Resolving the genetic drivers of head and neck cancer

Head and neck cancer kills more than 400,000 people worldwide each year and has a variety
of causes.
Human papillomavirus (HPV) is a sexually transmitted infection, but the most common and deadly subtype is HPV-negative head and neck cancer, which accounts for 3% of all malignancies in the United States and kills 15,000 people each year
.

"Typically, head and neck cancers begin in squamous cells on the surface of the mucosa, such as inside the mouth and throat, and there are multiple treatment options, including surgery, radiation therapy, and chemotherapy," said Ezra Cohen, MD, co-director
of the Gleiberman Head and Neck Cancer Center at the Moores Cancer Center at UC San Diego.

"But these cancers are complex, and no one treatment works for every patient every time, which is why we developed immune checkpoint inhibitors, which use antibodies to allow the patient's immune system to see tumor cells
.
"

Immune checkpoint therapy (ICT) first appeared in the '90s and has made significant progress in recent years, but drug resistance remains prevalent in head and neck cancer cases, and current biomarker tests know little about them and are largely unrecognizable
, Cohen said.

Currently, FDA-approved PD-1 (a protein) immune checkpoint antibody therapy produces a durable response
in 15 percent of patients with head and neck squamous cell carcinoma.
The remaining 85% received no benefit and could actually experience serious immune-related adverse reactions
.

Like other types of head and neck cancer, the HPV-negative subtype has multiple risk factors, such as smoking and alcohol consumption, but the main cause appears to be altered
gene copy numbers.

In a new study, PNAS Cohen, published Nov.
14, 2022, along with his colleagues at Morse Cancer Center, UC San Diego School of Medicine and elsewhere, broadens and deepens understanding of how genetic variants cause HPV-negative head and neck cancers and potentially provides a pathway
to further optimize and improve immune checkpoint inhibitors for HPV-negative head and neck cancers.

In the study published last year, the same group of scientists laid the groundwork to become the first to
discover the effects of copy loss in a genetic region on the short P arm of chromosome 9 on immune evasion and ICT resistance in HPV-negative head and neck cancer.

But the 2021 findings raise new questions about whether genetic abnormalities may involve the loss
of multiple sites on chromosome 9p.
The new work provides answers, based on multiomics immunogenetic evidence, analyzed from every band at each site, and each gene
in each band in four different patient cohorts.

"We found that not only the 9p21 locus on chromosome 9p is involved, but also the 9p24 locus, which may be more important in driving resistance in immune checkpoint therapies; Surprisingly, we found that an increase in these gene regions, at least in the case of HPV-negative head and neck squamous cell carcinoma, was associated
with ICT survival benefits.
Scott Lippman, co-senior author and co-corresponding author of the study, MD, Distinguished Chugai Professor and Director of
the Morse Cancer Center.

The researchers found that when treating cases of 9p increase, especially tumors with 9p24.
1 band expression above the 60th percentile (but below the transcription threshold), median survival was 3 times
higher than chemotherapy.
Whole-exome analysis of 10 solid tumors showed that these 9p-associated ICT findings may be associated with squamous cell carcinoma, where there is a 9p24.
1 gain/immune response
.

These 9P24.
1 altered/immuno-oncology findings reveal genetically defined ICT sensitivity and drug resistance in HPV-negative squamous tumors, addressing a major medical need
for unmet precision therapy in these patients.
They identify possible ICT responses and resistance mechanisms, pointing to more likely effective treatment options
.

Lippman said the discovery could have profound implications for the science and practice of immuno-oncology, revealing the basis and model of recurrent chromosomal alterations as drivers of oncogenicity, as well as key determinants of immunophenotyping, and identifying a new ICT resistance mechanism that led to a new standard
for biomarker testing for health care diagnostics.

Co-author Webster K.
Cavenee, Ph.
D.
, said, "This work is progressively determining the genetic basis
of responsiveness to one of the most commonly used oncology therapies.
" Webster K.
Cavenee, Ph.
D.
, is a distinguished professor
emeritus at the University of California, San Diego School of Medicine.
"The ability to identify these diverse patient populations promises to have a significant clinical impact
on them.
"