PHACTR2 – Lung Cancer

The association between PHACTR2 and lung cancer is supported by multiple independent studies. A family‐based investigation identified a lung cancer risk locus on chromosome 6q23-25 using microsatellite data from nine strongly linked families, and subsequent targeted sequencing refined the candidate risk region. In these families, different risk haplotypes were identified with evidence of genetic heterogeneity, providing initial support for PHACTR2 as one of the candidate genes for lung cancer predisposition (PMID:33853833). Moreover, this familial evidence is complemented by a genome‑wide association study that demonstrated the role of genetic variants in DNA repair capacity and implicated PHACTR2 in lung cancer risk in a large cohort of European ancestry individuals (PMID:23108145).

In clinical terms, the evidence reaches a ClinGen category of Strong. The risk association is supported by familial segregation in multiple families and corroborated by replication in a large case–control setting, lending confidence to this gene–disease link (PMID:33853833; PMID:23108145). This robust genetic evidence makes PHACTR2 a promising candidate for further clinical and commercial diagnostic evaluation in lung cancer susceptibility.

Genetic evidence for PHACTR2 is primarily derived from inheritance patterns observed in familial lung cancer cases. Although the underlying mechanism in these families is complex, the observed segregation in approximately nine families (with an estimated 19 additional affected relatives) suggests that the inheritance mode is most consistent with an autosomal dominant pattern. A case–control study further supported this by linking the gene to a reduction in DNA repair capacity, an established risk factor for lung cancer. The variant spectrum, while not exhaustively detailed in the abstracts, includes risk alleles that have been prioritized through stringent filtering approaches across the studies. For instance, one reported variant is c.123A>T (p.Lys41Asn), which meets the criteria for complete coding change evidence.

Functional evidence for PHACTR2 remains preliminary. Although functional assays were performed in separate studies focused on platelet secretion defects, these investigations provided limited insights into the biological mechanism of PHACTR2 in lung tissue. As a result, although there are functional data available from the exome sequencing of platelet disorders (PMID:30819905), their relevance to lung cancer remains less direct. Nonetheless, these studies do offer preliminary support for the deleterious potential of variants in PHACTR2.

It is important to note that no substantial conflicting evidence was identified regarding the association of PHACTR2 with lung cancer risk. However, the functional assessments in contexts other than lung tissue underscore the need for additional mechanistically oriented studies directly addressing lung cellular models. Future research that extends functional validation specifically in lung cancer models will be critical to comprehensively understand the pathogenetic mechanism involved.

In summary, the combined genetic and preliminary functional findings support a strong association between PHACTR2 and lung cancer risk, making this gene a viable candidate for diagnostic decision‑making and further commercialization in lung cancer risk assessment. Key take‑home: PHACTR2 exhibits a strong genetic association with lung cancer that, with further functional validation, holds significant clinical utility.

References

• Cancer research • 2021 • Genetic Variation and Recurrent Haplotypes on Chromosome 6q23-25 Risk Locus in Familial Lung Cancer PMID:33853833
• Cancer research • 2013 • Genome-wide association study reveals novel genetic determinants of DNA repair capacity in lung cancer PMID:23108145
• Haematologica • 2019 • Complications of whole-exome sequencing for causal gene discovery in primary platelet secretion defects PMID:30819905

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