Genotype and phenotype correlation of common cancer predisposition syndromes in sarcoma cases.

Abstract

1524 Background: Sarcomas are rare heterogenous cancers affecting a predominantly younger population. The most recognised autosomal dominant contributor being pathogenic TP53 variants associated with Li Fraumeni Syndrome (LFS). When referred, patient eligibility for germline TP53 testing is assessed using classic or Chompret LFS criteria. Other heritable cancer syndromes which can be associated with sarcoma (breast/ovarian, colorectal) are more commonly considered in clinical practice. In some centres germline testing is offered to only those who meet established clinical criteria. Heritable cancer predisposition has several implications including therapy and clinical risk management. Here we report the concordance between clinical criteria and genotypes in sarcoma families. Methods: We included 1,664 sarcoma probands from the International Sarcoma Kindred Study. Eligibility for genetic testing was assessed using internationally accepted clinical criteria for recognised cancer syndromes. Whole genome sequencing was performed on peripheral blood DNA and variants in the ACMG cancer gene list were classified as pathogenic or likely pathogenic using established bioinformatics pipelines. Results: The median age of sarcoma diagnosis in 1664 probands (798 males, 866 Females) was 48 years (range 1-93). The median age of first cancer diagnosis was 46.5 years (0-93) with 291 probands having multiple primary cancers. Of 1504 informative pedigrees, 243 (16%) met criteria for testing; 207 (14%) TP53; 19 (1%) BRCA1/2; 2 (<1%) colorectal cancer (CRC) genes and 15 (1%) familial melanoma. Of 12 TP53 PVs identified, 9 met TP53 testing criteria. Of 13 PVs identified in HR genes (7 BRCA2, 4 PALB2 and 2 BRCA1) only 1 ( PALB2) met BRCA1/2 testing criteria and 2 met Chompret criteria. Both BRCA1 cases were male with a 1st degree relative with ovarian cancer. In CRC genes (1 APC, 2 MSH2, 4 MSH6, 1 PMS2), none met CRC testing criteria but 4 met Chompret criteria. No CDKN2A PVs were identified in melanoma families. Conclusions: In probands with sarcoma, clinical criteria for eligibility for testing for common non-LFS heritable syndromes perform poorly. This should be considered when making decisions regarding germline testing.