Abstract:
Introduction: Identification of pathogenic variants will open up an opportunity to implement
surveillance and risk reducing measures that mitigate or prevent diseases. Although linkage
studies have been utilized for the investigation of genetic variants associated with risk of
hereditary breast cancer in many countries in the world, little is known about their role in non
BRCA1/2 individuals and their family members in the Sri Lankan population. Our objective was
to identify the susceptibility loci related to the inherited risk of cancer in a cohort of Sri Lankan
women affected with breast cancer. Method: Forty-eight members from four families, in which
at least three individuals within third degree relatives affected by breast cancer, were selected.
Genotyping using the Illumina Global Screening Array having 654,027 single nucleotide
polymorphism (SNP) markers was performed. Merlin software was used to conduct two-point
parametric linkage analysis with cancer at any site as the trait. An autosomal dominant model
with a disease allele frequency of 1% was assumed. Penetrance was set at 90% for carriers with
a 10% phenocopy rate. LOD (Logarithm Of Odds) scores were calculated for each of the four
families and heterogeneity LOD (HLOD) scores were calculated across families. Results: Thirty
one variants exhibited genome-wide suggestive HLODs. The top overall HLOD score was at
rs1856277, an intronic variant in MYO16 gene on chromosome 13. The two most informative
families also suggested several candidate linked loci in genes, including EXOC1, HUS1B,
STIM1 and TUSC1. Discussion and conclusion: This study provides the first step in identifying
germline variants that may be involved in risk in cancer-aggregated non-BRCA1/2 families from
the understudied Sri Lankan population. Several candidate linked regions showed suggestive
evidence of linkage to cancer risk. However, additional studies are required due to low power
in the existing families and probable genetic heterogeneity across families.
