My 2🪙 in closing:

Rigorous, large-scale WGS + analyses beyond coding SNVs/indels will be critical for

1. Fully understanding cancer susceptibility (esp. early-onset), and

2. Guiding evidence-based screening strategies for #earlydetection

15/15

And that's a wrap!

These studies are the outriders of a wave of germline projects coming down the pipe

Exciting time to be in the field. HUGE thanks to collaborators, funders, and patients who made this possible.

Want to learn more? Check out our lab:
labs.dana-farber.org/collins-geno...

14/15

Neither of these SVs signals were seen in the older never-smoker cohort

Yet both are similar to what we reported last year in pediatric cancers:
www.science.org/doi/10.1126/...

Could this imply a uniquely impt. role for rare germline SVs in early-onset, rearranged cancers?? 🤔

13/15

2. Another appearance from rare germline SVs!

Two main signals:

i. SVs disrupting lung-expressed, mutationally constrained genes

ii. Very large germline deletions in pts w/fusion+ tumors

12/15

Lots of findings in this one, too. I'll highlight two key discoveries:

1. Paired germline + somatic analyses reveals rare variants predispose to *specific molecular subtypes* of young LUAD

Germline IREB2 -> fusion-driven lung

Germline SMAD4 -> non-fusion-driven

🤔

11/15

Jackie + Pasi recruited & WGS'ed 251 early-onset lung cancer patients

Our team led computational analysis of these patients jointly with:

+ 196 lung patients with no smoking history (comparison pop.)

+ 1,883 cancer-free controls

10/15

Moving on to our second study:

Amazing translational collab. w/Jackie LoPiccolo, Pasi Janne + @sashagusevposts.bsky.social

to study a rare but v impt. patient population:

people Dx'ed with #lungcancer before 45 years old

www.medrxiv.org/content/10.6...

9/15

3. Gene discovery in cancer is not finished, even for highly studied cancers!

Noah found a rare 5' UTR variant in BRAT1 (BRCA/ATM-related gene) that confers 10x odds of breast cancer

CRISPR modeling by Wenbin Mei + JT Neal @broadinstitute.org confirmed UTR splice effect

8/15

In fact, large % of familial cancers had PRS effects as strong as rare pathogenic variants

Ex: 20% of familial breast cases had PRS as strong as path. CHEK2 variant 😮

🩺 insight: we clearly need to be thinking beyond rare variants even for patients with strong FHx

7/15

2. Despite enriching for presumably Mendelian inheritance, common polygenic risk #PRS was elevated in most cancer types and tracked with specific family histories 🤯

Turns out even familial cancers can (should?) be viewed as complex traits!

6/15

Lots of cool findings! Here are three of my favorites:

1. Rare SVs enriched in known cancer genes, like 6kb single-exon duplication in BRCA1 in familial breast cancer or 20kb deletion of MSH2 in familial colon cancer👀

5/15

We asked: why do these families have such strong burden of cancer?

Using whole-genome sequencing 🧬, Noah systematically tested several possibilities

Takeaway: we were able to explain ~11% of all cases by genetic factors *beyond* recognized pathogenic germline variants

4/15

Ok, on to the science!

Our first one was led by Noah Fields, who used the @AllofUsResearch cohort to ID 1,496 cancer patients with 3+ affected relatives but no recognized pathogenic variant.

www.medrxiv.org/content/10.6...

3/15

But first, a sentimental note:

These two are unusually special to me. They spanned the end of my postdoc w/@vanallenlab.bsky.social into the first year of my new lab @danafarber.bsky.social

with big 💪🧠 from some of our first lab members, Noah Fields + Carter Nakagawa

2/15

If you have a strong computational background and experience in functional genomics or cancer biology, we’d love to hear from you.

Apply here:
careers.dana-farber.org/job/637/post...

We're looking for someone to lead the integration of tens of thousands of germline genomes with tumor/normal transcriptomes and clinical data tackle a big question in cancer genetics: how does each patient's unique inherited genome influence tumor initiation and early evolution?

One in pediatric cancers (joint with Riaz Gillani's lab @DFCI / @bostonchildrens.bsky.social):
careers.dana-farber.org/job/12186/po...

Come work with us at the intersection of cutting-edge human genomics, cancer predisposition, and tumorigenesis!