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Germline Mutations Uncovered Through Tumor Sequencing Present Challenges for Providers

NEW YORK (GenomeWeb) – Genetic counselors focused on individuals with cancer are facing new challenges as in-depth genetic analyses of tumors — including genome or exome sequencing — begin unwittingly uncovering germline mutations increasing the risk of other diseases in cancer patients and their family members.

At the National Society of Genetic Counselors annual education conference in Seattle on Saturday, panelists at a session on tumor sequencing described accidental findings stemming from tumor sequencing studies and strategies for dealing with and distinguishing between somatic and germline risk variants.

The University of Chicago medical oncologist Daniel Catenacci provided a tumor sequencing framework for the discussion, touching on the types of information that can be gleaned from tumor-only sequencing relative to panel, exome, or genome sequencing on matched tumor and normal sample pairs.

While it may be easier to uncover germline mutations when both the tumor and a normal sample are sequenced from the same individual, Catenacci explained, there are situations in which germline events are detected by sequencing tumor samples alone. For example, he described a case involving a 61-year-old man with two genetically distinct tumors containing a BRCA2 mutation that was believed to be unlikely to arise spontaneously in both tumor types.

Likewise, he and his team tracked down germline mutations in a significant subset of individuals when they considered 111 cases of upper gastrointestinal cancers and other tumor types sequenced at the University of Chicago.

Such findings suggest germline mutations may be an increasingly important consideration for genetic counselors tasked with returning genetic information to cancer patients and their families.

Jennifer Morrissette, a clinical pathologist and clinical director of the University of Pennsylvania's Center for Personalized Diagnostics, outlined approaches being used to triage cases involving suspected germline mutations uncovered during the process of tumor sequencing and analyses.

Drawing from her center's experience sequencing more than 6,600 tumors, Morrissette explained that the detection of germline alterations in cancer patients are relatively rare but not necessarily surprising. In individuals who have hyper-mutated tumors or a cancer-heavy family history, for example, she noted that clinicians and genetic counselors should consider the possibility that an individual carries a germline mutation affecting a gene implicated in cancer predisposition.

It also becomes increasingly likely that germline changes not directly related to cancer risk will arise as larger and larger portions of a patient's genome are sequenced, she noted, though many oncologists may not be particularly keen to start teasing apart the relevance and risk of mutations that don't impact cancer treatment.

Consequently, clinicians need to be informed of the possibility that germline mutations might turn up in the tumor sequencing process and have resources available to them, Morrissette said, including genetic counselors, who can help to determine if further follow-up and germline testing is required.

Genetic counselor Dana Farengo Clark, Morrissette's colleague at Penn Medicine, provided additional perspective on the types of germline results that should be returned in the context of the genetic tests that are typically ordered for individuals with cancer, informed consent considerations, and the current recommendations from the American College of Medical Genetics and Genomics for returning incidental findings.

She noted that the panel of genes that's often sequenced in tumor samples at the Center for Personalized Diagnostics includes 10 genes from the "ACMG 56" list, suggesting secondary mutations identified in these genes should be reported.

But because mutations in some of these genes — particularly TP53 — are very common in cancer, Farengo Clark noted that criteria are needed to appropriately triage cases for germline sequencing referrals by considering a patient's phenotype, family history, and the likelihood that a given alteration might be a founder mutation.

University of Pennsylvania genetic counselor Jacquelyn Powers walked attendees through several such cases. The first involved a 57-year-old man with sinus cancer assessed by Foundation One testing who had suspicious mutations in the BRCA1 and TP53 genes. While the man had no significant family history of cancer, subsequent germline testing indicated that the BRCA1 mutation had been inherited.

In an 80-year-old woman with thyroid cancer and a potential family history of cancer predisposition, meanwhile, the Foundation One tumor test unearthed a BRCA2 mutation. Though the individual did not meet Medicare criteria for BRCA2 testing based on her case characteristics, the family paid out of pocket for further testing, which verified a germline change to BRCA2.

Powers noted that the patient died before those results could be returned to her, but the team was authorized to alert her daughter about the germline mutation so that she could be tested for the BRCA2 mutation.

In yet another patient with early-onset, advanced colorectal cancer, the team ordered germline testing after finding a TP53 mutation on the tumor sequencing panel — an alteration that was not confirmed in the germline.