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Testing tumors from different anatomic sites for clonal relatedness using somatic mutation data

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  • Irina Ostrovnaya
  • Audrey Mauguen
  • Venkatraman E. Seshan
  • Colin B. Begg

Abstract

A common task for the cancer pathologist is to determine, in a patient suffering from cancer, whether a new tumor in a distinct anatomic site from the primary is an independent occurrence of cancer or a metastasis. As mutational profiling of tumors becomes more widespread in routine clinical practice, this diagnostic task can be greatly enhanced by comparing mutational profiles of the tumors to determine if they are sufficiently similar to conclude that the tumors are clonally related, that is, one is a metastasis of the other. We present here a likelihood ratio test for clonal relatedness in this setting and provide evidence of its validity. The test is unusual in that there are two possible alternative hypotheses, representing the two anatomic sites from which the single clonal cell could have initially emerged. Although evidence for clonal relatedness is largely provided by the presence of exact mutational matches in the two tumors, we show that it is possible to observe data where the test is statistically significant even when no matches are observed. This can occur when the mutational profile of one of the tumors is closely aligned with the anatomic site of the other tumor, suggesting indirectly that the tumor originated in that other site. We exhibit examples of this phenomenon and recommend a strategy for interpreting the results of these tests in practice.

Suggested Citation

  • Irina Ostrovnaya & Audrey Mauguen & Venkatraman E. Seshan & Colin B. Begg, 2021. "Testing tumors from different anatomic sites for clonal relatedness using somatic mutation data," Biometrics, The International Biometric Society, vol. 77(1), pages 283-292, March.
    • Handle: RePEc:bla:biomet:v:77:y:2021:i:1:p:283-292
    DOI: 10.1111/biom.13256
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    References listed on IDEAS

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    1. Cyriac Kandoth & Michael D. McLellan & Fabio Vandin & Kai Ye & Beifang Niu & Charles Lu & Mingchao Xie & Qunyuan Zhang & Joshua F. McMichael & Matthew A. Wyczalkowski & Mark D. M. Leiserson & Christop, 2013. "Mutational landscape and significance across 12 major cancer types," Nature, Nature, vol. 502(7471), pages 333-339, October.
    2. Saptarshi Chakraborty & Arshi Arora & Colin B. Begg & Ronglai Shen, 2019. "Using somatic variant richness to mine signals from rare variants in the cancer genome," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    3. Colin B. Begg & Kevin H. Eng & Amanda J. Hummer, 2007. "Statistical Tests for Clonality," Biometrics, The International Biometric Society, vol. 63(2), pages 522-530, June.
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