Genome-wide linkage search for cancer susceptibility loci in a cohort of non BRCA1/2 families in Sri Lanka.

OBJECTIVE: Although linkage studies have been utilized for the identification of variants associated with cancer in the world, little is known about their role in non BRCA1/2 individuals in the Sri Lankans. Hence we performed linkage analysis to identify susceptibility loci related to the inherited risk of cancer in a cohort of Sri Lankans affected with hereditary breast cancer. The Illumina global screening array having 654,027 single nucleotide polymorphism markers was performed in four families, in which at least three individuals within third degree relatives were affected by breast cancer. Two-point parametric linkage analysis was conducted assuming disease allele frequency of 1%. Penetrance was set at 90% for carriers with a 10% phenocopy rate. RESULTS: Thirty-one variants exhibited genome-wide suggestive HLODs. The top overall HLOD score was at rs1856277, an intronic variant in MYO16 on chromosome 13. The two most informative families also suggested several candidate linked loci in genes, including ERAP1, RPRM, WWOX, CDH1, EXOC1, HUS1B, STIM1 and TUSC1. This study provides the first step in identifying germline variants that may be involved in risk of cancer 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.

Copy Number Variants Captured by the Array Comparative Genomic Hybridization in a Cohort of Patients Affected with Hereditary Colorectal Cancer in Sri Lanka: The First CNV Analysis Study of the Hereditary Colorectal Cancer in the Sri Lankan Population.

INTRODUCTION: Hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant disorder characterized by the development of multiple cancer types. Molecular diagnosis of HNPCC requires the precise identification of pathogenic germline variants in DNA mismatch repair (MMR) genes. Next Generation Sequencing (NGS) is now the gold standard test in practice, to identify these variants. However, large genomic rearrangements (LGR) in cancer predisposing genes (CPGs) are missed by NGS. This may lead to underestimation of the frequency of the variants, misleading the genetic diagnosis and delaying intervention in high risk individuals. Hence this study was aimed at identifying the presence of large genomic alterations that could explain the missing heritable risk of colon cancer in affected patients with family history strongly suggestive of hereditary colorectal cancer in Sri Lanka. METHODS: A cohort of six patients affected with hereditary colorectal cancer who tested negative for pathogenic variants in next generation sequencing studies was investigated using Sure Print G3 Human CGH 4x180K microarray platform. Agilent Genomic-Workbench-v7.0.4.0 software was used to identify the Copy Number Variants (CNV). Four healthy individuals (>55years) were used as controls.  Annotations of the CNV regions which were observed were done using the database of Genomic Variants. RESULTS: We identified 150 CNVs including regions of both genomic gains and losses in the patient cohort.  There was no difference in the average number or the average genomic burden of CNVs identified in the patients versus the controls.  CNVs were residing on the positions of 1q21.2, 2q37.3, 2p11.2-p11.1, 5q13.2, 6p12.3, 7q31.33, 7p14.1, 14q32.33, 15q11.1-11.2, 16p11.2, 22q11.22, 22q13.1 that were assessed by the array platform used in the study. CNVs in any of the well-known common CPG s or CNVs that reside on or in close proximity to genes corresponding to MMR pathway were not identified. We found several distinct pathways that have previously been identified as having a direct association with the progression of HNPCC. CONCLUSION: This study shows that CNVs are likely contributors to the colorectal cancer predisposition in a small but significant proportion of patients affected with hereditary colorectal cancer in this cohort. Further studies have to perform to get a better understanding on the contribution of CNVs to the cancer predisposition in this cohort of patients in the Sri Lankan population.

Awareness of female malignancies among women and their partners in Southern Sri Lanka and implications for screening: a cross sectional study.

BACKGROUND: The incidences of breast, cervical and uterine malignancies continue to increase in Sri Lanka. It is important to explore the awareness of both women and their male partners regarding these malignancies and available screening services as it would determine the health seeking behaviours of females. METHODS: This was a cross sectional survey of couples residing in the Galle District of the Southern province of Sri Lanka. The sample was selected from all 17 health administrative divisions of the district. An interviewer administered questionnaire was used to collect data on demography and level of awareness (risk factors, symptoms, signs, screening services) of breast, cervical and uterine cancers. Same questionnaire was used for both sexes except for gender specific questions. RESULTS: A total of 282 (n-282, 564 individuals) couples were interviewed. The level of awareness regarding all malignancies was low. More than 50% of participants in both sexes scored less than half the points on a questionnaire testing awareness. Better family income, better education and permanent employment showed a significant association with better awareness in both sexes (univariate analysis). Encouragement by male partner was associated with better participation in some instances. CONCLUSIONS: Community based health education on female malignancies needs to target both sexes. Educating males is important as, i) male partners can encourage females to utilize screening services and ii) some screening and preventive measures are relevant to males also. Better awareness of males may increase the uptake of screening services by females in societies with male dominant gender roles.