Cannon-Albright, L. A. | bioRxiv Science

bioRxiv2019

A novel ribosomal protein 20 variant in a family with unexplained colorectal cancer and polyposis

Colorectal cancer (CRC) has a large hereditary component, which is only partially explained by known genetic causes. Recently, variants in ribosomal protein S20 (RPS20, [OMIM: 603682]) were identified in a family with familial CRC type X and in a CRC cancer case-control screen. This study describes a novel splice donor variant in RPS20, NM_001023.3:c.177+1G>A. It segregates with CRC [OMIM: 114500] and polyposis [HP: 0200063] within the probands family. Reverse transcription-polymerase chain reaction (RT-PCR) confirms the variant results in two aberrantly-spliced transcripts that are absent in controls. The location of the novel RPS20 variant is near two previously-reported truncating RPS20 variants associated with CRC. DNA from colon adenocarcinoma showed no evidence of loss-of-heterozygosity, supporting a haploinsufficiency or dominant negative disease mechanism. These findings support designation of RPS20 as a CRC predisposition gene, and expand the phenotypic spectrum of RPS20 truncating variants to include polyposis.

genetics↗

bioRxiv2017

Population-Based Relative Risks For Specific Family History Constellations Of Breast Cancer - Towards Individualized Risk Estimation

PurposeUsing a large resource linking genealogy with decades of cancer data, RRs were estimated for breast cancer (BC) based on specific family history extending to first cousins.\n\nMethodsRRs for BC were estimated in 640,366 females with breast cancer family histories that included number of first-(FDR), second-(SDR), and third-degree relatives (TDR), maternal and paternal relatives, and age at earliest diagnosis.\n\nResultsRRs for first-degree relatives of BC cases ranged from 1.61 (=1 FDR affected, CI: 1.56, 1.67) to 5.00 ([≥]4 FDRs affected, CI: 3.35, 7.18). RRs for second degree relatives of probands with 0 affected FDRs ranged from 1.08 ([≥]1 SDR affected, CI: 1.04, 1.12) to 1.71 ([≥]4 SDRs affected, CI: 1.26, 2.27) and for second degree relatives of probands with exactly 1 FDR from 1.54 (0 SDRs affected, CI:1.47, 1.61) to 4.78 ([≥] 5 SDRs; CI 2.47, 8.35). RRs for third-degree relatives with no closer relatives affected were significantly elevated for probands with >=5 affected TDRs RR=1.32, CI: 1.11, 1.57).\n\nConclusionsThe majority of females analyzed had a family history of BC. Any number of affected FDRs or SDRs significantly increased risk for BC, and more than 4 TDRs, even with no affected FDRs or SDRs significantly increased risk. Risk prediction derived from specific and extended family history allows identification of females at highest risk even when they do not have a conventionally defined \"high risk\" family; these risks could be a powerful, efficient tool to individualize cancer prevention and screening.

genetics↗