Tracing cancer evolution and heterogeneity using Hi-C

Dan Daniel Erdmann-Pham; Sanjit Singh Batra; Timothy K Turkalo; James Durbin; Marco Blanchette; Iwei Yeh; Hunter Shain; Boris C Bastian; Yun S Song; Daniel S Rokhsar; Dirk Hockemeyer

doi:10.1038/s41467-023-42651-2

Tracing cancer evolution and heterogeneity using Hi-C

Nat Commun. 2023 Nov 6;14(1):7111. doi: 10.1038/s41467-023-42651-2.

Authors

Dan Daniel Erdmann-Pham^#^{1

2}, Sanjit Singh Batra^#³, Timothy K Turkalo⁴, James Durbin⁵, Marco Blanchette⁵, Iwei Yeh^{6

7}, Hunter Shain⁶, Boris C Bastian^{6

7}, Yun S Song^{8

9

10}, Daniel S Rokhsar^{11

12

13

14}, Dirk Hockemeyer^{15

16

17}

Affiliations

¹ Department of Mathematics, University of California, Berkeley, CA, 94720, USA.
² Department of Statistics, Stanford University, Stanford, CA, 94305, USA.
³ Computer Science Division, University of California, Berkeley, CA, 94720, USA.
⁴ Department of Molecular and Cell Biology, University of California, Berkeley, CA, 94720, USA.
⁵ Dovetail Genomics, Enterprise Way, Scotts Valley, CA, 95066, USA.
⁶ Department of Dermatology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94143, USA.
⁷ Department of Pathology, University of California, San Francisco, CA, 94143, USA.
⁸ Computer Science Division, University of California, Berkeley, CA, 94720, USA. [email protected].
⁹ Chan Zuckerberg Biohub, San Francisco, CA, 94158, USA. [email protected].
¹⁰ Department of Statistics, University of California, Berkeley, CA, 94720, USA. [email protected].
¹¹ Department of Molecular and Cell Biology, University of California, Berkeley, CA, 94720, USA. [email protected].
¹² Chan Zuckerberg Biohub, San Francisco, CA, 94158, USA. [email protected].
¹³ Innovative Genomics Institute, University of California, Berkeley, CA, 94720, USA. [email protected].
¹⁴ Okinawa Institute for Science and Technology, Tancha, Okinawa, Japan. [email protected].
¹⁵ Department of Molecular and Cell Biology, University of California, Berkeley, CA, 94720, USA. [email protected].
¹⁶ Chan Zuckerberg Biohub, San Francisco, CA, 94158, USA. [email protected].
¹⁷ Innovative Genomics Institute, University of California, Berkeley, CA, 94720, USA. [email protected].

^# Contributed equally.

Abstract

Chromosomal rearrangements can initiate and drive cancer progression, yet it has been challenging to evaluate their impact, especially in genetically heterogeneous solid cancers. To address this problem we developed HiDENSEC, a new computational framework for analyzing chromatin conformation capture in heterogeneous samples that can infer somatic copy number alterations, characterize large-scale chromosomal rearrangements, and estimate cancer cell fractions. After validating HiDENSEC with in silico and in vitro controls, we used it to characterize chromosome-scale evolution during melanoma progression in formalin-fixed tumor samples from three patients. The resulting comprehensive annotation of the genomic events includes copy number neutral translocations that disrupt tumor suppressor genes such as NF1, whole chromosome arm exchanges that result in loss of CDKN2A, and whole-arm copy-number neutral loss of homozygosity involving PTEN. These findings show that large-scale chromosomal rearrangements occur throughout cancer evolution and that characterizing these events yields insights into drivers of melanoma progression.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Chromosome Aberrations*
Chromosomes
DNA Copy Number Variations
Humans
Melanoma* / genetics
Translocation, Genetic

Abstract

Publication types

MeSH terms

Grants and funding