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Elucidating the role of somatic 3’UTR mutations in prostate cancer pathogenesis

Award Number: F31CA260920
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 06/09/2023

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Elucidating the role of somatic 3’UTR mutations in prostate cancer pathogenesis - PROJECT SUMMARY Prostate cancer is the second most common cause of cancer mortality in US men due to our poor understanding and treatment of metastatic, castration-resistant prostate cancer (mCRPC). New insights into mechanisms of prostate cancer pathogenesis may be found within historically understudied aspects of gene expression, including post-transcriptional regulation of oncogenes. An important mediator of post-transcriptional gene regulation is the 3’ untranslated region (3’UTR), which plays critical roles in controlling mRNA stability and translation. The 3’UTR harbors a significant mutational burden across cancer patients; however, these mutations have not been extensively studied. Individual 3’UTR variants have been associated with cancer risk and shown to regulate expression in reporter assays, but it is still unclear whether these mutations significantly affect pathogenesis in patients and how widespread this dysregulation may be across cancer. By performing somatic mutation calling on a unique cohort of 230 prostate cancer patients, I have uncovered over 13,000 3’UTR somatic mutations in cancer tissues genome-wide. Many of these are in known cancer-related genes and 3’UTR regulatory motifs, indicating they have potential to affect oncogenic expression and cancer pathogenesis. Furthermore, I have determined via ribosome profiling of a subset of patient samples that ~40% of 3’UTR mutations are associated with changes in post-transcriptional gene regulation. Using individual reporter assays, I have validated that several of these patient-identified 3’UTR mutations in known cancer-related genes significantly alter gene expression. One of these functional mutations is in PAK2, a p21-activated kinase involved in cell motility, hyperactivation of which is oncogenic in several cancers. Based on these preliminary data, I hypothesize that 3’UTR mutations drive oncogenic changes in post-transcriptional gene regulation, such as overexpression of PAK2, that contribute to pathogenesis in prostate cancer patients. I now aim to define the molecular and pathogenic mechanisms by which this PAK2 3’UTR mutation increases PAK2 expression and exacerbates cancerous phenotypes in vitro and in vivo using an endogenous cell line model of the mutation. Additionally, I will investigate the extent of 3’UTR mutation-mediated gene dysregulation in cancer by performing a massively-parallel reporter assay to determine the effects of >6,000 patient-identified 3’UTR mutations on transcript levels and translation efficiency. These studies will establish 3’UTR mutations as important drivers of oncogenic dysregulation, expanding the field of functional cancer genomics and our understanding of prostate cancer pathogenesis, in addition to potentially identifying new therapeutic targets.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$2,239 )
2024	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	000	4	4/24/2024	NON-COMPETING CONTINUATION	-$2,239
														Subtotal = -$2,239

Issue Date FY: 2023 ( Subtotal = $16,856 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	002	4	8/28/2023	NON-COMPETING CONTINUATION	-$6,107
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	000	4	2/28/2023	NON-COMPETING CONTINUATION	$22,963
														Subtotal = $16,856

Issue Date FY: 2022 ( Subtotal = $41,156 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	002	3	6/10/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$28,540
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	001	2	6/10/2022	NON-COMPETING CONTINUATION	$59
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	003	3	8/12/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$3,682
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	000	2	2/28/2022	NON-COMPETING CONTINUATION	$8,875
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	004	3	9/13/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $41,156

Issue Date FY: 2021 ( Subtotal = $40,440 )
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	002	1	3/16/2021	NEW	$0
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	000	1	2/25/2021	NEW	$40,440
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Research Manpower	001	1	2/25/2021	NEW	$0
														Subtotal = $40,440

Grand Total All Awards = $96,213

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Elucidating the role of somatic 3’UTR mutations in prostate cancer pathogenesis

Award Number: F31CA260920

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 06/09/2023

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