Genetic evaluation of patients with multiple primary cancers

Area of Science:

• Genetics
• Oncology
• Genomic Medicine

Background:

• Single pathogenic variants (PVs) in cancer predisposition genes are well-documented.
• Oligogenic coinheritance of heterozygous PVs is understudied.
• Increased cancer survivor rates lead to a higher incidence of multiple primary cancers (MPCs).

Purpose of the Study:

• Investigate the role of oligogenic coinheritance in young patients (≤45 years) with MPCs and no known common cancer predisposition gene PVs.
• Identify germline variants contributing to the development of multiple primary cancers.

Main Methods:

• Whole exome sequencing (WES) of germline and tumoral DNA.
• Chromosomal microarray analysis (CMA) for germline DNA.
• Karyotype testing for one patient.
• Analysis of 10 patients with a mean of 3 cancers each.

Main Results:

• CMA detected microduplications and a microdeletion.
• WES identified 1-3 single nucleotide variants of potential interest per patient, plus copy number variants.
• Most variants were classified as variants of uncertain significance.
• Germline variants were present in somatic samples; no second hits were identified.
• Pathway mapping suggested an additive effect of germline variants.

Conclusions:

• The study highlights the potential role of oligogenic coinheritance in MPCs.
• Findings suggest an additive effect of multiple low-penetrance variants.
• Further investigation into the cumulative impact of variants is warranted for comprehensive cancer risk assessment.