In turn, polygenic risk, as measured by cancer-associated SNPs from Genome-Wide Association Studies (GWAS) has a role in modifying cancer risk.…”